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51. Survival trade-offs in plant roots during colonization by closely related beneficial and pathogenic fungi

Author: Soledad Sacristán, Stéphane Hacquard, Michael R. Thon, Kei Hiruma, Ulrike Damm, Paul Schulze-Lefert, Jean-Félix Dallery, Barbara Kracher, Olivier Lespinet, Bernard Henrissat, Philipp C. Münch, Matthieu Hainaut, Richard J. O'Connell, Ruben Garrido-Oter, Alice C. McHardy, Emiel Ver Loren van Themaat, Eric Kemen, Aaron Weimann, Department of Plant Microbe Interactions, Max Planck Institute for Plant Breeding Research (MPIPZ), Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), German Center for Infection Research - Partner Site Bonn-Cologne (DZIF), Computational Biology of Infection Research [Braunschweig], Helmholtz Centre for Infection Research (HZI), Cluster of Excellence on Plant Sciences (CEPLAS), Department of Algorithmic Bioinformatics, Heinrich-Heine-Universität Düsseldorf [Düsseldorf], Centro Hispano-Luso de Investigaciones Agrarias, Departamento de Microbiología y Genétic, Universidad de Salamanca, Fungal Biodiversity Centre, BIOlogie et GEstion des Risques en agriculture (BIOGER), AgroParisTech-Institut National de la Recherche Agronomique (INRA), Architecture et fonction des macromolécules biologiques (AFMB), Institut National de la Recherche Agronomique (INRA)-Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), Department of Biological Sciences, King Abdulazziz University, Laboratoire de Recherche en Informatique (LRI), Université Paris-Sud - Paris 11 (UP11)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS), BioInformatique Moléculaire (BIM), Département Biologie des Génomes (DBG), Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Sud - Paris 11 (UP11)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Centro de Biotechnologia y Genomica de Plantas (UPM-INIA) and ETSI Agronomos, Universidad Politécnica de Madrid (UPM), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU)-Institut National de la Recherche Agronomique (INRA), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Max Planck Society, Agence Nationale de la Recherche [ANR-12-CHEX-0008-01], 'Cluster of Excellence on Plant Sciences' program - Deutsche Forschungsgemeinschaft, German Center for Infection Research, DZIF, Japan Society for the Promotion of Science, European Project: 323094,EC:FP7:ERC,ERC-2012-ADG_20120314,ROOTMICROBIOTA(2013), Institut National de la Recherche Agronomique (INRA)-AgroParisTech, Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Hacquard, Stéphane, Kracher, Barbara, and BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56, 38106 Braunschweig, Germany.
Subjects: roots, 0301 basic medicine, Colletotrichum tofieldiae, Arabidopsis thaliana, plant innate immunity, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Endophyte, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Symbiosis, Arabidopsis, Colletotrichum incanum, endophyte, genome, transcriptome, differential gene expression, symbiosis, Colonization, Gene, 2. Zero hunger, Genetics, Multidisciplinary, biology, Effector, Host (biology), fungi, food and beverages, General Chemistry, 15. Life on land, biology.organism_classification, 030104 developmental biology, Colletotrichum
Abstract: The sessile nature of plants forced them to evolve mechanisms to prioritize their responses to simultaneous stresses, including colonization by microbes or nutrient starvation. Here, we compare the genomes of a beneficial root endophyte, Colletotrichum tofieldiae and its pathogenic relative C. incanum, and examine the transcriptomes of both fungi and their plant host Arabidopsis during phosphate starvation. Although the two species diverged only 8.8 million years ago and have similar gene arsenals, we identify genomic signatures indicative of an evolutionary transition from pathogenic to beneficial lifestyles, including a narrowed repertoire of secreted effector proteins, expanded families of chitin-binding and secondary metabolism-related proteins, and limited activation of pathogenicity-related genes in planta. We show that beneficial responses are prioritized in C. tofieldiae-colonized roots under phosphate-deficient conditions, whereas defense responses are activated under phosphate-sufficient conditions. These immune responses are retained in phosphate-starved roots colonized by pathogenic C. incanum, illustrating the ability of plants to maximize survival in response to conflicting stresses.
Published: 2016

52. The current state of clinical mycology in Africa: a European Confederation of Medical Mycology and International Society for Human and Animal Mycology survey

Author: Cândida Driemeyer, Diego R Falci, Rita O Oladele, Felix Bongomin, Bright K Ocansey, Nelesh P Govender, Martin Hoenigl, Jean Pierre Gangneux, Cornelia Lass-Flörl, Oliver A Cornely, Alexandre Alanio, Jesus Guinea, C Orla Morrissey, Riina Rautemaa-Richardson, Arunaloke Chakrabarti, Jacques F Meis, Caroline Bruns, Jannik Stemler, Alessandro C Pasqualotto, Federal University of Health Sciences of Porto Alegre = Universidade Federal de Ciências da Saúde de Porto Alegre (UFCSPA), Hospital de Clínicas de Porto Alegre (HCPA), University of Lagos, Gulu University, Partenaires INRAE, University of Manchester [Manchester], University of the Witwatersrand [Johannesburg] (WITS), University of California [San Diego] (UC San Diego), University of California (UC), Medical University of Graz, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), CHU Pontchaillou [Rennes], Leopold Franzens Universität Innsbruck - University of Innsbruck, German Center for Infection Research - Partner Site Bonn-Cologne (DZIF), Hôpitaux Universitaire Saint-Louis, Lariboisière, Fernand-Widal, Mycologie moléculaire - Molecular Mycology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Consejo Superior de Investigaciones Científicas [Spain] (CSIC), Monash university, CSIR-Institute of Microbial Technology [Chandigarh] (IMTech), Council of Scientific and Industrial Research [India] (CSIR), and Radboud University Medical Center [Nijmegen]
Subjects: MESH: Fungi, Microbiology (medical), Antifungal Agents, MESH: Humans, [SDV]Life Sciences [q-bio], Fungi, Nigeria, Mycology, MESH: Antifungal Agents, Microbiology, Infectious Diseases, Mycoses, Virology, Animals, Humans, MESH: Animals, MESH: Nigeria
Abstract: International audience; Africa, although not unique in this context, is a favourable environment for fungal infections, given the high burden of risk factors. An online survey was developed asking about laboratory infrastructure and antifungal drug availability. We received 40 responses (24.4% response rate) of 164 researchers contacted from 21 African countries. Only five institutions (12.5%) of 40 located in Cameroon, Kenya, Nigeria, Sudan, and Uganda potentially fulfilled the minimum laboratory requirements for European Confederation of Medical Mycology Excellence Centre blue status. Difficulties included low access to susceptibility testing for both yeasts and moulds (available in only 30% of institutions) and Aspergillus spp antigen detection (available in only 47.5% of institutions as an in-house or outsourced test), as well as access to mould-active antifungal drugs such as amphotericin B deoxycholate (available for 52.5% of institutions), itraconazole (52.5%), voriconazole (35.0%), and posaconazole (5.0%). United and targeted efforts are crucial to face the growing challenges in clinical mycology.
Published: 2022

53. Associations of modern initial antiretroviral drug regimens with all-cause mortality in adults with HIV in Europe and North America: a cohort study

Author: Adam Trickey, Lei Zhang, M John Gill, Fabrice Bonnet, Greer Burkholder, Antonella Castagna, Matthias Cavassini, Piotr Cichon, Heidi Crane, Pere Domingo, Sophie Grabar, Jodie Guest, Niels Obel, Mina Psichogiou, Marta Rava, Peter Reiss, Christopher T Rentsch, Melchor Riera, Gundolf Schuettfort, Michael J Silverberg, Colette Smith, Melanie Stecher, Timothy R Sterling, Suzanne M Ingle, Caroline A Sabin, Jonathan A C Sterne, NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos), Medical Research Council (Reino Unido), NIHR - Senior Investigator (Reino Unido), Wellcome Trust, Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), Gilead Sciences (Spain), Ministère de la Santé (Francia), Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, Ministry of Health (Holanda), Ministry of Health Welfare and Sport (Países Bajos), German Center for Infection Research (Alemania), Instituto de Salud Carlos III, Red de Investigación Cooperativa en Investigación en Sida (España), Plan Nacional de I+D+i (España), Unión Europea. Fondo Europeo de Desarrollo Regional (FEDER/ERDF), Institut National de la Santé et de la Recherche Médicale (Francia), Bristol-Myers Squibb, Merck, Sharp & Dohme, Ministerio de Sanidad (España), Swiss National Science Foundation, CFAR Network of Integrated Clinical Systems (CNICS), United States Department of Veterans Affairs, NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), Global Health, AII - Infectious diseases, and APH - Aging & Later Life
Subjects: Adult, Male, Anti-HIV Agents, Epidemiology, Rilpivirine, Immunology, HIV Infections, Middle Aged, Cohort Studies, Europe, Infectious Diseases, Raltegravir Potassium, Virology, North America, Humans, Female, HIV Integrase Inhibitors, Darunavir
Abstract: Background: Over the past decade, antiretroviral therapy (ART) regimens that include integrase strand inhibitors (INSTIs) have become the most commonly used for people with HIV starting ART. Although trials and observational studies have compared virological failure on INSTI-based with other regimens, few data are available on mortality in people with HIV treated with INSTIs in routine care. Therefore, we compared all-cause mortality between different INSTI-based and non-INSTI-based regimens in adults with HIV starting ART from 2013 to 2018. Methods: This cohort study used data on people with HIV in Europe and North America from the Antiretroviral Therapy Cohort Collaboration (ART-CC) and UK Collaborative HIV Cohort (UK CHIC). We studied the most common third antiretroviral drugs (additional to nucleoside reverse transcriptase inhibitor) used from 2013 to 2018: rilpivirine, darunavir, raltegravir, elvitegravir, dolutegravir, efavirenz, and others. Adjusted hazard ratios (aHRs; adjusted for clinical and demographic characteristics, comorbid conditions, and other drugs in the regimen) for mortality were estimated using Cox models stratified by ART start year and cohort, with multiple imputation of missing data. Findings: 62 500 ART-naive people with HIV starting ART (12 422 [19·9%] women; median age 38 [IQR 30-48]) were included in the study. 1243 (2·0%) died during 188 952 person-years of follow-up (median 3·0 years [IQR 1·6-4·4]). There was little evidence that mortality rates differed between regimens with dolutegravir, elvitegravir, rilpivirine, darunavir, or efavirenz as the third drug. However, mortality was higher for raltegravir compared with dolutegravir (aHR 1·49, 95% CI 1·15-1·94), elvitegravir (1·86, 1·43-2·42), rilpivirine (1·99, 1·49-2·66), darunavir (1·62, 1·33-1·98), and efavirenz (2·12, 1·60-2·81) regimens. Results were similar for analyses making different assumptions about missing data and consistent across the time periods 2013-15 and 2016-18. Rates of virological suppression were higher for dolutegravir than other third drugs. Interpretation: This large study of patients starting ART since the introduction of INSTIs found little evidence that mortality rates differed between most first-line ART regimens; however, raltegravir-based regimens were associated with higher mortality. Although unmeasured confounding cannot be excluded as an explanation for our findings, virological benefits of first-line INSTIs-based ART might not translate to differences in mortality. We would like to thank our funders (US National Institute on Alcohol Abuse and Alcoholism and UK Medical Research Council) and all patients and the clinical teams associated with the participating cohort studies. The antiretroviral therapy cohort collaboration is funded by the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026209). UK Collaborative HIV Cohort is funded by the UK Medical Research Council (grant numbers G0000199, G0600337, G0900274, and M004236/1). JACS is funded by National Institute for Health Research Senior Investigator award (NF-SI-0611-10168). AT is funded by the Wellcome Trust under a Sir Henry Wellcome Postdoctoral Fellowship (222770/Z/21/Z). Funding for the individual antiretroviral therapy cohort collaboration cohorts included in this analysis was from Alberta Health, Gilead, National Agency for AIDS Research (France REcherche Nord&Sud Sida-hiv Hépatites), the French Ministry of Health, the Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, the Dutch Ministry of Health, Welfare and Sport through the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment, the TP-HIV by the German Centre for Infection Research (NCT02149004), Instituto de Salud Carlos III (through the Red Temática de Investigación Cooperativa en Sida [RD06/006, RD12/0017/0018, and RD16/0002/0006]) as part of the Plan Nacional I + D + i. Other funders of the individual cohorts participating data for this analysis are ISCIII-Subdirección General de Evaluación and the Fondo Europeo de Desarrollo Regional, ViiV Healthcare, Preben og Anna Simonsens Fond, ANRS-Maladies infectieuses émergentes, Institut National de la Santé et de la Recherche Médicale (INSERM), Bristol Myers Squibb, Janssen, Merck, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026230), the Spanish Ministry of Health, the Swiss National Science Foundation (grant 33CS30_134277), Centers for AIDS Research Network of Integrated Clinical Systems (1R24 AI067039-1, P30-AI-027757), the US Department of Veterans Affairs, the US National Institute on Alcohol Abuse and Alcoholism (U01-AA026224, U01-AA026209, U24-AA020794), the Veterans Health Administration Office of Research and Development, and the US National Institute of Allergy and Infectious Diseases (Tennessee Center for AIDS Research P30 AI110527). Sí
Published: 2022

54. Hepatitis B Virus Targets Lipid Transport Pathways to Infect Hepatocytes

Author: Knud Esser, Xiaoming Cheng, Jochen M. Wettengel, Julie Lucifora, Lea Hansen-Palmus, Katharina Austen, Armando A.R. Suarez, Sarah Heintz, Barbara Testoni, Firat Nebioglu, Minh Tu Pham, Shangqing Yang, Alma Zernecke, Dirk Wohlleber, Marc Ringelhan, Mathias Broxtermann, Daniel Hartmann, Norbert Hüser, Julia Mergner, Andreas Pichlmair, Wolfgang E. Thasler, Mathias Heikenwalder, Georg Gasteiger, Andreas Blutke, Axel Walch, Percy A. Knolle, Ralf Bartenschlager, Ulrike Protzer, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universität Heidelberg [Heidelberg] = Heidelberg University, University Hospital of Würzburg, Helmholtz Zentrum München = German Research Center for Environmental Health, German Center for Infection Research, Partnersite Munich (DZIF), Klinikums rechts der Isar, Ludwig-Maximilians University [Munich] (LMU), Technische Universität München = Technical University of Munich (TUM), and Helmholtz Zentrum München (HMGU)
Subjects: lipoprotein metabolism, liver targeting, Hepatology, trans-infection, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Gastroenterology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Transcytosis
Abstract: International audience; Background and aims: A single hepatitis B virus (HBV) particle is sufficient to establish chronic infection of the liver after intravenous injection, suggesting that the virus targets hepatocytes via a highly efficient transport pathway. We therefore investigated whether HBV utilizes a physiological liver-directed pathway that supports specific host-cell targeting in vivo.Methods: We established an ex vivo system of perfused human liver tissue that recapitulates the liver physiology to investigate HBV liver targeting. This model allowed us to investigate virus-host cell interactions in a cellular microenvironment mimicking the in vivo situation. Results: HBV was rapidly sequestered by liver macrophages within one hour after a virus pulse, but was detected in hepatocytes only after 16 hours. We found that HBV associates with lipoproteins. Electron- and immunofluorescence microscopy corroborated a co-localization in recycling endosomes within peripheral and liver macrophages. Importantly, recycling endosomes accumulated HBV and cholesterol, followed by transport of HBV back to the cell surface along the cholesterol efflux pathway. To reach hepatocytes as final target cells, HBV was able to utilise the hepatocyte-directed cholesterol transport machinery of macrophages.Conclusions: Our results propose that HBV by binding to liver targeted lipoproteins and utilizing the reverse cholesterol transport pathway of macrophages hijacks the physiological lipid transport pathways to the liver to most efficiently reach its target organ. This may involve trans-infection of liver macrophages and result in deposition of HBV in the perisinusoidal space from where HBV can bind its receptor on hepatocytes
Published: 2023

55. Hepatitis D virus interferes with hepatitis B virus RNA production via interferon-dependent and -independent mechanisms

Author: Julie Lucifora, Dulce Alfaiate, Caroline Pons, Maud Michelet, Ricardo Ramirez, Floriane Fusil, Fouzia Amirache, Axel Rossi, Anne-Flore Legrand, Emilie Charles, Serena Vegna, Rayan Farhat, Michel Rivoire, Guillaume Passot, Nicolas Gadot, Barbara Testoni, Charlotte Bach, Thomas F. Baumert, Anastasia Hyrina, Rudolf K. Beran, Fabien Zoulim, Andre Boonstra, Hildegard Büning, Eloi R. Verrier, François-Loïc Cosset, Simon P. Fletcher, Anna Salvetti, David Durantel, Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des Agents Infectieux [Lyon] (IAI), Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Gilead Sciences, Inc. [Foster City, CA, USA], Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Institute of Experimental Hematology [Hannover, Germany], Hannover Medical School [Hannover] (MHH), Application des ultrasons à la thérapie (LabTAU), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM), Service d'Oncologie Médicale [Centre hospitalier Lyon Sud - HCL], Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL)-Hospices Civils de Lyon (HCL), Centre pour l'innovation en cancérologie de Lyon (CICLY), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon, Centre Léon Bérard [Lyon], Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital de la Croix-Rousse [CHU - HCL], Gastroenterology and Hepatology, Erasmus University Medical Center [Rotterdam] (Erasmus MC), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), and Gastroenterology & Hepatology
Subjects: Hepatology, SDG 3 - Good Health and Well-being, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.MHEP.HEG]Life Sciences [q-bio]/Human health and pathology/Hépatology and Gastroenterology, Sciences du Vivant [q-bio]/Médecine humaine et pathologie
Abstract: Background & Aims: Chronic coinfection with HBV and HDV leads to the most aggressive form of chronic viral hepatitis. Herein, we aimed to elucidate the molecular mechanisms underlying the widely reported observation that HDV interferes with HBV in most coinfected patients. Methods: Patient liver tissues, primary human hepatocytes, HepaRG cells and human liver chimeric mice were used to analyze the effect of HDV on HBV using virological and RNA-sequencing analyses, as well as RNA synthesis, stability and association assays. Results: Transcriptomic analyses in cell culture and mouse models of coinfection enabled us to define an HDV-induced signature, mainly composed of interferon (IFN)-stimulated genes (ISGs). We also provide evidence that ISGs are upregulated in chronically HDV/HBV-coinfected patients but not in cells that only express HDV antigen (HDAg). Inhibition of the hepatocyte IFN response partially rescued the levels of HBV parameters. We observed less HBV RNA synthesis upon HDV infection or HDV protein expression. Additionally, HDV infection or expression of HDAg alone specifically accelerated the decay of HBV RNA, and HDAg was associated with HBV RNAs. On the contrary, HDAg expression did not affect other viruses such as HCV or SARS-CoV-2. Conclusions: Our data indicate that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms. Specifically, we uncover a new viral interference mechanism in which proteins of a satellite virus affect the RNA production of its helper virus. Exploiting these findings could pave the way to the development of new therapeutic strategies against HBV. Impact and implications: Although the molecular mechanisms remained unexplored, it has long been known that despite its dependency, HDV decreases HBV viremia in patients. Herein, using in vitro and in vivo models, we showed that HDV interferes with HBV through both IFN-dependent and IFN-independent mechanisms affecting HBV RNA metabolism, and we defined the HDV-induced modulation signature. The mechanisms we uncovered could pave the way for the development of new therapeutic strategies against HBV by mimicking and/or increasing the effect of HDAg on HBV RNA. Additionally, the HDV-induced modulation signature could potentially be correlated with responsiveness to IFN-α treatment, thereby helping to guide management of HBV/HDV-coinfected patients.
Published: 2023

56. BTG1 inactivation drives lymphomagenesis and promotes lymphoma dissemination through activation of BCAR1

Author: Lorric Delage, Mireille Lambert, Émilie Bardel, Cindy Kundlacz, Dimitri Chartoire, Axel Conchon, Anne-Laure Peugnet, Lucas Gorka, Patrick Auberger, Arnaud Jacquel, Carole Soussain, Olivier Destaing, Henri-Jacques Delecluse, Susanne Delecluse, Samir Merabet, Alexandra Traverse-Glehen, Gilles Salles, Emmanuel Bachy, Marc Billaud, Hervé Ghesquières, Laurent Genestier, Jean-Pierre Rouault, Pierre Sujobert, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon, Hospices Civils de Lyon (HCL), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Virologie UMR1161 (VIRO), École nationale vétérinaire - Alfort (ENVA)-Laboratoire de santé animale, sites de Maisons-Alfort et de Dozulé, Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Agence nationale de sécurité sanitaire de l'alimentation, de l'environnement et du travail (ANSES)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), C3M U1065, Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), Immunité et cancer (U932), Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Curie [Paris], Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), Unit F100 [Heidelberg, Allemagne], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Faculty of Biosciences [Heidelberg, Allemagne], Heidelberg University, Microbiology and infectious diseases, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), CNRS, UMR5242, Inst Genom Fonctionnelle Lyon,Ecole Normale Super, Weill Medical College of Cornell University [New York], Franche-Comté Électronique Mécanique, Thermique et Optique - Sciences et Technologies (UMR 6174) (FEMTO-ST), Université de Technologie de Belfort-Montbeliard (UTBM)-Ecole Nationale Supérieure de Mécanique et des Microtechniques (ENSMM)-Centre National de la Recherche Scientifique (CNRS)-Université de Franche-Comté (UFC), Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC), Génétique moléculaire, signalisation et cancer (GMSC), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), and Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS)
Subjects: [SDV]Life Sciences [q-bio], Immunology, Cell Biology, Hematology, Biochemistry
Abstract: Understanding the functional role of mutated genes in cancer is required to translate the findings of cancer genomics into therapeutic improvement. BTG1 is recurrently mutated in the MCD/C5 subtype of diffuse large B-cell lymphoma (DLBCL), which is associated with extranodal dissemination. Here, we provide evidence that Btg1 knock out accelerates the development of a lethal lymphoproliferative disease driven by Bcl2 overexpression. Furthermore, we show that the scaffolding protein BCAR1 is a BTG1 partner. Moreover, after BTG1 deletion or expression of BTG1 mutations observed in patients with DLBCL, the overactivation of the BCAR1-RAC1 pathway confers increased migration ability in vitro and in vivo. These modifications are targetable with the SRC inhibitor dasatinib, which opens novel therapeutic opportunities in BTG1 mutated DLBCL.
Published: 2022

57. HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

Author: Michel C. Nussenzweig, Elena Knops, Michael S. Seaman, Pamela J. Bjorkman, Eva Billerbeck, Joshua A. Horwitz, Hildegard Büning, Ariel Halper-Stromberg, Marine Malbec, Olivier Schwartz, Rolf Kaiser, Alexander Ploss, Charles M. Rice, Thomas Eisenreich, Alexander D. Gitlin, Hugo Mouquet, Florian Klein, Marcus Dorner, Anna Tretiakova, Sophia Gravemann, James M. Wilson, Laboratory of Molecular Immunology, Rockefeller University [New York], Réponse humorale aux pathogènes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Department of Pathology and Laboratory Medicine, University of Pennsylvania, Virus et Immunité - Virus and immunity (CNRS-UMR3569), Institute for Virology, University of Cologne, Laboratory of Virology and Infectious Disease, Rockefeller University [New York]-Center for the Study of Hepatitis C, Beth Israel Deaconess Medical Center, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), Department of Molecular Biology, Princeton University, Division of Biology and Howard Hughes Medical Institute, California Institute of Technology (CALTECH), Howard Hughes Medical Institute (HHMI), supported by grants from the Agence Nationale de Recherche sur le Sida, Sidaction, AREVA Foundation, Vaccine Research Institute, the Labex Integrative Biology of Emerging Infectious Diseases program, the Seventh Framework ProgrammeHIT Hidden HIV (Health-F3-2012-305762), and Institut Pasteur. This work was supported in part by the Bill and Melinda Gates Foundation with Comprehensive Antibody Vaccine Immune Monitoring Consortium Grant 1032144 (to M.S.S.) and Collaboration for AIDS Vaccine Discovery Grants 38660 (to P.J.B.) and 38619s (to M.C.N.). This work was also supported by the German Center for Infection Research (S.G. and H.B.), UL1 TR000043 Translational Science Award (Clinical and Translational Science Award) program, AI 100663-01 (to M.C.N.), Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and AI 100148-01 (to P.J.B. and M.C.N.). P.J.B. and M.C.N. are Howard Hughes Medical Institute Investigators., European Project: 305762,HEALTH,FP7-HEALTH-2012-INNOVATION-1,HIT HIDDEN HIV(2012), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Pennsylvania [Philadelphia], Virus et Immunité - Virus and immunity, The Rockefeller University, Institut Pasteur [Paris], Virus et Immunité, Institut Pasteur [Paris] - Centre National de la Recherche Scientifique (CNRS), Princeton University [Pinceton], California Institute of Technology, and F.K. was supported by the Stavros Niarchos Foundation. E.B., M.D., A.P., and C.M.R. were supported by the Starr Foundation. O.S. is supported by grants from the Agence Nationale de Recherche sur le Sida, Sidaction, AREVA Foundation, Vaccine Research Institute, the Labex Integrative Biology of Emerging Infectious Diseases program, the Seventh Framework Programme HIT Hidden HIV (Health-F3-2012-305762), and Institut Pasteur. This work was supported in part by the Bill and Melinda Gates Foundation with Comprehensive Antibody Vaccine Immune Monitoring Consortium Grant 1032144 (to M.S.S.) and Collaboration for AIDS Vaccine Discovery Grants 38660 (to P.J.B.) and 38619s (to M.C.N.). This work was also supported by the German Center for Infection Research (S.G. and H.B.), UL1 TR000043 Translational Science Award (Clinical and Translational Science Award) program, AI 100663-01 (to M.C.N.), Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery, and AI 100148-01 (to P.J.B. and M.C.N.). P.J.B. and M.C.N. are Howard Hughes Medical Institute Investigators.
Subjects: medicine.medical_treatment, [SDV]Life Sciences [q-bio], Human immunodeficiency virus (HIV), HIV Infections, Mice, Transgenic, Viremia, Real-Time Polymerase Chain Reaction, medicine.disease_cause, Virus, Mice, 03 medical and health sciences, 0302 clinical medicine, medicine, Animals, Humans, DNA Primers, 030304 developmental biology, 0303 health sciences, glycan, Multidisciplinary, biology, CD4bs, Sequence Analysis, DNA, Single injection, Immunotherapy, Biological Sciences, Dependovirus, Viral Load, medicine.disease, Antibodies, Neutralizing, Virology, Antiretroviral therapy, 3. Good health, Anti-Retroviral Agents, gp160, [SDV.IMM.IA] Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, DNA, Viral, Immunology, HIV-1, biology.protein, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Drug Therapy, Combination, Antibody, Viral load
Abstract: International audience; Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1-infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA. Moreover, lowering the initial viral load by coadministration of ART and immunotherapy enabled prolonged viremic control by a single bNAb after ART was withdrawn. Similarly, a single injection of adeno-associated virus directing expression of one bNAb produced durable viremic control after ART was terminated. We conclude that immunotherapy reduces plasma viral load and cell-associated HIV-1 DNA and that decreasing the initial viral load enables single bNAbs to control viremia in hu-mice.
Published: 2013

58. Cross-Talk Between the Intestinal Epithelium and Salmonella Typhimurium

Author: Sandrine Ménard, Sonia Lacroix-Lamandé, Katrin Ehrhardt, Jin Yan, Guntram A. Grassl, Agnès Wiedemann, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), The Second Xiangya Hospital of Central South University [Hunan, China], Central South University [Changsha], France Région Occitanie/FEDER, Fondation Allemande pour la recherche (SFB900/3 - 158989968, TP08), Centre allemand de recherche sur les infections (DZIF), and Wiedemann, Agnès
Subjects: Microbiology (medical), [SDV] Life Sciences [q-bio], host defense, [SDV]Life Sciences [q-bio], gastrointestinal tract, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, bacteria, invasion, Microbiology, survival, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: Salmonella entericaserovars are invasive gram-negative bacteria, causing a wide range of diseases from gastroenteritis to typhoid fever, representing a public health threat around the world.Salmonellagains access to the intestinal lumen after oral ingestion of contaminated food or water. The crucial initial step to establish infection is the interaction with the intestinal epithelium. Human-adapted serovars such asS.Typhi orS.Paratyphi disseminate to systemic organs and induce life-threatening disease known as typhoid fever, whereas broad-host serovars such asS.Typhimurium usually are limited to the intestine and responsible for gastroenteritis in humans. To overcome intestinal epithelial barrier,Salmonelladeveloped mechanisms to induce cellular invasion, intracellular replication and to face host defence mechanisms. Depending on the serovar and the respective host organism, disease symptoms differ and are linked to the ability of the bacteria to manipulate the epithelial barrier for its own profit and cross the intestinal epithelium.This review will focus onS.Typhimurium (STm). To better understand STm pathogenesis, it is crucial to characterize the crosstalk between STm and the intestinal epithelium and decipher the mechanisms and epithelial cell types involved. Thus, the purpose of this review is to summarize our current knowledge on the molecular dialogue between STm and the various cell types constituting the intestinal epithelium with a focus on the mechanisms developed by STm to cross the intestinal epithelium and access to subepithelial or systemic sites and survive host defense mechanisms.
Published: 2022

59. An early warning system for emerging SARS-CoV-2 variants

Author: Lorenzo Subissi, Anne von Gottberg, Lipi Thukral, Nathalie Worp, Bas B. Oude Munnink, Surabhi Rathore, Laith J. Abu-Raddad, Ximena Aguilera, Erik Alm, Brett N. Archer, Homa Attar Cohen, Amal Barakat, Wendy S. Barclay, Jinal N. Bhiman, Leon Caly, Meera Chand, Mark Chen, Ann Cullinane, Tulio de Oliveira, Christian Drosten, Julian Druce, Paul Effler, Ihab El Masry, Adama Faye, Simani Gaseitsiwe, Elodie Ghedin, Rebecca Grant, Bart L. Haagmans, Belinda L. Herring, Shilpa S. Iyer, Zyleen Kassamali, Manish Kakkar, Rebecca J. Kondor, Juliana A. Leite, Yee-Sin Leo, Gabriel M. Leung, Marco Marklewitz, Sikhulile Moyo, Jairo Mendez-Rico, Nada M. Melhem, Vincent Munster, Karen Nahapetyan, Djin-Ye Oh, Boris I. Pavlin, Thomas P. Peacock, Malik Peiris, Zhibin Peng, Leo L. M. Poon, Andrew Rambaut, Jilian Sacks, Yinzhong Shen, Marilda M. Siqueira, Sofonias K. Tessema, Erik M. Volz, Volker Thiel, Sylvie van der Werf, Sylvie Briand, Mark D. Perkins, Maria D. Van Kerkhove, Marion P. G. Koopmans, Anurag Agrawal, World Health Organisation (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), National Institute for Communicable Diseases [Johannesburg] (NICD), University of the Witwatersrand [Johannesburg] (WITS), Central Scientific Instruments Organisation (CSIR), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Weill Cornell Medicine [Qatar], Universidad del Desarollo [Santiago, Chile] (UDD), European Centre for Disease Prevention and Control [Stockholm, Sweden] (ECDC), WHO - Regional Office for the Eastern Mediterranean [Cairo, Egypt] (EMRO), Imperial College London, Victorian Infectious Diseases Reference Laboratory [Melbourne, Australia] (VIDRL), UK Health Security Agency [London] (UKHSA), World Organisation for Animal Health (WOAH), Stellenbosch University, Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Infection Research, Partnersite Munich (DZIF), The University of Western Australia (UWA), Food and Agriculture Organization of the United Nations [Rome, Italie] (FAO), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Botswana Harvard AIDS Institute Partnership, Harvard T.H. Chan School of Public Health, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), World Health Organization [Kinshasa, Democratic Republic of Congo] (WHO-DRC), United States Centers for Disease Control and Prevention, The University of Hong Kong (HKU), American University of Beirut [Beyrouth] (AUB), Robert Koch Institute [Berlin] (RKI), Chinese Center for Disease Control and Prevention, University of Edinburgh, Fudan University [Shanghai], Instituto Oswaldo Cruz / Oswaldo Cruz Institute [Rio de Janeiro] (IOC), Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centers for Disease Control and Prevention [Pretoria, South Africa] (CDC-South Africa), Centers for Disease Control and Prevention (CDC), University of Bern, Génétique Moléculaire des Virus à ARN - Molecular Genetics of RNA Viruses (GMV-ARN (UMR_3569 / U-Pasteur_2)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Centre National de Référence des virus des infections respiratoires (dont la grippe) - National Reference Center Virus Influenzae [Paris] (CNR - laboratoire coordonnateur), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Ashoka University, We acknowledge scientists, public health professionals and Ministries of Health across the world for early generation and sharing of data on SARS-CoV-2 variants., and Virology
Subjects: 630 Agriculture, SARS-CoV-2, [SDV]Life Sciences [q-bio], COVID-19, Humans, General Medicine, General Biochemistry, Genetics and Molecular Biology
Abstract: International audience
Published: 2022

60. Rifapentine access in Europe:growing concerns over key tuberculosis treatment component

Author: Lorenzo Guglielmetti, Gunar Günther, Claude Leu, Daniela Cirillo, Raquel Duarte, Alberto L. Garcia-Basteiro, Delia Goletti, Mateja Jankovic, Liga Kuksa, Florian P. Maurer, Frédéric Méchaï, Simon Tiberi, Frank van Leth, Nicolas Veziris, Christoph Lange, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Avicenne [AP-HP], Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux [CHU Pitié-Salpêtrière] (CNR-MyRMA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University of Bern, University of Namibia (UNAM), IRCCS San Raffaele Scientific Institute [Milan, Italie], Universidade do Porto = University of Porto, Directorate-General of Health [Lisbonne], Centro de Investigação em Saúde de Manhiça [Maputo, Mozambique] (CISM), Universitat de Barcelona (UB), National Institute for Infectious Diseases 'Lazzaro Spallanzani', Zagreb School of Medicine [Zagreb, Croatia] (Dubrava University Hospital), University of Zagreb, Riga East University Hospital, Riga Stradins University (RSU), Forschungszentrum Borstel - Research Center Borstel, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Infection, Anti-microbiens, Modélisation, Evolution (IAME (UMR_S_1137 / U1137)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPC)-Université Sorbonne Paris Nord, Queen Mary University of London (QMUL), Royal Free Hospital [London, UK], Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Amsterdam Public Health Research Institute [The Netherlands], CHU Saint-Antoine [AP-HP], Universität zu Lübeck = University of Lübeck [Lübeck], Baylor College of Medicine (BCM), Baylor University, Study Group on Mycobacteria of the European Society of Microbiology and Infectious Diseases (ESGMYC), European Society of Mycobacteriology (ESM), European Respiratory Society (ERS) and, Tuberculosis Network European Trials group (TBnet), Health Economics and Health Technology Assessment, APH - Global Health, and APH - Methodology
Subjects: Pulmonary and Respiratory Medicine, Antitubercular Agents/therapeutic use, Antitubercular Agents, Tuberculosis / epidemiology, [SDV.MHEP.PSR]Life Sciences [q-bio]/Human health and pathology/Pulmonology and respiratory tract, Drug Therapy, SDG 3 - Good Health and Well-being, Antibiotics, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Antibiotics, Antitubercular* / therapeutic use, Tuberculosis, Humans, Rifampin / analogs & derivatives, 610 Medicine & health, Antibiotics, Antitubercular, Antitubercular Agents / therapeutic use, Tuberculosis/drug therapy, Tuberculosis / drug therapy, Rifampin/analogs & derivatives, Antitubercular/therapeutic use, rifapentine, tuberculosis, Europe, Combination, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Drug Therapy, Combination, Rifampin, Rifampin / therapeutic use, Antibiotics, Antitubercular/therapeutic use
Abstract: International audience; Rifapentine, a synthetic derivate of rifampicin which was developed in 1965, has interesting pharmacological properties, including a long terminal half-life (13 h, compared to 2-3 h for rifampicin) and promising bactericidal activity against Mycobacterium tuberculosis. Despite being approved in 1998 by the US Food and Drug Administration (FDA) for the treatment of pulmonary tuberculosis, its global use has been limited by unavailability. In the past decade, new evidence has emerged to define rifapentine as a key component for treatment of active disease and latent infection with M. tuberculosis (LTBI).
Published: 2022

61. Hypoxia inducible factors regulate hepatitis B virus replication by activating the basal core promoter

Author: Valentina D'Arienzo, David R. Mole, Luis Nobre, Helene Borrmann, Ulrike Protzer, James M. Harris, Ester M. Hammond, Thomas F. Baumert, Laurent Mailly, Jochen M. Wettengel, Peter Balfe, Rosalba Minisini, Mathias Heikenwalder, Jane A. McKeating, Tobias Riedl, Peter Jianrui Liu, Peter A C Wing, Nicholas R. Frampton, Xiaodong Zhuang, Mario Pirisi, Michael P. Weekes, Thomas Michler, Andrea Magri, univOAK, Archive ouverte, University of Oxford, German Center for Infection Research, Partnersite Munich (DZIF), Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), University of Birmingham [Birmingham], Institut de Recherche sur les Maladies Virales et Hépatiques (IVH), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), and University of Cambridge [UK] (CAM)
Subjects: Transcriptional Activation, 0301 basic medicine, Hepatitis B virus, Sciences du Vivant [q-bio]/Médecine humaine et pathologie, Hepadnaviridae, Virus Replication, medicine.disease_cause, Virus, Hypoxia-Inducible Factor-Proline Dioxygenases, 03 medical and health sciences, Hepatitis B, Chronic, 0302 clinical medicine, Kruppel-Like Factor 6, medicine, Animals, HIF, Humans, Anaerobiosis, Hypoxia-Responsive Elements, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Host Microbial Interactions, Hepatology, biology, hypoxia, Liver cell, biology.organism_classification, Hepatitis B, ddc, Cell biology, Oxygen tension, Oxygen, 030104 developmental biology, Cellular Microenvironment, Liver, Viral replication, Hypoxia-inducible factors, 030211 gastroenterology & hepatology, Hypoxia-Inducible Factor 1, transcription, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Signal Transduction, Research Article
Abstract: Background & Aims Hypoxia inducible factors (HIFs) are a hallmark of inflammation and are key regulators of hepatic immunity and metabolism, yet their role in HBV replication is poorly defined. HBV replicates in hepatocytes within the liver, a naturally hypoxic organ, however most studies of viral replication are performed under conditions of atmospheric oxygen, where HIFs are inactive. We therefore investigated the role of HIFs in regulating HBV replication. Methods Using cell culture, animal models, human tissue and pharmacological agents inhibiting the HIF-prolyl hydroxylases, we investigated the impact of hypoxia on the HBV life cycle. Results Culturing liver cell-based model systems under low oxygen uncovered a new role for HIFs in binding HBV DNA and activating the basal core promoter, leading to increased pre-genomic RNA and de novo HBV particle secretion. The presence of hypoxia responsive elements among all primate members of the hepadnaviridae highlights an evolutionary conserved role for HIFs in regulating this virus family. Conclusions Identifying a role for this conserved oxygen sensor in regulating HBV transcription suggests that this virus has evolved to exploit the HIF signaling pathway to persist in the low oxygen environment of the liver. Our studies show the importance of considering oxygen availability when studying HBV-host interactions and provide innovative routes to better understand and target chronic HBV infection. Lay summary Viral replication in host cells is defined by the cellular microenvironment and one key factor is local oxygen tension. Hepatitis B virus (HBV) replicates in the liver, a naturally hypoxic organ. Hypoxia inducible factors (HIFs) are the major sensors of low oxygen; herein, we identify a new role for these factors in regulating HBV replication, revealing new therapeutic targets., Graphical abstract, Highlights • Primate hepadnaviridae encode conserved hypoxia response elements. • Hypoxia inducible factors bind HBV DNA and activate the basal core promoter. • Pharmacological stabilization of hypoxia inducible factors and low oxygen increases HBV transcription and particle genesis. • Knockdown studies show a role for both HIF-1α and HIF-2α in regulating HBV transcription.
Published: 2021

62. CXCR3 Expression Pattern on CD4+ T Cells and IP-10 Levels with Regard to the HIV-1 Reservoir in the Gut-Associated Lymphatic Tissue

Author: Max Augustin, Carola Horn, Meryem Seda Ercanoglu, Ute Sandaradura de Silva, Vincent Bondet, Isabelle Suarez, Seung-Hun Chon, Dirk Nierhoff, Elena Knops, Eva Heger, Carlo Vivaldi, Hartmut Schäfer, Mark Oette, Gerd Fätkenheuer, Florian Klein, Darragh Duffy, Michaela Müller-Trutwin, Clara Lehmann, University of Cologne, Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), HIV, Inflammation et persistance - HIV, Inflammation and Persistence, and This research was funded by the German Center for Infection Research (grant nos 80185MDCAH, 8018804915, TI 07.001_IS_00 and TI 07.001_IS_01) and the French Agency for Research on AIDS and Viral Hepatitis (ANRS): maladies infectieuses émergentes and Institut Pasteur (grant no. 17066). For the remaining authors none are declared.
Subjects: Microbiology (medical), CXCR3, General Immunology and Microbiology, cART, IP-10, HIV reservoir, immune activation, Infectious Diseases, memory CD4+ T cell subsets, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, GALT, Immunology and Allergy, Molecular Biology
Abstract: (1) Background: The gut-associated lymphatic tissue (GALT) represents the largest lymphoid organ, and is considered to be the largest HIV reservoir. The exact size of the GALT reservoir remains unclear. Several markers, such as the chemokine receptor CXCR3 and its pro-inflammatory ligand IP-10, have been proposed to define the size of HIV reservoirs in the peripheral blood (PB). However, little is known about the role of CXCR3 and IP-10 within the GALT. (2) Methods: We compared the CXCR3 expression, IP-10 levels, and cell-associated HIV DNA of distinct memory CD4+ T cell subsets from the terminal ileum (TI), PB and rectum (RE) of 18 HIV+ patients with antiretroviral therapy (ART), 6 HIV+ treatment-naive patients and 16 healthy controls. (3) Results: While the relative distributions of CD4+ T cell subsets were similar in PB, TI and RE, HIV DNA and CXCR3 expression were markedly increased and IP-10 levels were decreased in TI when compared to PB. No significant correlation was found between the CXCR3 expression and memory CD4+ T cell subsets, IP-10 levels and the HIV DNA amounts measured in PB, TI or RE. (4) Conclusions: During a chronic HIV-1 infection, neither CXCR3 nor IP-10 are indicative of the size of the viral reservoir in the GALT (TI and RE).
Published: 2022

63. Critical Assessment of Metagenome Interpretation: the second round of challenges

Author: Fernando Meyer, Adrian Fritz, Zhi-Luo Deng, David Koslicki, Till Robin Lesker, Alexey Gurevich, Gary Robertson, Mohammed Alser, Dmitry Antipov, Francesco Beghini, Denis Bertrand, Jaqueline J. Brito, C. Titus Brown, Jan Buchmann, Aydin Buluç, Bo Chen, Rayan Chikhi, Philip T. L. C. Clausen, Alexandru Cristian, Piotr Wojciech Dabrowski, Aaron E. Darling, Rob Egan, Eleazar Eskin, Evangelos Georganas, Eugene Goltsman, Melissa A. Gray, Lars Hestbjerg Hansen, Steven Hofmeyr, Pingqin Huang, Luiz Irber, Huijue Jia, Tue Sparholt Jørgensen, Silas D. Kieser, Terje Klemetsen, Axel Kola, Mikhail Kolmogorov, Anton Korobeynikov, Jason Kwan, Nathan LaPierre, Claire Lemaitre, Chenhao Li, Antoine Limasset, Fabio Malcher-Miranda, Serghei Mangul, Vanessa R. Marcelino, Camille Marchet, Pierre Marijon, Dmitry Meleshko, Daniel R. Mende, Alessio Milanese, Niranjan Nagarajan, Jakob Nissen, Sergey Nurk, Leonid Oliker, Lucas Paoli, Pierre Peterlongo, Vitor C. Piro, Jacob S. Porter, Simon Rasmussen, Evan R. Rees, Knut Reinert, Bernhard Renard, Espen Mikal Robertsen, Gail L. Rosen, Hans-Joachim Ruscheweyh, Varuni Sarwal, Nicola Segata, Enrico Seiler, Lizhen Shi, Fengzhu Sun, Shinichi Sunagawa, Søren Johannes Sørensen, Ashleigh Thomas, Chengxuan Tong, Mirko Trajkovski, Julien Tremblay, Gherman Uritskiy, Riccardo Vicedomini, Zhengyang Wang, Ziye Wang, Zhong Wang, Andrew Warren, Nils Peder Willassen, Katherine Yelick, Ronghui You, Georg Zeller, Zhengqiao Zhao, Shanfeng Zhu, Jie Zhu, Ruben Garrido-Oter, Petra Gastmeier, Stephane Hacquard, Susanne Häußler, Ariane Khaledi, Friederike Maechler, Fantin Mesny, Simona Radutoiu, Paul Schulze-Lefert, Nathiana Smit, Till Strowig, Andreas Bremges, Alexander Sczyrba, Alice Carolyn McHardy, Braunschweig Integrated Centre of Systems Biology [Braunschweig] (BRICS), Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig]-Helmholtz Centre for Infection Research (HZI), Pennsylvania State University (Penn State), Penn State System, German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Saint Petersburg State University (SPBU), Department of Information Technology and Electrical Engineering [Zürich] (D-ITET), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Center for Algorithmic Biotechnology [Saint Petersburg], Institute of Translational Biomedicine [Saint-Petersburg], Saint Petersburg University (SPBU)-Saint Petersburg University (SPBU), Centre for Integrative Biology (CIBIO), University of Trento (CIBIO), University of Trento [Trento], Genome Institute of Singapore (GIS), University of Southern California (USC), University of California [Davis] (UC Davis), University of California (UC), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Lawrence Berkeley National Laboratory [Berkeley] (LBNL), Institut Pasteur [Paris] (IP), National Food Institute [Lyngby] (Forside), Drexel University, Robert Koch Institute [Berlin] (RKI), University of Technology Sydney (UTS), DOE Joint Genome Institute [Walnut Creek], University of California [Los Angeles] (UCLA), Intel Corporation [Santa Clara], Intel Corporation [USA], Department of Plant and Environmental Sciences [Frederiksberg], University of Copenhagen = Københavns Universitet (UCPH), Fudan University [Shanghai], Beijing Genomics Institute [Shenzhen] (BGI), Novo Nordisk Foundation Center for Biosustainability, Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Université de Genève = University of Geneva (UNIGE), The Arctic University of Norway [Tromsø, Norway] (UiT), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], University of California [San Diego] (UC San Diego), University of Wisconsin-Madison, Scalable, Optimized and Parallel Algorithms for Genomics (GenScale), Inria Rennes – Bretagne Atlantique, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-GESTION DES DONNÉES ET DE LA CONNAISSANCE (IRISA-D7), Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-Institut National de Recherche en Informatique et en Automatique (Inria)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Université de Rennes (UR)-Institut National des Sciences Appliquées - Rennes (INSA Rennes), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT)-Institut de Recherche en Informatique et Systèmes Aléatoires (IRISA), Institut National des Sciences Appliquées (INSA)-Institut National des Sciences Appliquées (INSA)-Université de Bretagne Sud (UBS)-École normale supérieure - Rennes (ENS Rennes)-CentraleSupélec-Centre National de la Recherche Scientifique (CNRS)-IMT Atlantique (IMT Atlantique), Institut Mines-Télécom [Paris] (IMT)-Institut Mines-Télécom [Paris] (IMT), Centre National de la Recherche Scientifique (CNRS), Centre de Recherche en Informatique, Signal et Automatique de Lille - UMR 9189 (CRIStAL), Centrale Lille-Université de Lille-Centre National de la Recherche Scientifique (CNRS), Hasso Plattner Institute [Potsdam, Germany], The University of Sydney, Inria Lille - Nord Europe, Institut National de Recherche en Informatique et en Automatique (Inria), Amsterdam UMC - Amsterdam University Medical Center, Structural and Computational Biology, European Molecular Biology Laboratory [Heidelberg] (EMBL), DTU Electrical Engineering [Lyngby], National Institutes of Health [Bethesda] (NIH), Department of Biology [ETH Zürich] (D-BIOL), University of Virginia, IT University of Copenhagen (ITU), Freie Universität Berlin, University of Potsdam = Universität Potsdam, Florida International University [Miami] (FIU), National Research Council of Canada (NRC), Phase Genomics [Seattle], Max Planck Institute for Plant Breeding Research (MPIPZ), Helmholtz Centre for Infection Research (HZI), Aarhus University [Aarhus], Center for Biotechnology (CeBiTec), Universität Bielefeld = Bielefeld University, Open access funding provided by Helmholtz-Zentrum für Infektionsforschung GmbH (HZI), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), ANR-19-P3IA-0001,PRAIRIE,PaRis Artificial Intelligence Research InstitutE(2019), and Medical Microbiology and Infection Prevention
Subjects: 06 Biological Sciences, 10 Technology, 11 Medical and Health Sciences, Reproducibility of Results, Cell Biology, DNA, Sequence Analysis, DNA, Biochemistry, Archaea, Software, Metagenome, Metagenomics, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Molecular Biology, Sequence Analysis, Biotechnology, Developmental Biology
Abstract: Evaluating metagenomic software is key for optimizing metagenome interpretation and focus of the Initiative for the Critical Assessment of Metagenome Interpretation (CAMI). The CAMI II challenge engaged the community to assess methods on realistic and complex datasets with long- and short-read sequences, created computationally from around 1,700 new and known genomes, as well as 600 new plasmids and viruses. Here we analyze 5,002 results by 76 program versions. Substantial improvements were seen in assembly, some due to long-read data. Related strains still were challenging for assembly and genome recovery through binning, as was assembly quality for the latter. Profilers markedly matured, with taxon profilers and binners excelling at higher bacterial ranks, but underperforming for viruses and Archaea. Clinical pathogen detection results revealed a need to improve reproducibility. Runtime and memory usage analyses identified efficient programs, including top performers with other metrics. The results identify challenges and guide researchers in selecting methods for analyses., Nature Methods, 19 (8), ISSN:1548-7105, ISSN:1548-7091
Published: 2022

64. Intrinsic Differential Scanning Fluorimetry for Fast and Easy Identification of Adeno-Associated Virus Serotypes

Author: Martin Biel, Stylianos Michalakis, Gerhard Winter, Tim Menzen, Axel Rossi, Ruth Rieser, Eduard Ayuso, Hildegard Büning, Magalie Penaud-Budloo, Mohammed Bouzelha, Department of Pharmacy [Munich, Germany] (Center for Drug Research), Ludwig-Maximilians-Universität München (LMU), Laboratoire de Thérapie Génique Translationnelle des Maladies Génétiques (Inserm UMR 1089), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Institute of Experimental Hematology [Hannover, Germany], Hannover Medical School [Hannover] (MHH), Coriolis Pharma [Martinsried, Germany], Center for Integrated Protein Science (CIPSM), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-Ludwig Maximilian University of Munich [Germany] (LMU München), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Department of Ophthalmology [Munich, Germany], This work was supported by the Deutsche Forschungsgemeinschaft (EXC114)., JAULIN, Nicolas, and Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Ludwig-Maximilians-Universität München (LMU)-Helmholtz Zentrum München = German Research Center for Environmental Health
Subjects: Protein Denaturation, Time Factors, [SDV]Life Sciences [q-bio], viruses, Genetic enhancement, Pharmaceutical Science, adeno-associated virus, medicine.disease_cause, melting temperature, 030226 pharmacology & pharmacy, Virus, Workflow, law.invention, high-throughput technology, 03 medical and health sciences, Transduction (genetics), capsid thermal stability, 0302 clinical medicine, law, Gene expression, medicine, Transition Temperature, High throughput technology, Fluorometry, Adeno-associated virus, Fluorescent Dyes, Protein Unfolding, 030304 developmental biology, 0303 health sciences, Protein Stability, Chemistry, intrinsic fluorescence, Dependovirus, High-Throughput Screening Assays, Cell biology, [SDV] Life Sciences [q-bio], AAV vector, Capsid, Recombinant DNA, Capsid Proteins, Hydrophobic and Hydrophilic Interactions
Abstract: International audience; Recombinant adeno-associated virus (AAV) vectors have evolved as the most promising technology for gene therapy due to their good safety profile, high transduction efficacy, and long-term gene expression in non-dividing cells. AAV-based gene therapy holds great promise for treating genetic disorders like inherited blindness, muscular atrophy, or bleeding disorders. Multiple naturally occurring and engineered AAV serotypes exist, which differ in capsid sequence and as a consequence in cellular tropism. Individual AAV capsids differ in thermal stability and have a characteristic melting temperature (Tm), which enables serotype-specific discrimination of AAV vectors. Differential scanning fluorimetry (DSF) combined with a dye-like SYPRO Orange (SO-DSF), which binds to hydrophobic regions of unfolded proteins, has been successfully applied to determine the Tm of AAV capsids. Here, we present DSF measurement of intrinsic fluorescence signal (iDSF) as a simple alternative method for determination of AAV capsid Tm. The study demonstrates that DSF measurement of intrinsic fluorescence signal is a simple, accurate, and rapid alternative to SO-DSF, which enables characterization of AAV capsid stability with excellent precision and without the need of SO or any other dye.
Published: 2020

65. Zika Virus Circulation in Mali

Author: Abdoulaye Dabo, Simon Cauchemez, Souleymane Sacko, Bourema Kouriba, Abdoulaye Djimde, Jan Felix Drexler, Anna-Bella Failloux, Pierre Gallian, Abdoul Karim Sangaré, Ogobara K. Doumbo, Issa Diarra, Drissa Coulibaly, Amatigue Zeguime, Xavier de Lamballerie, Nathanaël Hozé, Elif Nurtop, Bakary Fofana, Boris Pastorino, Stéphane Priet, Issaka Sagara, Mahamadou Ali Thera, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Malaria Research and Training Center [Bamako, Mali], Université de Bamako, Ministère de la Santé et des Affaires Sociales du Mali [Bamako, Mali], Université des Sciences, des Techniques et des Technologies de Bamako (USTTB), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, German Center for Infection Research, Partnersite Munich (DZIF), Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors, Institut Pasteur [Paris] (IP), Modélisation mathématique des maladies infectieuses - Mathematical modelling of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), BUISINE, Soline, Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université des sciences, des techniques et des technologies de Bamako (USTTB), Institut Pasteur [Paris], and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)
Subjects: Microbiology (medical), Male, Epidemiology, 030231 tropical medicine, Population, vector-borne infections, lcsh:Medicine, Blood Donors, Zika Virus Circulation in Mali, Mali, Asymptomatic, Arbovirus, lcsh:Infectious and parasitic diseases, Zika virus, Serology, 03 medical and health sciences, 0302 clinical medicine, Seroepidemiologic Studies, medicine, Seroprevalence, Humans, lcsh:RC109-216, viruses, 030212 general & internal medicine, education, mosquitoes, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, education.field_of_study, biology, seroprevalence, Transmission (medicine), Zika Virus Infection, Research, lcsh:R, Outbreak, Zika Virus, biology.organism_classification, medicine.disease, Virology, 3. Good health, Infectious Diseases, arbovirus, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Female, medicine.symptom
Abstract: International audience; The circulation of Zika virus (ZIKV) in Mali has not been clearly characterized. Therefore, we conducted a serologic survey of 793 asymptomatic volunteers >15 years of age (2016), and 637 blood donors (2013) to assess the seroprevalence of ZIKV infection in 2 ecoclimatic regions of Mali, tropical savannah and warm semiarid region, using ELISA and seroneutralization assays. The overall seroprevalence was ≈12% and increased with age, with no statistical difference between male and female participants. In the warm semiarid study sites we detected immunological markers of an outbreak that occurred in the late 1990s in 18% (95% CI 13%-23%) of participants. In tropical savannah sites, we estimated a low rate of endemic transmission, with 2.5% (95% CI 2.0%-3.1%) of population infected by ZIKV annually. These data demonstrate the circulation of ZIKV in Mali and provide evidence of a previously unidentified outbreak that occurred in the late 1990s.
Published: 2020

66. Transcontinental spread and evolution of Mycobacterium tuberculosis W148 European/Russian clade toward extensively drug resistant tuberculosis

Author: Matthias Merker, Jean-Philippe Rasigade, Maxime Barbier, Helen Cox, Silke Feuerriegel, Thomas A. Kohl, Egor Shitikov, Kadri Klaos, Cyril Gaudin, Rudy Antoine, Roland Diel, Sonia Borrell, Sebastien Gagneux, Vladyslav Nikolayevskyy, Sönke Andres, Valeriu Crudu, Philip Supply, Stefan Niemann, Thierry Wirth, Forschungszentrum Borstel - Research Center Borstel, German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Institut de Systématique, Evolution, Biodiversité (ISYEB ), Muséum national d'Histoire naturelle (MNHN)-École Pratique des Hautes Études (EPHE), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université des Antilles (UA), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Cape Town, Clinical Centre of Physical-Chemical Medicine [Moscow], Genoscreen [Lille], Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), CHU Lille, University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, German Center for Lung Research, University of Basel (Unibas), Swiss Tropical and Public Health Institute [Basel], Imperial College London, Supply, Philip, Muséum national d'Histoire naturelle (MNHN)-École pratique des hautes études (EPHE), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Multidisciplinary, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Extensively Drug-Resistant Tuberculosis, Antitubercular Agents, General Physics and Astronomy, Bayes Theorem, Microbial Sensitivity Tests, Mycobacterium tuberculosis, General Chemistry, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, General Biochemistry, Genetics and Molecular Biology, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Drug Resistance, Multiple, Bacterial, Tuberculosis, Multidrug-Resistant, [SDV.GEN.GPO] Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Humans, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology
Abstract: International audience; Abstract Transmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB) is the largest single contributor to human mortality due to antimicrobial resistance. A few major clades of the Mycobacterium tuberculosis complex belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia, show outstanding transnational distributions. Here, we determined factors underlying the emergence and epidemic spread of the W148 clade by genome sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries. We dated a common ancestor around 1963 and identified two successive epidemic expansions in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet Era. These population expansions favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR evolving toward additional resistances to fluoroquinolones and second-line injectable drugs within 20 years on average. Timescaled haplotypic density analysis revealed that widespread acquisition of compensatory mutations was associated with transmission success of XDR strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. The outstanding genetic arsenal of this geographically widespread M/XDR strain clade represents a “perfect storm” that jeopardizes the successful introduction of new anti-M/XDR-TB antibiotic regimens.Transmission-driven multi-/extensively drug resistant (M/XDR) tuberculosis (TB) is the largest single contributor to human mortality due to antimicrobial resistance. A few major clades of the Mycobacterium tuberculosis complex belonging to lineage 2, responsible for high prevalence of MDR-TB in Eurasia, show outstanding transnational distributions. Here, we determined factors underlying the emergence and epidemic spread of the W148 clade by genome sequencing and Bayesian demogenetic analyses of 720 isolates from 23 countries. We dated a common ancestor around 1963 and identified two successive epidemic expansions in the late 1980s and late 1990s, coinciding with major socio-economic changes in the post-Soviet Era. These population expansions favored accumulation of resistance mutations to up to 11 anti-TB drugs, with MDR evolving toward additional resistances to fluoroquinolones and second-line injectable drugs within 20 years on average. Timescaled haplotypic density analysis revealed that widespread acquisition of compensatory mutations was associated with transmission success of XDR strains. Virtually all W148 strains harbored a hypervirulence-associated ppe38 gene locus, and incipient recurrent emergence of prpR mutation-mediated drug tolerance was detected. The outstanding genetic arsenal of this geographically widespread M/XDR strain clade represents a “perfect storm” that jeopardizes the successful introduction of new anti-M/XDR-TB antibiotic regimens.
Published: 2022
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67. Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

Author: Antimycobacterial Susceptibility Testing Group, Georghiou, Sophia B., Rodwell, Timothy C., Korobitsyn, Alexei, Abbadi, Said H., Ajbani, Kanchan, Alffenaar, Jan-Willem, Alland, David, Alvarez, Nataly, Andres, Sönke, Ardizzoni, Elisa, Aubry, Alexandra, Baldan, Rossella, Ballif, Marie, Barilar, Ivan, Böttger, Erik C., Chakravorty, Soumitesh, Claxton, Pauline M., Cirillo, Daniela M., Comas, Iñaki, Coulter, Chris, Denkinger, Claudia M., Derendinger, Brigitta, Desmond, Edward P., Steenwinkel, Jurriaan E. M. de, Dheda, Keertan, Diacon, Andreas H., Dolinger, David L., Dooley, Kelly E., Egger, Matthias, Ehsani, Soudeh, Farhat, Maha R., Fattorini, Lanfranco, Finci, Iris, Fournier Le Ray, Laure, Furió, Victoria, Groenheit, Ramona, Gumbo, Tawanda, Heysell, Scott K., Hillemann, Doris, Hoffmann, Harald, Hsueh, Po-Ren, Hu, Yi, Huang, Hairong, Hussain, Alamdar, Ismail, Farzana, Izumi, Kiyohiko, Jagielski, Tomasz, Johnson, John L., Kambli, Priti, Kaniga, Koné, Karunaratne, G. H. R. Eranga, Sharma, Meenu Kaushal, Keller, Peter M., Kelly, Ellis C., Kholina, Margarita, Kohli, Mikashmi, Kranzer, Katharina, Laurenson, Ian F., Limberis, Jason, Lin, S-Y. Grace, Liu, Yongge, López-Gavín, Alexandre, Lyander, Anna, Machado, Diana, Martínez, Elena, Masood, Faisal, Mitarai, Satoshi, Mvelase, Nomonde R., Niemann, Stefan, Nikolayevskyy, Vladyslav, Maurer, Florian P., Merker, Matthias, Miotto, Paolo, Omar, Shaheed V., Otto-Knapp, Ralf, Palaci, Moisés, Palacios Gutiérrez, Juan José, Peacock, Sharon J., Peloquin, Charles A., Perera, Jennifer, Pierre-Audigier, Catherine, Pholwat, Suporn, Posey, James E., Prammananan, Therdsak, Rigouts, Leen, Robledo, Jaime, Rockwood, Neesha, Rodrigues, Camilla, Salfinger, Max, Schechter, Marcos C., Seifert, Marva, Sengstake, Sarah, Shinnick, Thomas, Shubladze, Natalia, Sintchenko, Vitali, Sirgel, Frederick, Somasundaram, Sulochana, Sterling, Timothy R., Spitaleri, Andrea, Streicher, Elizabeth, Supply, Philip, Svensson, Erik, Tagliani, Elisa, Tahseen, Sabira, Takaki, Akiko, Theron, Grant, Torrea, Gabriela, Van Deun, Armand, van Ingen, Jakko, Van Rie, Annelies, van Soolingen, Dick, Vargas Jr, Roger, Venter, Amour, Veziris, Nicolas, Villellas, Cristina, Viveiros, Miguel, Warren, Robin, Wen, Shu'an, Werngren, Jim, Wilkinson, Robert J., Yang, Caie, Yılmaz, F. Ferda, Zhang, Tingting, Zimenkov, Danila, Ismail, Nazir, Köser, Claudio U., Schön, Thomas, University of Zurich, Antimycobacterial Susceptibility Testing Group, Department of Genetics [Cambridge], University of Cambridge [UK] (CAM), Centre d'Immunologie et des Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Centre Médical de l'Institut Pasteur (CMIP), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institut de médecine et d'épidémiologie appliquée [AP-HP Hôpital Bichat-Claude Bernard] (IMEA), AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), As current or former employees or consultants for FIND, the work of R.B. Baldan, I. Comas, C.M. Denkinger, D.L. Dolinger, S.B. Georghiou, C.U. Köser and T.C. Rodwell on the systematic reviews, including this viewpoint, was supported by Unitaid (grant 2019-32-FIND MDR), BMGF (grant OPP1105925), the German Federal Ministry of Education and Research through KfW, the Dutch Ministry of Foreign Affairs, the Australian Department of Foreign Affairs and Trade, and UK aid from the British people. N. Alvarez and J. Robledo are funded by MinCiencias, Colombia (number 221389666216 CT-783-2018). A. Aubry and N. Veziris work at the Centre National de Reference des Mycobactéries, which receives an annual grant from Santé Publique France and have received research grants from Janssen for studies on bedaquiline. P. Claxton and I.F. Laurenson are funded through National Services Scotland. I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038). M. Egger is supported by the Swiss National Science Foundation (grant number 320030_153442 and 189498) and the US National Institutes of Health, National Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Cancer Institute, the National Institute of Mental Health, the National Institute on Drug Abuse, the National Heart, Lung, and Blood Institute, the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Diabetes and Digestive and Kidney Diseases, the Fogarty International Center, and the National Library of Medicine: Asia-Pacific, U01AI069907, CCASAnet, U01AI069923, Central Africa, U01AI096299, East Africa, U01AI069911, NA-ACCORD, U01AI069918, Southern Africa, U01AI069924, West Africa, U01AI069919. M.R. Farhat is supported by NIH NIAID R01AI155765. S.K. Heysell was funded by NIH NIAID grants R01 AI137080 and U01 AI150508. T. Jagielski was supported by a DAINA grant (number 2017/27/L/NZ6/03279) from the National Science Centre, Poland. J.L. Johnson was supported by contracts NO1-AI95383 and NO1-AI-70022 of the US National Institutes of Health. P.M. Keller was supported by Innosuisse 36198.1 IP-LS. C.U. Köser is a research associate at Wolfson College and visiting scientist at the Department of Genetics, University of Cambridge. The Federal Government of Germany supported C.U. Köser as part of his work for the European Laboratory Initiative, WHO Regional Office for Europe. C.U. Köser was further supported by the Royal Society of Tropical Medicine and Hygiene and the National Institute for Health Research Cambridge Biomedical Research Centre and received an observership by the European Society of Clinical Microbiology and Infectious Diseases to the EUCAST Development Laboratory for Bacteria (Växjö, Sweden), hosted by Gunnar Kahlmeter and Erika Matuschek. D. Machado and M. Viveiros are funded in part by Fundação para a Ciência e a Tecnologia, Portugal (PTDC/BIA-MIC/30692/2017, UID/Multi/04413/2020 and DL57/ CEECIND/0256/2017). S. Niemann is supported by the German Center for Infection Research, Excellenz Cluster Precision Medicine in Chronic Inflammation EXC 2167, Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). S.V. Omar has received funding to prepare and provide training for Janssen Pharmaceutica activities. L. Rigouts is supported by the Belgian Directorate General for Development. T.C. Rodwell was additionally funded in part by FIND and NIH NIAD, grants: P30 AI036214 and R21 AI135756. T. Schön is funded by the Swedish Heart and Lung Foundation and the Swedish Research Council. T.R. Sterling has received funding from the US National Institutes of Health and the Centers for Disease Control and Prevention. G. Theron and R. Warren are supported by baseline funding from the South African Medical Research Council. R.J. Wilkinson receives funding from the Wellcome Trust (203135) and from the Francis Crick Institute, which is supported by Cancer Research UK (FC0010218), UKRI (FC0010218) and the Wellcome Trust (FC0010218), Ministerio de Ciencia e Innovación (España), European Research Council, Comas, Iñaki, Comas, Iñaki [0000-0001-5504-9408], Antimycobacterial Susceptibility T, and Wellcome Trust
Subjects: [SDV]Life Sciences [q-bio], Respiratory System, Drug Resistance, Antitubercular Agents, Infektionsmedicin, Medical and Health Sciences, Drug Resistance, Multiple, Bacterial, Tuberculosis, Multidrug-Resistant, 11 Medical and Health Sciences, Human Biology & Physiology, MESH: Microbial Sensitivity Tests, 10179 Institute of Medical Microbiology, Bacterial, Multidrug-Resistant, Infectious Diseases, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Infection, Life Sciences & Biomedicine, Multiple, Model organisms, Pulmonary and Respiratory Medicine, Infectious Medicine, Immunology, Infectious Disease, 610 Medicine & health, Microbial Sensitivity Tests, Vaccine Related, Rare Diseases, Clinical Research, Biodefense, MESH: Drug Resistance, Bacterial, Drug Resistance, Bacterial, Tuberculosis, Humans, Science & Technology, MESH: Humans, Antimycobacterial Susceptibility Testing Group, FOS: Clinical medicine, Prevention, MESH: Drug Resistance, Multiple, Bacterial, Mycobacterium tuberculosis, Eucast, MESH: Antitubercular Agents, lnfectious Diseases and Global Health Radboud Institute for Health Sciences [Radboudumc 4], Orphan Drug, Emerging Infectious Diseases, Good Health and Well Being, 2740 Pulmonary and Respiratory Medicine, 570 Life sciences, biology, Human medicine, Antimicrobial Resistance, Model
Abstract: 11 páginas, 2 figuras, 1 tabla, Inappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance., I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038)
Published: 2022

68. Intracellular Salmonella Paratyphi A is motile and differs in the expression of flagella-chemotaxis, SPI-1 and carbon utilization pathways in comparison to intracellular S. Typhimurium

Author: Helit Cohen, Claire Hoede, Felix Scharte, Charles Coluzzi, Emiliano Cohen, Inna Shomer, Ludovic Mallet, Sébastien Holbert, Remy Felix Serre, Thomas Schiex, Isabelle Virlogeux-Payant, Guntram A. Grassl, Michael Hensel, Hélène Chiapello, Ohad Gal-Mor, Chaim Sheba Medical Center, Unité de Mathématiques et Informatique Appliquées de Toulouse (MIAT INRAE), Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Plateforme Bio-Informatique - Génotoul, Universität Osnabrück - Osnabrück University, Mathématiques et Informatique Appliquées du Génome à l'Environnement [Jouy-En-Josas] (MaIAGE), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Génome et Transcriptome - Plateforme Génomique ( GeT-PlaGe), Plateforme Génome & Transcriptome (GET), Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Génopole Toulouse Midi-Pyrénées [Auzeville] (GENOTOUL), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Artificial and Natural Intelligence Toulouse Institute (ANITI), Université Fédérale Toulouse Midi-Pyrénées, Hannover Medical School [Hannover] (MHH), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Tel Aviv University (TAU), The work at the Gal-Mor laboratory was supported by grant numbers: 2616/18 from the joint ISF-Broad Institute program, 3-12435 from Infect-Era/Chief Scientist Ministry of Health, I-41-416.6-2018 from the German-Israeli Foundation for Scientific Research and Development (GIF, awarded to OGM and MH), and A128055 from the Research Cooperation Lower Saxony -Israel (The Volkswagen Foundation, awarded to OGM, MH and GG)., ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), ANR-15-IFEC-0003,Sal host trop,Understanding the Human-Restricted Host Tropism of Typhoidal Salmonella(2015), Chanteloup, Nathalie Katy, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, and Understanding the Human-Restricted Host Tropism of Typhoidal Salmonella - - Sal host trop2015 - ANR-15-IFEC-0003 - Infect-ERA - VALID
Subjects: Salmonella typhimurium, Chemotaxis, Immunology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Microbiology, Carbon, Bacterial Proteins, Flagella, Virology, Salmonella paratyphi A, Genetics, Intercellular Signaling Peptides and Proteins, Parasitology, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Molecular Biology, Phylogeny
Abstract: Although Salmonella Typhimurium (STM) and Salmonella Paratyphi A (SPA) belong to the same phylogenetic species, share large portions of their genome and express many common virulence factors, they differ vastly in their host specificity, the immune response they elicit, and the clinical manifestations they cause. In this work, we compared their intracellular transcriptomic architecture and cellular phenotypes during human epithelial cell infection. While transcription induction of many metal transport systems, purines, biotin, PhoPQ and SPI-2 regulons was similar in both intracellular SPA and STM, we identified 234 differentially expressed genes that showed distinct expression patterns in intracellular SPA vs. STM. Surprisingly, clear expression differences were found in SPI-1, motility and chemotaxis, and carbon (mainly citrate, galactonate and ethanolamine) utilization pathways, indicating that these pathways are regulated differently during their intracellular phase. Concurring, on the cellular level, we show that while the majority of STM are non-motile and reside within Salmonella-Containing Vacuoles (SCV), a significant proportion of intracellular SPA cells are motile and compartmentalized in the cytosol. Moreover, we found that the elevated expression of SPI-1 and motility genes by intracellular SPA results in increased invasiveness of SPA, following exit from host cells. These findings demonstrate unexpected flagellum-dependent intracellular motility of a typhoidal Salmonella serovar and intriguing differences in intracellular localization between typhoidal and non-typhoidal salmonellae. We propose that these differences facilitate new cycles of host cell infection by SPA and may contribute to the ability of SPA to disseminate beyond the intestinal lamina propria of the human host during enteric fever.
Published: 2021

69. Towards the sustainable discovery and development of new antibiotics

Author: Ian H. Gilbert, Kenneth Pfarr, Timo Jaeger, Mika Lindvall, Anders Karlén, Philippe Glaser, Jennifer Herrmann, Marco Pieroni, Bertrand Aigle, Evi Stegmann, Heather Graz, Andrea Schiefer, Jean-Luc Pernodet, Thomas Hesterkamp, Rui Moreira, Heike Brötz-Oesterhelt, Andrew W. Truman, Andreas Keller, Ludovic Halby, Alexander Titz, José R. Tormo, Michael Graz, Kira J. Weissman, Olga Genilloud, Marc Stadler, Claus-Michael Lehr, Paola B. Arimondo, Mark Brönstrup, Savithri Ramurthy, Eriko Takano, Frédéric Peyrane, Mathias Winterhalter, Marnix H. Medema, Maarten van Dongen, Anna K. H. Hirsch, Achim Hoerauf, Helge B. Bode, Laurent Fraisse, Laura J. V. Piddock, Martin Empting, Brigitta Loretz, Yanyan Li, Heinz E. Moser, Tilmann Weber, Marcus Miethke, Silke Alt, Stefano Sabatini, Wolfgang Wohlleben, Peter Hammann, Stefano Donadio, Andriy Luzhetskyy, Myriam Seemann, Rolf Müller, Hrvoje Petković, Institut de Chimie de Strasbourg, Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS)-Institut de Chimie du CNRS (INC), Helmholtz-Zentrum für Infektionsforschung GmbH (HZI), Universität des Saarlandes [Saarbrücken], German Centre for Infection Research (DZIF), University of Parma = Università degli studi di Parma [Parme, Italie], Technical University of Denmark [Lyngby] (DTU), Justus-Liebig-Universität Gießen (JLU), Chimie biologique épigénétique - Epigenetic Chemical Biology (EpiCBio), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Ecologie et Evolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance (EERA), Institut Pasteur [Paris]-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Dynamique des Génomes et Adaptation Microbienne (DynAMic), Université de Lorraine (UL)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Goethe-Universität Frankfurt am Main, Max Planck Institute for Terrestrial Microbiology, Max-Planck-Gesellschaft, Universidade de Lisboa (ULISBOA), Molécules de Communication et Adaptation des Micro-organismes (MCAM), Muséum national d'Histoire naturelle (MNHN)-Centre National de la Recherche Scientifique (CNRS), Wageningen University and Research [Wageningen] (WUR), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Fundación MEDINA, John Innes Centre [Norwich], Ingénierie Moléculaire et Physiopathologie Articulaire (IMoPA), Université de Lorraine (UL)-Centre National de la Recherche Scientifique (CNRS), University of Manchester [Manchester], Università degli Studi di Perugia (UNIPG), University of Tübingen, Jacobs University [Bremen], University Hospital Bonn, Biophys [Usk, UK], University of Bristol [Bristol], Recursion [Salt Lake City, UT], HiberCell [New York], Uppsala Universitet [Uppsala], AMR Insights, University of Ljubljana, BEAM Alliance, Naicons, Drugs for Neglected Diseases Initiative, Global Antibiotic Research and Development Partnership [Geneva, Switzerland] (GARDP), University of Dundee, Novartis Institutes for BioMedical Research (NIBR), The project on PqsR pathoblocker development acknowledges funding through the German Center for Infection Research (DZIF, projects TTU09.908 and TTU09.916), the Helmholtz Association (Helmholtz Validation Fund) and additional contributions by the associated academic institutes (HZI and HIPS). The development of chelocardins is supported by the DZIF (TTU09.814/09.821), the Helmholtz Innovation Fund (Pre-4D), by the Slovenian Research Agency, ARRS, grant no. J4-8226, and in collaboration with AciesBio, Slovenia. The corallopyronin project is funded by the DZIF (TTU09.807/09.816, TTU09.914), the German Federal Ministry of Education and Research (BMBF), the federal state of North Rhine-Westphalia (EFRE.NRW) and EU Horizon 2020. Eriko Takano was funded by the European Union’s Horizon 2020 research and innovation programme under grant agreement no. 720793 'TOPCAPI: Thoroughly Optimised Production Chassis for Advanced Pharmaceutical Ingredients'., European Project: 720793,H2020-EU.2.1.4.,TOPCAPI(2017), Università degli studi di Parma = University of Parma (UNIPR), Danmarks Tekniske Universitet = Technical University of Denmark (DTU), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Écologie et Évolution de la Résistance aux Antibiotiques / Ecology and Evolution of Antibiotics Resistance (EERA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris-Saclay-Université Paris Cité (UPCité)-Microbiologie Intégrative et Moléculaire (UMR6047), Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Universidade de Lisboa = University of Lisbon (ULISBOA), Fundación MEDINA [Granada], Biotechnology and Biological Sciences Research Council (BBSRC), Università degli Studi di Perugia = University of Perugia (UNIPG), and Université de Strasbourg (UNISTRA)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, 030306 microbiology, Bioinformatics, General Chemical Engineering, [SDV]Life Sciences [q-bio], General Chemistry, [CHIM.THER]Chemical Sciences/Medicinal Chemistry, Investment (macroeconomics), 3. Good health, 03 medical and health sciences, Roadmap, Risk analysis (engineering), 13. Climate action, Order (exchange), Blueprint, ddc:570, Business strategy in drug development, Bioinformatica, Life Science, ddc:610, Business, Drug therapy, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology
Abstract: An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations., Antimicrobial resistance is an increasing threat to public health and encouraging the development of new antimicrobials is one of the most important ways to address the problem. This Roadmap article aims to bring together industrial, academic and political partners, and proposes both short-term and long-term solutions to this challenge.
Published: 2021

70. Early-Life Immune System Maturation in Chickens Using a Synthetic Community of Cultured Gut Bacteria

Author: Klaus Neuhaus, Eva Miriam Buhl, Esther Wortmann, Birte Abt, Thomas Riedel, Thomas Clavel, Thomas C. A. Hitch, Bernd Kaspers, Christian Zenner, Philippe Velge, Jörg Overmann, Stefan Tiede, Department for Veterinary Sciences, Ludwig Maximilians University of Munich, Institute of Medical Microbiology, Functional Microbiome Research Group, University Hospital RWTH Aachen, Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH / Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures (DSMZ), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Electron microscopy facility, Universitätsklinikum RWTH Aachen - University Hospital Aachen [Aachen, Germany] (UKA), RWTH Aachen University-RWTH Aachen University, Else Kroener Fresenius Centre - Zentralinstitut für Ernährungs und Lebensmittelfors (ZIEL), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Infectiologie et Santé Publique (UMR ISP), Université de Tours (UT)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Technical University of Munich (TUM), and Université de Tours-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)
Subjects: Physiology, medicine.drug_class, chicken, Antibiotics, gut microbiome, Colonisation resistance, Gut flora, Biochemistry, Microbiology, 03 medical and health sciences, Immune system, mucosal immunology, Genetics, medicine, Colonization, Microbiome, Molecular Biology, Ecology, Evolution, Behavior and Systematics, Feces, 030304 developmental biology, 2. Zero hunger, 0303 health sciences, biology, 030306 microbiology, [SDV.BA]Life Sciences [q-bio]/Animal biology, anaerobes, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, QR1-502, Computer Science Applications, synthetic bacterial community, Mucosal immunology, Modeling and Simulation, Research Article
Abstract: MSystems 6(3), e01300-20 (2021). doi:10.1128/mSystems.01300-20, Published by American Society for Microbiology, Washington, DC
Published: 2021

71. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author: Stephan Spahn, Florian Müller, Revant Gupta, Dominik Pfister, Kornelius Schulze, Pierre Bedossa, Eleni Kotsiliti, Lars Zender, Mathias Heikenwalder, Nicolás Gonzalo Núñez, Peter Schirmacher, Axel Schulz, Jan Kosla, Adrian T. Billeter, Thomas Engleitner, Aleksandra Deczkowska, Danijela Heide, Donato Inverso, Susanne Roth, Olivier Govaere, Carla Montironi, Martha M. Kirstein, Dan G. Duda, Antonio D'Alessio, Jörn M. Schattenberg, Ekaterina Friebel, Tiziana Pressiani, F. Hucke, Jörg Trojan, Michael Bitzer, Suhail Yousuf, Bernhard Scheiner, Marina Ruiz de Galarreta, Markus Peck-Radosavljevic, Michael Allison, Nuh N. Rahbari, Simon Cockell, Brinda Emu, Ahmed Kaseb, David J. Pinato, Matthias P. Ebert, Joachim C. Mertens, Jean-François Dufour, Fabian Rössler, Achim Weber, Katharina Wolter, Thomas Decaens, Amaia Lujambio, Anja Moncsek, Daniela Lenggenhager, Katharina Pomej, Nisar P. Malek, Fabian Finkelmeier, Elisabetta Bugianesi, Valentina Leone, Ann K. Daly, Michael Dudek, Manfred Claassen, Zuzana Macek Jilkova, Henning Wege, Florian Castet, Marta Szydlowska, Beat P. Müller-Stich, Ramy Younes, Nicola Personeni, Philipp K. Haber, Marco Bueter, Manfred Jugold, Andrea Schietinger, Hiroto Kikuchi, Ido Amit, Sandra Koch, Dina Tiniakos, Ana Teijeiro, Jan-Philipp Mallm, Josep M. Llovet, Indrabahadur Singh, Percy A. Knolle, Sara De Dosso, Roland Rad, Arndt Vogel, Henrik E. Mei, Burkhard Becher, Nabil Djouder, Tom Luedde, Felix Meissner, Oliver Waidmann, Parice N. Marche, Viktor Umansky, Hellmut G. Augustin, Thomas U. Marron, Matthias Pinter, Mengjie Qiu, Arndt Weinmann, Ankit Sinha, Kristian Unger, Assaf Weiner, Vlad Ratziu, Quentin M. Anstee, Kristin Stirm, Yi Hsiang Huang, Alexander Siebenhüner, Fabian Kütting, Lorenza Rimassa, Dirk Waldschmidt, Masatoshi Kudo, Marc Ringelhan, Michele Vacca, Roser Pinyol, Fabio Marra, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Novo Nordisk A/S [Maløv, Denmark], Universität Zürich [Zürich] = University of Zurich (UZH), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Newcastle University [Newcastle], Medizinische Universität Wien = Medical University of Vienna, University of Tübingen, UniversitätsKlinikum Heidelberg, Weizmann Institute of Science [Rehovot, Israël], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Technical University of Munich (TUM), University hospital of Zurich [Zurich], Helmholtz-Zentrum München (HZM), Heidelberg University, Spanish National Cancer Research Center (CNIO), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National and Kapodistrian University of Athens (NKUA), University of Turin, Addenbrooke's Hospital, Cambridge University NHS Trust, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University Medical Center [Mainz], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Hannover Medical School [Hannover] (MHH), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Klinikum Klagenfurt am Wörthersee, Universitätsklinikum Frankfurt, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Oncology Institute of Southern Switzerland (IOSI), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Heidelberg University Hospital [Heidelberg], Medical Faculty [Mannheim], Massachusetts General Hospital [Boston], University of Cologne, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, German Center for Infection Research, Partnersite Munich (DZIF), University Medical Center [Tubingen, Germany], Inselspital Bern, University of Bern, The University of Texas M.D. Anderson Cancer Center [Houston], Kindai University, National Yang Ming University (NYMU), Taipei Veterans General Hospital [Taiwan], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Eberhard Karls University [Tübingen, Germany], Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Hammersmith Hospital NHS Imperial College Healthcare, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Pfister, Dominik [0000-0002-0542-2638], Núñez, Nicolás Gonzalo [0000-0003-3837-270X], Govaere, Olivier [0000-0002-4426-6930], Szydlowska, Marta [0000-0002-4660-899X], Gupta, Revant [0000-0002-0881-5074], Deczkowska, Aleksandra [0000-0003-0844-4346], Friebel, Ekaterina [0000-0003-1419-2376], Lenggenhager, Daniela [0000-0002-5382-9854], Moncsek, Anja [0000-0002-1191-5842], Inverso, Donato [0000-0003-0987-3345], Vacca, Michele [0000-0002-1973-224X], Marra, Fabio [0000-0001-8629-0878], Allison, Michael [0000-0003-3677-3294], D'Alessio, Antonio [0000-0002-9164-3671], Personeni, Nicola [0000-0002-7995-272X], Rimassa, Lorenza [0000-0001-9957-3615], Pomej, Katharina [0000-0002-2807-3565], Peck-Radosavljevic, Markus [0000-0002-0597-2728], Mallm, Jan-Philipp [0000-0002-7059-4030], Schietinger, Andrea [0000-0003-3644-1687], Augustin, Hellmut G [0000-0002-7173-4242], Kikuchi, Hiroto [0000-0002-3601-8435], Duda, Dan G [0000-0001-7065-8797], Mei, Henrik E [0000-0003-0697-7755], Schulz, Axel Ronald [0000-0002-5106-0148], Ringelhan, Marc [0000-0003-3131-5657], Lujambio, Amaia [0000-0002-2798-1481], Dufour, Jean-Francois [0000-0002-8062-1346], Kudo, Masatoshi [0000-0002-4102-3474], Djouder, Nabil [0000-0001-8423-1030], Zender, Lars [0000-0001-7626-2849], Pinato, David J [0000-0002-3529-0103], Rad, Roland [0000-0002-6849-9659], Mertens, Joachim C [0000-0003-2007-0308], Weber, Achim [0000-0003-0073-3637], Meissner, Felix [0000-0003-1000-7989], Amit, Ido [0000-0003-2968-877X], Knolle, Percy [0000-0003-2983-0414], Becher, Burkhard [0000-0002-1541-7867], Llovet, Josep M [0000-0003-0547-2667], Heikenwalder, Mathias [0000-0002-3135-2274], Apollo - University of Cambridge Repository, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz Zentrum München = German Research Center for Environmental Health, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), MARCHE, Patrice, D’Alessio, Antonio [0000-0002-9164-3671], Augustin, Hellmut G. [0000-0002-7173-4242], Duda, Dan G. [0000-0001-7065-8797], Mei, Henrik E. [0000-0003-0697-7755], Pinato, David J. [0000-0002-3529-0103], Mertens, Joachim C. [0000-0003-2007-0308], and Llovet, Josep M. [0000-0003-0547-2667]
Subjects: Male, Carcinogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 13/2, 13/1, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, LIVER-CANCER, R PACKAGE, RNA-SEQ, 14/19, Cancer, 0303 health sciences, Multidisciplinary, NONALCOHOLIC STEATOHEPATITIS, Liver Neoplasms, article, ddc, 3. Good health, 13/31, Multidisciplinary Sciences, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Science & Technology - Other Topics, [SDV.IMM]Life Sciences [q-bio]/Immunology, 64/60, Tumor necrosis factor alpha, Immunotherapy, Adjuvant, 631/67, Carcinoma, Hepatocellular, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, 14/32, 03 medical and health sciences, 14/34, 13/21, [SDV.CAN] Life Sciences [q-bio]/Cancer, ADVANCED HEPATOCELLULAR-CARCINOMA, NAFLD, medicine, Animals, Humans, 14/35, 030304 developmental biology, Science & Technology, Tumor Necrosis Factor-alpha, business.industry, 631/250/251, medicine.disease, PHASE-III, digestive system diseases, 13/51, 14/63, 59/57, T-CELLS, Cancer research, Steatohepatitis, business, CD8
Abstract: Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.
Published: 2021

72. Interventions to reduce infections caused by multidrug resistant Enterobacteriaceae (MDR-E): A systematic review and meta-analysis

Author: Heyam Atamna-Mawassi, Axel Kola, Maayan Huberman-Samuel, Luis Eduardo López Cortés, Leonard Leibovici, Nitzan Karny-Epstein, Dafna Yahav, Shimrit hershcovitz, Federal Ministry of Education and Research (Germany), Charité - Universitätsmedizin Berlin, German Center for Infection Research, Martin Luther University Halle-Wittenberg, ZonMw, Ministry of Health (Israel), National Science Centre (Poland), and European Commission
Subjects: 0301 basic medicine, Microbiology (medical), Adult, medicine.medical_specialty, Infection prevention and control, Cost effectiveness, 030106 microbiology, Systematic review and meta-analysis, Psychological intervention, Cochrane Library, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, Enterobacteriaceae, law, Internal medicine, Medicine, Antimicrobial stewardship, Humans, 030212 general & internal medicine, MDR-E, business.industry, Incidence (epidemiology), Multidrug resistant Enterobacteriaceae, Infectious Diseases, Meta-analysis, Observational study, business
Abstract: [Objectives] We aimed to evaluate different interventions to reduce multidrug-resistant Enterobacteriaceae (MDR-E) infection/colonization., [Methods] A systematic review and meta-analysis evaluating interventions for prevention of MDR-E infection/colonization among hospitalized adult patients. The co-primary outcomes were mortality and MDR-E infections. PubMed, Cochrane library, and LILACS databases were searched up till December 2019, as well as grey literature sources. We included randomized controlled trials and observational studies. Infection/colonization/acquisition outcomes were reported per patient-days as pooled incidence ratios (IRs) with 95% confidence intervals (CIs). Interrupted time series (ITS) analysis studies were reported separately., [Results] Sixty-three studies were included, 16 RCTs, 33 observational studies, and 14 ITS. For the intervention of antimicrobial stewardship program (ASP), 23 studies were included. No differences in mortality or MDR-E infections were observed with ASP, however, MDR-E colonization was significantly reduced (IR 0.69, 95% CI 0.57–0.82). Seventeen studies examined decolonization without significant difference in outcomes. Other interventions were scarcely represented. Among 14 ITS publications, most evaluating ASP, 11 showed benefit of the intervention., [Conclusions] ASP is an effective measure in preventing MDR-E colonization. Decolonization did not show significant benefit in reducing infection or colonization. Studies are needed to evaluate the cost effectiveness of ASP and assess bundles of interventions., This publication was made possible by grants from following national funding agencies: Germany BMBF 01KI1704A (Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Institute of Hygiene and Environmental Medicine); 01KI1704B (Helmholtz Center for Infection Research GmbH) and 01KI1704C (Martin-Luther-University Halle-Wittenberg, medical faculty, Institute of medical epidemiology, biostatistics and informatics); the Netherlands ZonMw grant number 547001005 (Julius centre, University Medical centre Utrecht); Israel CSO-MOH grant number 3000013820 (Rabin Medical Center, Beilinson Hospital / Department of Medicine), and Poland National Science centre Poland, Unisono: 2016/22/Z/ST1/00690 (University of Warsaw, Faculty of Mathematics, Informatics and Mechanics, Institute of Applied Mathematics and Mechanics and Department of Microbiology, Ludwik Rydygier Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University); within the 3rd JPI ARM framework (Joint Programming Initiative on Antimicrobial Resistance) cofound grant no. 681055 for the consortium EMerGE-Net (Effectiveness of infection control strategies against intra- and inter-hospital transmission of Multidrug-resistant Enterobacteriaceae).
Published: 2021

73. At least seven distinct rotavirus genotype constellations in bats with evidence of reassortment and zoonotic transmissions

Author: Ceren Simsek, Alexander N. Lukashev, Ward Deboutte, Yaw Adu Sarkodie, Daan Jansen, Hermann Ulrich Everling, Kwe Claude Yinda, Tabea Binger, Florian Gloza-Rausch, Eric M. Leroy, Mathieu Bourgarel, Leen Beller, Victor M. Corman, Augustina Sylverken, Stoian Yordanov, Marc Van Ranst, Jan Felix Drexler, Samuel Oppong, Gael Darren Maganga, Jelle Matthijnssens, Peter Vallo, Christian Drosten, Antje Seebens-Hoyer, Andrea Rasche, Rega Institute for Medical Research [Leuven, België], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], German Center for Infection Research, Partnersite Munich (DZIF), University of Bonn, Sechenov First Moscow State Medical University, Université des Sciences et Techniques de Masuku [Franceville, Gabon] (USTM), Centre International de Recherches Médicales de Franceville (CIRMF), Kumasi Centre for Collaborative Research in Tropical Medicine (KCCR), Noctalis, Centre for Bat Protection and Information, Forestry Board Directorate of Strandja Natural Park, Strandja Natural Park, Kwame Nkrumah University of Science and Technology [GHANA] (KNUST), Institute of Vertebrate Biology of the Czech Academy of Sciences (IVB / CAS), Czech Academy of Sciences [Prague] (CAS), Maladies infectieuses et vecteurs : écologie, génétique, évolution et contrôle (MIVEGEC), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS)-Institut de Recherche pour le Développement (IRD [France-Sud]), Animal, Santé, Territoires, Risques et Ecosystèmes (UMR ASTRE), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Département Systèmes Biologiques (Cirad-BIOS), Centre de Coopération Internationale en Recherche Agronomique pour le Développement (Cirad), This project has received funding from the European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie agreement no. 721367 granted to J.F.D., J.M., and M.V.R. EU Horizon 2020 projects EVAg (grant agreement number 653316) and COMPARE (agreement number 643476) granted to C.D., and the Russian Science Foundation grant 19-15-00055 to A.N.L. also provided funding to the current study. H.U.E. had a personal scholarship from the BONFOR intramural program at the University of Bonn. German Federal Ministry of Education and Research (BMBF) (project code 01KIO16D), Deutsche Forschungsgemeinschaft (DFG DR 772-3/1), Deutsche Forschungsgemeinschaft within the Africa Infectious Diseases program gave grants to C.D. and Y.A.S. (DR 772/3-1) and to S.O. (KA1241/18-1) that were also among the funding contributions. A personal scholarship granted to A.R. from the German Academic Exchange Service (DAAD) supported field work in Costa Rica. D. J. was supported by the Fonds Wetenschappelijk Onderzoek (Research foundation Flanders) (1S78019N). L.B. was supported by the Fonds Wetenschappelijk Onderzoek (1S61618N). K.C.Y. was funded by the Interfaculty Council for Development Cooperation (IRO) from the KU Leuven. The computing power in this work was provided by the VSC (Flemish Supercomputer Centre), financed by the FWO and the Flemish government, department EWI., European Project: 777657,H2020-EU.1.3.3. - Stimulating innovation by means of cross-fertilisation of knowledge,777657,MSCA-RISE(2018), European Project: 653316,H2020,H2020-INFRAIA-2014-2015,EVAg(2015), European Project: 643476,H2020,H2020-PHC-2014-single-stage,COMPARE(2014), Universität Bonn = University of Bonn, Université des Sciences et Techniques de Masuku (USTM), and Kwame Nkrumah University of Science and Technology (KNUST)
Subjects: Rotavirus, Viral metagenomics, [SDV]Life Sciences [q-bio], viruses, Reassortment, medicine.disease_cause, L73 - Maladies des animaux, Genome, Zoonoses, Chiroptera, Genotype, Phylogeny, 0303 health sciences, Phylogenetic tree, Strain (biology), [SDV.BA]Life Sciences [q-bio]/Animal biology, Zoonosis, virus diseases, QR1-502, 3. Good health, S50 - Santé humaine, Middle East Respiratory Syndrome Coronavirus, Research Article, Diarrhea, zoonose, Middle East respiratory syndrome coronavirus, relation homme-faune, Genome, Viral, Ecological and Evolutionary Science, Biology, Microbiology, Rotavirus Infections, rotavirus genetic diversity, SA11, 03 medical and health sciences, Coronavirus 2 du syndrome respiratoire aigu sévère, Virology, medicine, Animals, Humans, Horses, Transmission des maladies, 030304 developmental biology, Genetic diversity, 030306 microbiology, SARS-CoV-2, COVID-19, Genetic Variation, zoonosis, medicine.disease, respiratory tract diseases, Evolutionary biology, bat rotavirus, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Metagenomics, Virus pathogène
Abstract: The increased research on bat coronaviruses after severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) allowed the very rapid identification of SARS-CoV-2. This is an excellent example of the importance of knowing viruses harbored by wildlife in general, and bats in particular, for global preparedness against emerging viral pathogens., Bats host many viruses pathogenic to humans, and increasing evidence suggests that rotavirus A (RVA) also belongs to this list. Rotaviruses cause diarrheal disease in many mammals and birds, and their segmented genomes allow them to reassort and increase their genetic diversity. Eighteen out of 2,142 bat fecal samples (0.8%) collected from Europe, Central America, and Africa were PCR-positive for RVA, and 11 of those were fully characterized using viral metagenomics. Upon contrasting their genomes with publicly available data, at least 7 distinct bat RVA genotype constellations (GCs) were identified, which included evidence of reassortments and 6 novel genotypes. Some of these constellations are spread across the world, whereas others appear to be geographically restricted. Our analyses also suggest that several unusual human and equine RVA strains might be of bat RVA origin, based on their phylogenetic clustering, despite various levels of nucleotide sequence identities between them. Although SA11 is one of the most widely used reference strains for RVA research and forms the backbone of a reverse genetics system, its origin remained enigmatic. Remarkably, the majority of the genotypes of SA11-like strains were shared with Gabonese bat RVAs, suggesting a potential common origin. Overall, our findings suggest an underexplored genetic diversity of RVAs in bats, which is likely only the tip of the iceberg. Increasing contact between humans and bat wildlife will further increase the zoonosis risk, which warrants closer attention to these viruses.
Published: 2021

74. Modulation of alternative splicing during early infection of human primary B lymphocytes with Epstein-Barr virus (EBV): a novel function for the viral EBNA-LP protein

Author: Paulina Mrozek-Gorska, Fabrice Mure, Wolfgang Hammerschmidt, Didier Auboeuf, Florian Roisné-Hamelin, Evelyne Manet, Henri Gruffat, Hélène Polvèche, Manet, Evelyne, Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institut des cellules souches pour le traitement et l'étude des maladies monogéniques (I-STEM), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, German Center for Infection Research [Heidelberg, Germany] (DZIF), Heidelberg University, Laboratoire de biologie et modélisation de la cellule (LBMC UMR 5239), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Herpesvirus 4, Human, AcademicSubjects/SCI00010, [SDV.CAN]Life Sciences [q-bio]/Cancer, Biology, medicine.disease_cause, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Virus, 03 medical and health sciences, Exon, Viral Proteins, 0302 clinical medicine, [SDV.CAN] Life Sciences [q-bio]/Cancer, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Genetics, medicine, RNA and RNA-protein complexes, Humans, Cells, Cultured, 030304 developmental biology, Regulation of gene expression, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, 0303 health sciences, Messenger RNA, B-Lymphocytes, Alternative splicing, Membrane Proteins, RNA-Binding Proteins, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Exons, Epstein–Barr virus, 3. Good health, Cell biology, Alternative Splicing, 030220 oncology & carcinogenesis, RNA splicing, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, NUMB, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, RNA Splice Sites
Abstract: Epstein-Barr virus (EBV) is a human herpesvirus associated with human cancers worldwide. Ex vivo, the virus efficiently infects resting human B lymphocytes and induces their continuous proliferation. This process is accompanied by a global reprogramming of cellular gene transcription. However, very little is known on the impact of EBV infection on the regulation of alternative splicing, a pivotal mechanism that plays an essential role in cell fate determination and is often deregulated in cancer. In this study, we have developed a systematic time-resolved analysis of cellular mRNA splice variant expression during EBV infection of resting B lymphocytes. Our results reveal that major modifications of alternative splice variant expression appear as early as day 1 post-infection and suggest that splicing regulation provides—besides transcription—an additional mechanism of gene expression regulation at the onset of B cell activation and proliferation. We also report a role for the viral proteins, EBNA2 and EBNA-LP, in the modulation of specific alternative splicing events and reveal a previously unknown function for EBNA-LP—together with the RBM4 splicing factor—in the alternative splicing regulation of two important modulators of cell proliferation and apoptosis respectively, NUMB and BCL-X.
Published: 2021

75. Resurgence of Ebola Virus in 2021 in Guinea Suggests a New Paradigm for Outbreaks

Author: Fodé B. Sako, Jacob Camara, Amadou A. Sall, Ariane Düx, Giuditta Annibaldis, Meike Pahlmann, Abdoulaye Toure, Ousmane Faye, Mamadou Condé, Haby Diallo, Steven T. Pullan, Amadou Sidibe, Moriba Povogui, Fara Raymond Koundouno, Christophe Peyrefitte, Liana E. Kafetzopoulou, Alpha Kabinet Keita, Saa L. Millimono, Mandiou Diakite, Ahmadou Doré, Karla Pietro, N'. Faly Magassouba, Fabian H. Leendertz, Nicole Vidal, Stephan Günther, Anke Thielebein, Julia Hinzmann, Dembo Diakite, Ahidjo Ayouba, Cheikh Loucoubar, Kaka Kourouma, Martin Faye, Philippe Lemey, Moussa Moïse Diagne, Mamadou D. Barry, Fodé Y. Soumah, Annick Renevey, Georges Ki-Zerbo, Kékoura Ifono, Andrew Rambaut, Abdoul K. Soumah, Miles W. Carroll, Mamadou S. Bah, Joseph Akoi Bore, Ibrahima Camara, Mamadou S. Sow, Sébastien Calvignac-Spencer, Fodé A. Traore, Sophie Duraffour, Assaïtou Bah, John T. McCrone, Nathalie J. Vielle, Joshua Quick, Noël Tordo, Moussa Baldé, Mamadou Diop, Youssouf Sidibé, Martine Peeters, Madeleine Kourouma, Sakoba Keita, Mamadou B. Keita, Frédéric Le Marcis, Cé D. Saouromou, Anais Legand, Amadou Diallo, Pierre Formenty, Almudena Mari-Saez, Michael R. Wiley, Karifa Kourouma, Eric Delaporte, Barré Soropogui, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Université Gamal Abdel Nasser de Conakry, Laboratoire des Fièvres Hémorragiques en Guinée, Bernhard Nocht Institute for Tropical Medicine - Bernhard-Nocht-Institut für Tropenmedizin [Hamburg, Germany] (BNITM), Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Robert Koch Institute [Berlin] (RKI), German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Centre de Recherche et de Formation en Infectiologie de Guinée [Conakry, Guinée] (CERFIG), Triangle : action, discours, pensée politique et économique (TRIANGLE), École normale supérieure de Lyon (ENS de Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Centre National de la Recherche Scientifique (CNRS), Hôpital National Donka, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, Epidemiology of Highly Pathogenic Microorganisms, Vecteurs - Infections tropicales et méditerranéennes (VITROME), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), CEA Tech Grand-Est (DGDE), CEA Tech en régions (CEA-TECH-Reg), Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Technologique (CEA) (DRT (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Institut National de Santé Publique [Conakry, Guinée] (INSP), Ministère de la Santé [Conakry, Guinea], Laboratoire de Physique de l'Atmosphère et de l'Océan Siméon Fongang (LPAO-SF), École Supérieure Polytechnique de Dakar (ESP), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Public Health England, University of Birmingham [Birmingham], Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), World Health Organization [Geneva], The University of Texas Medical Branch (UTMB), University of Nebraska Medical Center, University of Nebraska System, Institut Pasteur de Guinée, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut de Recherche Biomédicale des Armées [Antenne Marseille] (IRBA), University of Edinburgh, Division Prévention et Lutte contre la Maladie, Ministère de la Santé et de l’Hygiène Publique, Ecole Nationale Superieure de Lyon, Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Infectious and Tropical Diseases Department [Montpellier], Institut de Recherche pour le Développement (IRD)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD), Max Planck Institute for Evolutionary Anthropology [Leipzig], Max-Planck-Gesellschaft, ANR-16-IDEX-0006,MUSE,MUSE(2016), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1), Centre National de la Recherche Scientifique (CNRS)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Université Lumière - Lyon 2 (UL2)-École normale supérieure - Lyon (ENS Lyon), University of Oxford [Oxford], Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes (URMITE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-IFR48, INSB-INSB-Centre National de la Recherche Scientifique (CNRS), CEA Tech Alsace Champagne-Ardenne Lorraine, École normale supérieure - Lyon (ENS Lyon)-Université Lumière - Lyon 2 (UL2)-Sciences Po Lyon - Institut d'études politiques de Lyon (IEP Lyon), Université de Lyon-Université de Lyon-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Aix Marseille Université (AMU)-Institut de Recherche pour le Développement (IRD)-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Michel de l'Hospital : laboratoire de recherche en sciences juridiques et politiques (CMH ), and Université Clermont Auvergne (UCA)
Subjects: Male, Zaire ebolavirus, Time Factors, viruses, Disease, Biology, medicine.disease_cause, Disease cluster, Models, Biological, Viral Zoonoses, Virus, Disease Outbreaks, 03 medical and health sciences, Ebola virus, 0302 clinical medicine, medicine, Animals, Humans, Survivors, 030212 general & internal medicine, Clade, Phylogeny, 030304 developmental biology, 0303 health sciences, Multidisciplinary, Transmission (medicine), Guinea-2021, High-Throughput Nucleotide Sequencing, Outbreak, Hemorrhagic Fever, Ebola, [SHS.ANTHRO-SE]Humanities and Social Sciences/Social Anthropology and ethnology, Ebolavirus, Virology, 3. Good health, Democratic Republic of the Congo, Female, Persistent Infection, epidemiology, Guinea, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract: Seven years after the declaration of the first epidemic of Ebola virus disease in Guinea, the country faced a new outbreak—between 14 February and 19 June 2021—near the epicentre of the previous epidemic1,2. Here we use next-generation sequencing to generate complete or near-complete genomes of Zaire ebolavirus from samples obtained from 12 different patients. These genomes form a well-supported phylogenetic cluster with genomes from the previous outbreak, which indicates that the new outbreak was not the result of a new spillover event from an animal reservoir. The 2021 lineage shows considerably lower divergence than would be expected during sustained human-to-human transmission, which suggests a persistent infection with reduced replication or a period of latency. The resurgence of Zaire ebolavirus from humans five years after the end of the previous outbreak of Ebola virus disease reinforces the need for long-term medical and social care for patients who survive the disease, to reduce the risk of re-emergence and to prevent further stigmatization. The viral lineage responsible for the February 2021 outbreak of Ebola virus disease in Guinea is nested within a clade that predominantly consists of genomes sampled during the 2013–2016 epidemic, suggesting that the virus might have re-emerged after a long period of latency within a previously infected individual.
Published: 2021

76. Epidemiological situation, laboratory capacity and preparedness for carbapenem-resistant Acinetobacter baumannii in Europe, 2019

Author: Marc Struelens, Serap Suzuk Yıldız, Monica Monaco, Giulia Errico, Alexandre Mzabi, Vera Manageiro, Manuela Caniça, Maja Travar, Rainer Hartl, BELÉN ARACIL, European Centre for Disease Prevention and Control (ECDC), German Center for Infection Research - Partner Site Bonn-Cologne (DZIF), University Hospital of Cologne [Cologne], Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Centre National de Référence de la Résistance aux Antibiotiques (CNR), Laboratoire Chrono-environnement - CNRS - UBFC (UMR 6249) (LCE), Université de Franche-Comté (UFC), and Université Bourgogne Franche-Comté [COMUE] (UBFC)-Université Bourgogne Franche-Comté [COMUE] (UBFC)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0303 health sciences, medicine.medical_specialty, animal structures, biology, 030306 microbiology, Epidemiology, business.industry, Public Health, Environmental and Occupational Health, biology.organism_classification, Acinetobacter baumannii, 03 medical and health sciences, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 0302 clinical medicine, Virology, Preparedness, Environmental health, medicine, 030212 general & internal medicine, Reference function, business, Carbapenem resistant Acinetobacter baumannii, Carbapenem resistance
Abstract: To update information on the epidemiological situation and national capacity for detection, surveillance and containment of carbapenem-resistant Acinetobacter baumannii (CRAb) in Europe, we performed a survey in 37 countries. Nine countries reported regional or inter-regional spread and seven an endemic situation. Laboratories with a reference function, surveillance systems, and a national containment plan for CRAb existed in 30, 23 and eight countries, respectively. A pan-European molecular survey would provide in-depth understanding of the CRAb epidemiology.
Published: 2020

77. SARS-CoV-2 targets neurons of 3D human brain organoids

Author: Henning Gruell, Heiner Schaal, Sandra Hauka, Pranty Abida‐Islam, Kai Wohlgemuth, Anand Ramani, Aruljothi Mariappan, Jörg Timm, Jay Gopalakrishnan, Elke Gabriel, Lisa Müller, Olivier Goureau, Carsten Korth, Dagmar Wieczorek, Alexander T. Dilthey, Torsten Houwaart, Ortwin Adams, Florian Klein, Heymut Omran, Philipp Niklas Ostermann, Marcel Andree, Andreas Müller-Schiffmann, Andreas Walker, Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Institut de la Vision, Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital of Cologne [Cologne], University Hospital Münster - Universitaetsklinikum Muenster [Germany] (UKM), German Center for Infection Research, Partnersite Munich (DZIF), Center for Molecular Medicine [Cologne] (CMMC), and University of Cologne
Subjects: SARS‐CoV-2, Programmed cell death, Tau pathology, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), viruses, [SDV]Life Sciences [q-bio], Central nervous system, Hyperphosphorylation, neurons, tau Proteins, Biology, Article, General Biochemistry, Genetics and Molecular Biology, Betacoronavirus, 03 medical and health sciences, 0302 clinical medicine, Chlorocebus aethiops, medicine, Organoid, Animals, Humans, Molecular Biology of Disease, skin and connective tissue diseases, Vero Cells, Molecular Biology, 030304 developmental biology, 0303 health sciences, General Immunology and Microbiology, brain organoids, SARS-CoV-2, General Neuroscience, fungi, Brain, Articles, Human brain, Microbiology, Virology & Host Pathogen Interaction, 3. Good health, respiratory tract diseases, Organoids, body regions, medicine.anatomical_structure, cell death, Soma, Nervous System Diseases, Neuroscience, 030217 neurology & neurosurgery
Abstract: COVID‐19 pandemic caused by SARS‐CoV‐2 infection is a public health emergency. COVID‐19 typically exhibits respiratory illness. Unexpectedly, emerging clinical reports indicate that neurological symptoms continue to rise, suggesting detrimental effects of SARS‐CoV‐2 on the central nervous system (CNS). Here, we show that a Düsseldorf isolate of SARS‐CoV‐2 enters 3D human brain organoids within 2 days of exposure. We identified that SARS‐CoV‐2 preferably targets neurons of brain organoids. Imaging neurons of organoids reveal that SARS‐CoV‐2 exposure is associated with altered distribution of Tau from axons to soma, hyperphosphorylation, and apparent neuronal death. Our studies, therefore, provide initial insights into the potential neurotoxic effect of SARS‐CoV‐2 and emphasize that brain organoids could model CNS pathologies of COVID‐19., In vitro exposure of cerebral organoids to coronavirus results in preferential infection and cell death of neuronal cells.
Published: 2020

78. Rapid incorporation of Favipiravir by the fast and permissive viral RNA polymerase complex results in SARS-CoV-2 lethal mutagenesis

Author: Shannon, Ashleigh, Selisko, Barbara, Le, Nhung-Thi-Tuyet, Huchting, Johanna, Touret, Franck, Piorkowski, Géraldine, Fattorini, Véronique, Ferron, François, Decroly, Etienne, Meier, Chris, Coutard, Bruno, Peersen, Olve, Canard, Bruno, Architecture et fonction des macromolécules biologiques (AFMB), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), University of Hamburg, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Colorado State University [Fort Collins] (CSU), This work was supported by the Fondation pour la Recherche Médicale (Aide aux équipes), the SCORE project H2020 SC1-PHE-Coronavirus-2020 (grant#101003627) to BCa, REACTing Covid-19 initiative (REsearch and ACTion targeting emerging infectious diseases) with the support of the Ministry of Solidarity and Health and the Ministry of Higher Eductation to BCa, ED and BCo, National Institutes of Health grant AI059130 to OP, and a grant from DZIF (German Center for Infection Research) to J.H. and C.M., European Commission GA 871029SCORE project H2020 SC1-PHE-Coronavirus-2020 101003627United States Department of Health & Human Services National Institutes of Health (NIH) - USA AI059130, ANR-20-COVI-0059,PROTEO-SARS-CoV-2,Protéomique du SARS-CoV-2(2020), and Ferron, François
Subjects: Models, Molecular, Science, viruses, Pneumonia, Viral, Viral Nonstructural Proteins, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Virus Replication, Antiviral Agents, Article, Betacoronavirus, Chlorocebus aethiops, Animals, lcsh:Science, Pandemics, Vero Cells, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Coronavirus RNA-Dependent RNA Polymerase, SARS-CoV-2, COVID-19, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Viral proteins, RNA-Dependent RNA Polymerase, Amides, COVID-19 Drug Treatment, Mutagenesis, [SDV.SP.PHARMA] Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, Pyrazines, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.SP.PHARMA]Life Sciences [q-bio]/Pharmaceutical sciences/Pharmacology, RNA, Viral, lcsh:Q, Coronavirus Infections, Sequence Analysis
Abstract: The ongoing Corona Virus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has emphasized the urgent need for antiviral therapeutics. The viral RNA-dependent-RNA-polymerase (RdRp) is a promising target with polymerase inhibitors successfully used for the treatment of several viral diseases. We demonstrate here that Favipiravir predominantly exerts an antiviral effect through lethal mutagenesis. The SARS-CoV RdRp complex is at least 10-fold more active than any other viral RdRp known. It possesses both unusually high nucleotide incorporation rates and high-error rates allowing facile insertion of Favipiravir into viral RNA, provoking C-to-U and G-to-A transitions in the already low cytosine content SARS-CoV-2 genome. The coronavirus RdRp complex represents an Achilles heel for SARS-CoV, supporting nucleoside analogues as promising candidates for the treatment of COVID-19., Favipiravir (T-705) is an inhibitor of viral RNA-dependent-RNA-polymerases (RdRp) and clinical trials for the treatment of COVID-19 are ongoing. Here, the authors show that SARS-CoV nsp12 is the fastest known viral RdRp and they provide insights into the mechanism of action of Favipiravir, demonstrating that its antiviral effect on SARS-CoV-2 is primarily mediated through lethal mutagenesis.
Published: 2020

79. Erratum for Wallenstein et al., 'ClbR Is the Key Transcriptional Activator of Colibactin Gene Expression in Escherichia coli'

Author: Jean-Philippe Nougayrède, Simone König, Rolf Müller, Nadège Bossuet-Greif, Nadine Rehm, Daniel Sauer, Marina Brinkmann, Alexander Wallenstein, Eric Oswald, Martina Selle, Jörg Overmann, Stefan Homburg, Boyke Bunk, Ulrich Dobrindt, Rudolf von Bünau, Cathrin Spröer, Haleluya Wami, Westfälische Wilhelms-Universität Münster = University of Münster (WWU), University of Würzburg, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Helmholtz Centre for Infection Research (HZI), Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH / Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures (DSMZ), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Pharma Zentrale GmbH, Interdisciplinary Center for Clinical Research of the Medical Faculty Münster (Dob2/013/12), German Research Foundation (DO789/11-1)., German Research Foundation (SFB 479, TP A1)., Jean-Philippe, Nougayrede, and University of Münster
Subjects: Transcriptional Activation, Iron, VNTR, lcsh:QR1-502, secondary metabolite, medicine.disease_cause, Microbiology, lcsh:Microbiology, cytopathic effect, Host-Microbe Biology, 03 medical and health sciences, polyketide, Colibactin, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Escherichia coli, medicine, Molecular Biology, Transcriptional Activator, 030304 developmental biology, 0303 health sciences, 030306 microbiology, Chemistry, Escherichia coli Proteins, Gene Expression Regulation, Bacterial, Molecular biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, QR1-502, Polyketides, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Erratum, RNA-seq, [SDV.MP.BAC] Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Peptides, Research Article
Abstract: The nonribosomal peptide/polyketide hybrid colibactin can be considered a bacterial virulence factor involved in extraintestinal infection and also a procarcinogen. Nevertheless, and despite its genotoxic effect, colibactin expression can also inhibit bacterial or tumor growth and correlates with probiotic anti-inflammatory and analgesic properties. Although the biological function of this natural compound has been studied extensively, our understanding of the regulation of colibactin expression is still far from complete. We investigated in detail the role of regulatory elements involved in colibactin expression and in the growth conditions that promote colibactin expression. In this way, our data shed light on the regulatory mechanisms involved in colibactin expression and may support the expression and purification of this interesting nonribosomal peptide/polyketide hybrid for further molecular characterization., Colibactin is a nonribosomal peptide/polyketide hybrid natural product expressed by different members of the Enterobacteriaceae which can be correlated with induction of DNA double-strand breaks and interference with cell cycle progression in eukaryotes. Regulatory features of colibactin expression are only incompletely understood. We used Escherichia coli strain M1/5 as a model to investigate regulation of expression of the colibactin determinant at the transcriptional level and to characterize regulatory elements located within the colibactin pathogenicity island itself. We measured clbR transcription in vitro and observed that cultivation in defined minimal media led to increased colibactin expression relative to rich media. Transcription of clbR directly responds to iron availability. We also characterized structural DNA elements inside the colibactin determinant involved in ClbR-dependent regulation, i.e., ClbR binding sites and a variable number of tandem repeats located upstream of clbR. We investigated the impact of clbR overexpression or deletion at the transcriptome and proteome levels. Moreover, we compared global gene regulation under these conditions with that occurring upon overexpression or deletion of clbQ, which affects the flux of colibactin production. Combining the results of the transcriptome and proteome analyses with indirect measurements of colibactin levels by cell culture assays and an approximate quantification of colibactin via the second product of colibactin cleavage from precolibactin, N-myristoyl-d-asparagine, we demonstrate that the variable number of tandem repeats plays a significant regulatory role in colibactin expression. We identify ClbR as the only transcriptional activator known so far that is specific and essential for efficient regulation of colibactin production. IMPORTANCE The nonribosomal peptide/polyketide hybrid colibactin can be considered a bacterial virulence factor involved in extraintestinal infection and also a procarcinogen. Nevertheless, and despite its genotoxic effect, colibactin expression can also inhibit bacterial or tumor growth and correlates with probiotic anti-inflammatory and analgesic properties. Although the biological function of this natural compound has been studied extensively, our understanding of the regulation of colibactin expression is still far from complete. We investigated in detail the role of regulatory elements involved in colibactin expression and in the growth conditions that promote colibactin expression. In this way, our data shed light on the regulatory mechanisms involved in colibactin expression and may support the expression and purification of this interesting nonribosomal peptide/polyketide hybrid for further molecular characterization.
Published: 2020

80. ClbR Is the Key Transcriptional Activator of Colibactin Gene Expression in Escherichia coli

Author: Jörg Overmann, Boyke Bunk, Martina Selle, Daniel Sauer, Nadège Bossuet-Greif, Ulrich Dobrindt, Simone König, Marina Brinkmann, Alexander Wallenstein, Cathrin Spröer, Stefan Homburg, Haleluya Wami, Jean-Philippe Nougayrède, Rudolf von Bünau, Eric Oswald, Rolf Müller, Nadine Rehm, Institute of Hygiene, University of Münster, Università cattolica del Sacro Cuore [Roma] (Unicatt), Interdisciplinary Center for Clinical Research, Medical Faculty of Münster, Institute of Molecular Infection Biology, University of Würzburg, Institut de Recherche en Santé Digestive (IRSD ), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Ecole Nationale Vétérinaire de Toulouse (ENVT), Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National Polytechnique (Toulouse) (Toulouse INP), Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Helmholtz Institute for Pharmaceutical Research Saarland, Helmholtz Centre for Infection Research and Department of Pharmaceutical Biotechnology, Saarland University, German Collection of Microorganismes and Cell Cultures (DSMZ), DSMZ, German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Pharma Zentrale GmbH, Leibniz-Institut Deutsche Sammlung von Mikroorganismen und Zelllkulturen GmBH - DSMZ (GERMANY), the Interdisciplinary Center for Clinical Research of the Medical Faculty Münster (Dob2/013/12), the German Research Foundation (DO789/11-1), the German Research Foundation (SFB 479, TP A1), SEGUIN, Nathalie, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), and HIPS, Helmholtz-Institut für Pharmazeutische Forschung Saarland, Universitätscampus E8.1 66123 Saarbrücken, Germany.
Subjects: VNTR, lcsh:QR1-502, secondary metabolite, Biology, 010402 general chemistry, [SDV.BBM.BM] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, 01 natural sciences, Microbiology, lcsh:Microbiology, cytopathic effect, Transcriptome, 03 medical and health sciences, Polyketide, polyketide, Transcription (biology), Nonribosomal peptide, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Gene expression, Molecular Biology, 030304 developmental biology, Regulation of gene expression, chemistry.chemical_classification, 0303 health sciences, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, Pathogenicity island, QR1-502, 0104 chemical sciences, 3. Good health, Cell biology, chemistry, Proteome, [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], RNA-seq
Abstract: Colibactin is a nonribosomal peptide/polyketide hybrid natural product expressed by different members of the Enterobacteriaceae which can be correlated with induction of DNA double-strand breaks and interference with cell cycle progression in eukaryotes. Regulatory features of colibactin expression are only incompletely understood. We used Escherichia coli strain M1/5 as a model to investigate regulation of expression of the colibactin determinant at the transcriptional level and to characterize regulatory elements located within the colibactin pathogenicity island itself. We measured clbR transcription in vitro and observed that cultivation in defined minimal media led to increased colibactin expression relative to rich media. Transcription of clbR directly responds to iron availability. We also characterized structural DNA elements inside the colibactin determinant involved in ClbR-dependent regulation, i.e., ClbR binding sites and a variable number of tandem repeats located upstream of clbR. We investigated the impact of clbR overexpression or deletion at the transcriptome and proteome levels. Moreover, we compared global gene regulation under these conditions with that occurring upon overexpression or deletion of clbQ, which affects the flux of colibactin production. Combining the results of the transcriptome and proteome analyses with indirect measurements of colibactin levels by cell culture assays and an approximate quantification of colibactin via the second product of colibactin cleavage from precolibactin, N-myristoyl-d-asparagine, we demonstrate that the variable number of tandem repeats plays a significant regulatory role in colibactin expression. We identify ClbR as the only transcriptional activator known so far that is specific and essential for efficient regulation of colibactin production. IMPORTANCE The nonribosomal peptide/polyketide hybrid colibactin can be considered a bacterial virulence factor involved in extraintestinal infection and also a procarcinogen. Nevertheless, and despite its genotoxic effect, colibactin expression can also inhibit bacterial or tumor growth and correlates with probiotic anti-inflammatory and analgesic properties. Although the biological function of this natural compound has been studied extensively, our understanding of the regulation of colibactin expression is still far from complete. We investigated in detail the role of regulatory elements involved in colibactin expression and in the growth conditions that promote colibactin expression. In this way, our data shed light on the regulatory mechanisms involved in colibactin expression and may support the expression and purification of this interesting nonribosomal peptide/polyketide hybrid for further molecular characterization.
Published: 2020

81. COVID-19 Disease Map, building a computational repository of SARS-CoV-2 virus-host interaction mechanisms

Author: Reinhard Schneider, Jan Hasenauer, Egon Willighagen, Francesco Messina, Hiroaki Kitano, Charles Auffray, Marc Gillespie, Joaquín Dopazo, Emmanuel Barillot, Andreas Dräger, Akira Funahashi, Alexander R. Pico, Anna Niarakis, Aurelio Orta-Resendiz, Alfonso Valencia, Henning Hermjakob, Falk Schreiber, Chris T. Evelo, Rudi Balling, Laura I. Furlong, Inna Kuperstein, Olaf Wolkenhauer, Emek Demir, Alexander Mazein, Marek Ostaszewski, Bioinformatica, RS: NUTRIM - R1 - Obesity, diabetes and cardiovascular health, RS: FHML MaCSBio, [Ostaszewski,M, Mazein,A, Balling,R, Schneider,R] Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Belvaux, Luxembourg. [Gillespie,ME] Ontario Institute for Cancer Research, Toronto, Canada. [Gillespie,ME] College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA. [Kuperstein,I, Barillot,E] Institut Curie, PSL Research University, Mines Paris Tech, Inserm, Paris, France. [Niarakis,A] Department of Biology, Univ. Évry, University of Paris-Saclay, Genopole, 91025, Évry, France. [Hermjakob,H] European Molecular Biology Laboratory, European Bioinformatics Institute (EMBL-EBI), Hinxton, UK. [Pico,AR] Institute of Data Science and Biotechnology, Gladstone Institutes, San Francisco, United States. [Willighagen,EL, and Evelo,CT] Department of Bioinformatics-BiGCaT, NUTRIM, Maastricht University, Maastricht, The Netherlands. [Evelo,CT] Maastricht Centre for Systems Biology, Maastricht University, Maastricht, The Netherlands. [Hasenauer,J] Helmholtz Zentrum München, Institute of Computational Biology, Neuherberg, Germany. [Hasenauer,J] Center for Mathematics, Technische Universität München, Garching, Germany. [Hasenauer,J] Faculty of Mathematics and Natural Sciences, University of Bonn, Bonn, Germany. [Schreiber,F] University of Konstanz, Department of Computer and Information Science, Konstanz, Germany. [Schreiber,F] Monash University, Faculty of Information Technology, Melbourne, Australia. [Dräger,A] Computational Systems Biology of Infection and Antimicrobial-Resistant Pathogens, Institute for Bioinformatics and Medical Informatics (IBMI), University of Tübingen, 72076, Tübingen, Germany. [Dräger,A] Department of Computer Science, University of Tübingen, 72076, Tübingen, Germany. [Dräger,A] German Center for Infection Research (DZIF), partner site, Tübingen, Germany. [Demir,E] Department of Molecular and Medical Genetics, School of Medicine, Oregon Health & Science University, Portland, USA. [Wolkenhauer,O] Department of Systems Biology & Bioinformatics, University of Rostock, Rostock, Germany. [Wolkenhauer,O] Stellenbosch Institute of Advanced Study (STIAS), Wallenberg Research Centre at Stellenbosch University, 7602, Stellenbosch, South Africa. [Furlong,LI] Research Programme on Biomedical Informatics, Hospital del Mar Medical Research Institute, Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain. [Dopazo,J] Clinical Bioinformatics Area, Fundación Progreso y Salud. Hosp. Virgen del Rocío, Sevilla, Spain. [Dopazo,J] Bioinformatics in Rare Diseases. Centro de Investigación Biomédica en Red de Enfermedades Raras, Fundación Progreso y Salud, Hosp. Virgen del Rocío, Sevilla, Spain. [Dopazo,J] INB-ELIXIR-es, FPS, Hospital Virgen del Rocío, Sevilla, 42013, Spain. [Dopazo,J] Institute of Biomedicine of Seville (IBIS), Hospital Virgen del Rocio, 41013, Sevilla, Spain. [Orta-Resendiz,A] HIV, Inflammation and Persistence Unit, Virology Department, Institut Pasteur, Paris, France. [Orta-Resendiz,A] Bio Sorbonne Paris Cité, Université de Paris, Paris, France. [Messina,F] Dipartimento di Epidemiologia Ricerca Pre-Clinica e Diagnostica Avanzata, National Institute for Infectious Diseases 'Lazzaro Spallanzani' I.R.C.C.S., Rome, Italy. [Messina,F] COVID 19 INMI Network Medicine for IDs Study Group, National Institute for Infectious Diseases 'Lazzaro Spallanzani' I.R.C.C.S., Rome, Italy. [Valencia,A] Barcelona Supercomputer Center (BSC), Barcelona, Spain. [Valencia,A] Institucio Catalana de Recerca I Estudis Avançats (ICREA), Barcelona, Spain. [Funahashi,A] Department of Biosciences and Informatics, Keio University, Yokohama, Kanagawa, Japan. [Kitano,H] The Systems Biology Institute, Shinagawa, Tokyo, Japan. [Kitano,H] Okinawa Institute of Science and Technology Graduate University, Kunigami, Okinawa, Japan. [Kitano,H] Sony Computer Science Laboratories, Inc., Tokyo, Japan. [Auffray,C] European Institute for Systems Biology and Medicine (EISBM), Vourles, France.
Subjects: Databases, Factual, 010504 meteorology & atmospheric sciences, Computer science, International Cooperation, Disease, 01 natural sciences, Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings], Multidisciplinaire, généralités & autres [C99] [Ingénierie, informatique & technologie], Pandemic, Modelos biológicos, Analytical, Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Models, Theoretical::Models, Biological [Medical Subject Headings], Molècules, lcsh:Science, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries), 0303 health sciences, Multidisciplinary, general & others [C99] [Engineering, computing & technology], Humanos, Computer Science Applications, Pademia, Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Biology::Computational Biology [Medical Subject Headings], Host-Pathogen Interactions, Biología computacional, Bases de datos factuales, Statistics, Probability and Uncertainty, Diseases::Respiratory Tract Diseases::Respiratory Tract Infections::Pneumonia::Pneumonia, Viral [Medical Subject Headings], Coronavirus Infections, Information Systems, Statistics and Probability, 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Phenomena and Processes::Microbiological Phenomena::Microbiological Processes::Host-Pathogen Interactions [Medical Subject Headings], Infecciones por coronavirus, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Pneumonia, Viral, Computational biology, Library and Information Sciences, Virus-host interaction, Models, Biological, Education, Betacoronavirus, 03 medical and health sciences, Cooperación internacional, Information Science::Information Science::Medical Informatics::Medical Informatics Applications::Information Systems::Databases as Topic::Databases, Factual [Medical Subject Headings], Humans, Interacciones huésped-patógeno, Anthropology, Education, Sociology and Social Phenomena::Social Sciences::Internationality::International Cooperation [Medical Subject Headings], Pandemics, Viral immunology, 030304 developmental biology, 0105 earth and related environmental sciences, Host Microbial Interactions, SARS-CoV-2, Health Care::Environment and Public Health::Public Health::Disease Outbreaks::Epidemics::Pandemics [Medical Subject Headings], Computational Biology, COVID-19, Diseases::Virus Diseases::RNA Virus Infections::Nidovirales Infections::Coronaviridae Infections::Coronavirus Infections [Medical Subject Headings], Coronavirus, Neumonía viral, lcsh:Q, ddc:004, COVID-19 -- Malaltia
Abstract: Researchers around the world join forces to reconstruct the molecular processes of the virus-host interactions aiming to combat the cause of the ongoing pandemic.
Published: 2020

82. Dynamic changes in circulating T follicular helper cell composition predict neutralising antibody responses after yellow fever vaccination

Author: Johanna E Huber, Julia Ahlfeld, Magdalena K Scheck, Magdalena Zaucha, Klaus Witter, Lisa Lehmann, Hadi Karimzadeh, Michael Pritsch, Michael Hoelscher, Frank vonSonnenburg, Andrea Dick, Giovanna Barba‐Spaeth, Anne B Krug, Simon Rothenfußer, Dirk Baumjohann, Biomedical Center = Biomedizinisches centrum [Munich, Germany] (BMC), Ludwig-Maximilians-Universität München (LMU), Klinikum der Universität [München], Einheit für Klinische Pharmakologie [Neuherberg, Germany] (EKLIP), German Research Center for Environmental Health - Helmholtz Center München (GmbH)-Helmholtz Zentrum München = German Research Center for Environmental Health, Department of Transfusion Medicine, Cell Therapeutics and Hemostaseology [Munich, Germany], Klinikum der Universität [München]-Ludwig Maximilian University [Munich] (LMU), Division of Infectious Diseases and Tropical Medicine = Abteilung für infektions und tropenmedizin [Munich, Germany], Ludwig-Maximilians-Universität München (LMU)-Klinikum der Universität [München], German Center for Infection Research, Partnersite Munich (DZIF), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Medizinische Klinik und Poliklinik III [Bonn, Germany], Universitätsklinikum Bonn (UKB), This work was supported by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Emmy Noether Programme BA 5132/1‐1 and BA 5132/1‐2 (252623821), SFB 1054 Project B12 (210592381), and Germany's Excellence Strategy EXC2151 (390873048), as well as by LMUexcellent to DB, by the Einheit für Klinische Pharmakologie (EKLIP), Helmholtz Zentrum München, Neuherberg, Germany, to SR, JA and HK, by the transnational Agence Nationale de la Recherche/Deutsche Forschungsgemeinschaft grant FlavImmunity/ANR‐17‐CE15‐0031‐01 to GB‐S, by the Deutsche Forschungsgemeinschaft (SFB 1054 Teilprojekt A06) to ABK, by the Deutsche Forschungsgemeinschaft Grant Number 391217598 and SFB/TR‐237‐Teilprojekt B14 Grant Number 404450088 to SR and ABK, by the FöFoLe Program of the Medical Faculty of the LMU Munich to MS and LL, and by the Metiphys fellowship of the Medical Faculty of the LMU Munich to MP., The authors thank the NIH Tetramer Core Facility for providing tetramers, the BMC Core Facility Flow Cytometry of LMU Munich for providing equipment, and Natalie Röder, Nicole Lichter and Christine Hörth for technical assistance. The authors also thank Arne Kroidl, Günter Fröschl and Kristina Huber for serving as clinical study investigators., ANR-17-CE15-0031,FLAVIMMUNITY,Comprendre les mécanismes de l'efficacité du vaccin de la fièvre jaune 17D: Une approche immuno-structurelle vers la conception d'un vaccin Pan-flavivirus(2017), German Research Center for Environmental Health - Helmholtz Center München (GmbH)-Helmholtz-Zentrum München (HZM), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]
Subjects: lcsh:Immunologic diseases. Allergy, YF‐17D, Neutralising Antibodies, T Follicular Helper (tfh) Cells, Vaccination, Viral Infection, Yellow Fever, Yf-17d, [SDV.IMM]Life Sciences [q-bio]/Immunology, Original Article, T follicular helper (Tfh) cells, Original Articles, viral infection, [SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology, lcsh:RC581-607, vaccination, neutralising antibodies, yellow fever
Abstract: Objectives T follicular helper (Tfh) cells are the principal T helper cell subset that provides help to B cells for potent antibody responses against various pathogens. In this study, we took advantage of the live‐attenuated yellow fever virus (YFV) vaccine strain, YF‐17D, as a model system for studying human antiviral immune responses in vivo following exposure to an acute primary virus challenge under safe and highly controlled conditions, to comprehensively analyse the dynamics of circulating Tfh (cTfh) cells. Methods We tracked and analysed the response of cTfh and other T and B cell subsets in peripheral blood of healthy volunteers by flow cytometry over the course of 4 weeks after YF‐17D vaccination. Results Using surface staining of cell activation markers to track YFV‐specific T cells, we found increasing cTfh cell frequencies starting at day 3 and peaking around 2 weeks after YF‐17D vaccination. This kinetic was confirmed in a subgroup of donors using MHC multimer staining for four known MHC class II epitopes of YF‐17D. The subset composition of cTfh cells changed dynamically during the course of the immune response and was dominated by the cTfh1‐polarised subpopulation. Importantly, frequencies of cTfh1 cells correlated with the strength of the neutralising antibody response, whereas frequencies of cTfh17 cells were inversely correlated. Conclusion In summary, we describe detailed cTfh kinetics during YF‐17D vaccination. Our results suggest that cTfh expansion and polarisation can serve as a prognostic marker for vaccine success. These insights may be leveraged in the future to improve current vaccine design and strategies., We tracked circulating T follicular helper (cTfh) cells in the blood of healthy individuals who received the yellow fever (YF) vaccine YF‐17D. We found that cTfh1‐polarised cells dominated the cTfh response and that their frequency on day 14 predicted YF virus‐neutralising antibody levels detected on day 28 after vaccination, thus highlighting the prognostic value of cTfh cells for monitoring of vaccine outcomes.
Published: 2020

83. Labyrinthopeptins as virolytic inhibitors of respiratory syncytial virus cell entry

Author: Gesine Hansen, Jean-François Eléouët, Marie Galloux, Hans Prochnow, Sebastian Blockus, Mark Brönstrup, Thomas Pietschmann, Theresa Graalmann, Sibylle Haid, Zeljka Rupcic, Martin Wetzke, Marina Pils, Ronald Dijkman, Ronan Le Goffic, Bettina Wiegmann, Katharina Rox, Stephan Hüttel, Svenja M. Sake, W. Paul Duprex, Volker Thiel, Marie-Anne Rameix-Welti, Christina Grethe, TWINCORE, Zentrum für experimentelle und klinische Infektionsforschung GmbH,Feodor-Lynen Str. 7, 30625 Hannover, Germany., Centre for Experimental and Clinical Infection Research (TWINCORE), Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), Institute for Experimental Virology [Hanovre, Allemagne], Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH)-Helmholtz Centre for Infection Research (HZI)-Medizinische Hochschule Hannover (MHH), Hannover Medical School [Hannover] (MHH), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Institute for Experimental Infection Research, Centre for Experimental and Clinical Infection Research [Hanover] (TWINCORE), Helmholtz Centre for Infection Research (HZI), Virologie et Immunologie Moléculaires (VIM (UR 0892)), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Department of Chemical Biology, German Research Centre for Biotechnology, Institute of Virology and Immunology [Mittelhäusern] (IVI), University of Bern, Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), National Emerging Infectious Diseases Laboratories (NEIDL), Boston University [Boston] (BU), Supported by the Innovation Fonds of the Helmholtz Association, by the Pre-4D-Fonds of the Helmholtz Centre for Infection Research, and by the Helmholtz-Alberta Initiative for Infectious Disease Research (HAI-IDR), Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany's Excellence Strategy – EXC 2155 'RESIST' – Project ID 39087428., Clinical leave scholarship from the German Centre for Infection Research (DZIF), Scholarship from the Young Academy of Hannover Medical School, and Swiss National Science Foundation (grants 310030_179260 and 310030_173085)
Subjects: 0301 basic medicine, [SDV]Life Sciences [q-bio], 030106 microbiology, Cell, 610 Medicine & health, Respiratory Syncytial Virus Infections, Antiviral Agents, Virus, Virolytic, Cell Line, Labyrinthopeptin, Lanthipeptide, 03 medical and health sciences, Virus entry, Mice, Therapeutic index, Bacteriocins, In vivo, Viral entry, Virology, medicine, Animals, Humans, Antiviral activity, Lung, Cells, Cultured, Pharmacology, Mice, Inbred BALB C, Respiratory tract infections, 630 Agriculture, business.industry, Viral membrane, Virus Internalization, 3. Good health, Human respiratory syncytial virus (hRSV), 030104 developmental biology, medicine.anatomical_structure, Respiratory Syncytial Virus, Human, 570 Life sciences, biology, Female, business, Ex vivo
Abstract: International audience; Acute lower respiratory tract infections (ALRI) caused by respiratory syncytial virus (RSV) are associated with a severe disease burden among infants and elderly patients. Treatment options are limited. While numerous drug candidates with different viral targets are under development, the utility of RSV entry inhibitors is challenged by a low resistance barrier and by single mutations causing cross-resistance against a wide spectrum of fusion inhibitor chemotypes. We developed a cell-based screening assay for discovery of compounds inhibiting infection with primary RSV isolates. Using this system, we identified labyrinthopeptin A1 and A2 (Laby A1/A2), lantibiotics isolated from Actinomadura namibiensis, as effective RSV cell entry inhibitors with IC50s of 0.39 μM and 4.97 μM, respectively, and with favourable therapeutic index (>200 and > 20, respectively). Both molecules were active against multiple RSV strains including primary isolates and their antiviral activity against RSV was confirmed in primary human airway cells ex vivo and a murine model in vivo. Laby A1/A2 were antiviral in prophylactic and therapeutic treatment regimens and displayed synergistic activity when applied in combination with each other. Mechanistic studies showed that Laby A1/A2 exert virolytic activity likely by binding to phosphatidylethanolamine moieties within the viral membrane and by disrupting virus particle membrane integrity. Probably due to its specific mode of action, Laby A1/A2 antiviral activity was not affected by common resistance mutations to known RSV entry inhibitors. Taken together, Laby A1/A2 represent promising candidates for development as RSV inhibitors. Moreover, the cell-based screening system with primary RSV isolates described here should be useful to identify further antiviral agents.
Published: 2020

84. Antibiotic resistance prediction for Mycobacterium tuberculosis from genome sequence data with Mykrobe

Author: Jennifer L. Gardy, Phillip Fowler, Simon Heys, Kerri M. Malone, Vanessa Mathys, Phelim Bradley, Penelope Wintringer, Timothy M Walker, Simon Grandjean Lapierre, Martin Hunt, Iñaki Comas, Dick van Soolingen, Vitali Sintchenko, Thomas Kohl, Sabira Tahseen, Zamin Iqbal, Grace Smith, Mark Thomsit, Shaheed V. Omar, Derrick W. Crook, Tim E. A. Peto, Philip Supply, Daniela Maria Cirillo, Maha R. Farhat, Stefan Niemann, Matthias Merker, Nazir Ahmed Ismail, Mark H. Wilcox, Michael B Hall, Irena Arandjelovic, European Bioinformatics Institute [Hinxton] (EMBL-EBI), EMBL Heidelberg, University of Oxford [Oxford], Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal (UdeM), Oxford University Clinical Research Unit [Ho Chi Minh City] (OUCRU), IRCCS Ospedale San Raffaele [Milan, Italy], Instituto de biomedicina [Valencia] (IBV), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Fundación para el Fomento de la Investigación Sanitaria y Biomédica de la Comunitat Valenciana [Espagne] (FISABIO), CIBER de Epidemiología y Salud Pública (CIBERESP), Harvard Medical School [Boston] (HMS), British Columbia Centre for Disease Control [Vancouver] (BCCDC), Bill & Melinda Gates Foundation [Seattle], National Institute for Communicable Diseases [Johannesburg] (NICD), Forschungszentrum Borstel - Research Center Borstel, Maladies bactériennes = Bacterial diseases [Bruxelles], Sciensano [Bruxelles], Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), The University of Sydney, Public Health England - Midlands and east of England regional office [Birmimgham], Public Health England [London], National Institute for Public Health and the Environment [Bilthoven] (RIVM), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, National TB control Program [Islamabad, Pakistan], Leeds Teaching Hospitals NHS Trust, University of Leeds, University of Belgrade [Belgrade], ZI was funded by a Wellcome Trust/Royal Society Sir Henry Dale Fellowship, grant number 102541. MH was supported by Wellcome Trust/Newton Fund-MRC Collaborative Award [200205], and Bill & Melinda Gates Foundation Trust [OPP1133541]. TMW is a Wellcome Trust Clinical Career Development Fellow, grant number 214560., Royal Society (UK), Newton Fund, Bill & Melinda Gates Foundation, University of Oxford, Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Nanopore, Tuberculosis, antibiotic treatment Reviewer Status, [SDV]Life Sciences [q-bio], 030106 microbiology, Medicine (miscellaneous), diagnostic, Context (language use), Computational biology, Drug resistance, Biology, Antimicrobial resistance, General Biochemistry, Genetics and Molecular Biology, Mycobacterium tuberculosis, 03 medical and health sciences, medicine, Diagnostic, nanopore, Ethambutol, whole genome sequencing, Software Tool Article, Articles, Pyrazinamide, biology.organism_classification, medicine.disease, Antibiotic treatment, 3. Good health, 030104 developmental biology, tuberculosis, Whole genome sequencing, Nanopore sequencing, Rifampicin, medicine.drug
Abstract: 32 páginas, 7figuras, 9 tablas. This project contains European Nucleotide Archive accession numbers for Illumina sequence data and associated metatdata, Two billion people are infected with Mycobacterium tuberculosis, leading to 10 million new cases of active tuberculosis and 1.5 million deaths annually. Universal access to drug susceptibility testing (DST) has become a World Health Organization priority. We previously developed a software tool, Mykrobe predictor, which provided offline species identification and drug resistance predictions for M. tuberculosis from whole genome sequencing (WGS) data. Performance was insufficient to support the use of WGS as an alternative to conventional phenotype-based DST, due to mutation catalogue limitations. Here we present a new tool, Mykrobe, which provides the same functionality based on a new software implementation. Improvements include i) an updated mutation catalogue giving greater sensitivity to detect pyrazinamide resistance, ii) support for user-defined resistance catalogues, iii) improved identification of non-tuberculous mycobacterial species, and iv) an updated statistical model for Oxford Nanopore Technologies sequencing data. Mykrobe is released under MIT license at https://github.com/mykrobe-tools/mykrobe. We incorporate mutation catalogues from the CRyPTIC consortium et al. (2018) and from Walker et al. (2015), and make improvements based on performance on an initial set of 3206 and an independent set of 5845 M. tuberculosis Illumina sequences. To give estimates of error rates, we use a prospectively collected dataset of 4362 M. tuberculosis isolates. Using culture based DST as the reference, we estimate Mykrobe to be 100%, 95%, 82%, 99% sensitive and 99%, 100%, 99%, 99% specific for rifampicin, isoniazid, pyrazinamide and ethambutol resistance prediction respectively. We benchmark against four other tools on 10207 (=5845+4362) samples, and also show that Mykrobe gives concordant results with nanopore data. We measure the ability of Mykrobe-based DST to guide personalized therapeutic regimen design in the context of complex drug susceptibility profiles, showing 94% concordance of implied regimen with that driven by phenotypic DST, higher than all other benchmarked tools., ZI was funded by a Wellcome Trust/Royal Society Sir Henry Dale Fellowship, grant number 102541. MH was supported by Wellcome Trust/Newton Fund-MRC Collaborative Award [200205]; and Bill & Melinda Gates Foundation Trust [OPP1133541]. TMW is a Wellcome Trust Clinical Career Development Fellow, grant number 214560. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Published: 2020

85. Human microbial metabolite mimicry as a strategy to expand the chemical space of potential drugs

Author: Zdeněk Dvořák, Harmit S. Ranhotra, Harry Sokol, Sridhar Mani, Rolf Müller, Hao Li, Albert Einstein College of Medicine [New York], Palacky University Olomouc, Service de Gastroentérologie et nutrition [CHU Saint-Antoine], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), MICrobiologie de l'ALImentation au Service de la Santé (MICALIS), AgroParisTech-Université Paris-Saclay-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), and HIRI, Helmholtz-Institut für RNA-basierte Infektionsforschung, Josef-Shneider Strasse 2, 97080 Würzburg, Germany.
Subjects: 0301 basic medicine, Drug, media_common.quotation_subject, Metabolite, [SDV]Life Sciences [q-bio], Computational biology, Biology, Inflammatory bowel disease, Article, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Drug Discovery, medicine, Animals, Humans, Microbial metabolite, ComputingMilieux_MISCELLANEOUS, media_common, Pharmacology, Drug discovery, Extramural, Microbiota, Molecular Mimicry, medicine.disease, Chemical space, 3. Good health, 030104 developmental biology, chemistry, 030220 oncology & carcinogenesis, Mimicry
Abstract: The concept of small-molecule mimicry even of weak microbial metabolites present in rodents and humans, as a means to expand drug repertoires, is new. Hitherto, there are few proof-of-concept papers demonstrating utility of this concept. More recently, papers demonstrating mimicry of intestinal microbial metabolites could expand the drug repertoire for diseases such as inflammatory bowel disease (IBD). We opine that, as more functional metabolite-receptor pairings are discovered, small-molecule metabolite mimicry could be a significant effort in drug discovery.
Published: 2020

86. Prediction of Esophageal Varices by Liver Stiffness and Platelets in Persons with HIV infection and Compensated Advanced Chronic Liver Disease

Author: Merchante, Nicolás, Saroli Palumbo, Chiara, Mazzola, Giovanni, Pineda, Juan A., Téllez, Francisco, Rivero-Juárez, Antonio, Ríos-Villegas, María José, Maurice, James B., Westbrook, Rachel H., Judge, Rebekah, Guaraldi, Giovanni, Schepis, Filippo, Perazzo, Hugo, Rockstroh, Juergen, Boesecke, Christoph, Klein, Marina B., Cervo, Adriana, Ghali, Peter, Wong, Philip, Petta, Salvatore, Ledinghen, Victor de, Macias, Juan, Sebastiani, Giada, McGill University, Fonds de la Recherche en Sante du Québec, German Center for Infection Research, Junta de Andalucía, Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades (España), Red Española de Investigación en SIDA, European Commission, Merchante, Nicola, Saroli Palumbo, Chiara, Mazzola, Giovanni, Pineda, Juan A, Téllez, Francisco, Rivero-Juárez, Antonio, Ríos-Villegas, Maria José, Maurice, James B, Westbrook, Rachel H, Judge, Rebekah, Guaraldi, Giovanni, Schepis, Filippo, Perazzo, Hugo, Rockstroh, Juergen, Boesecke, Christoph, Klein, Marina B, Cervo, Adriana, Ghali, Peter, Wong, Philip, Petta, Salvatore, De Ledinghen, Victor, Macías, Juan, and Sebastiani, Giada
Subjects: Variceal bleeding, Transient elastography, Baveno VI criteria, HCV coinfection, esophagogastroduodenoscopy, transient elastography, variceal bleeding, Esophagogastroduodenoscopy
Abstract: In Press., [Background] People living with human immunodeficiency virus (PLWH) are at increased risk of cirrhosis and esophageal varices. Baveno VI criteria, based on liver stiffness measurement (LSM) and platelet count, have been proposed to avoid unnecessary esophagogastroduodenoscopy (EGD) screening for esophageal varices needing treatment (EVNT). This approach has not been validated in PLWH. [Methods] PLWH from 8 prospective cohorts were included if they fulfilled the following criteria: (1) compensated advanced chronic liver disease (LSM >10 kPa); (2) availability of EGD within 6 months of reliable LSM. Baveno VI (LSM 150 000/μL), expanded Baveno VI (LSM 110 000/μL), and Estudio de las Hepatitis Víricas (HEPAVIR) criteria (LSM 110 000/μL and LSM, ViiV and Merck provided a grant to establish the diagnostic center for hepatic fibrosis and steatosis at McGill University Health Centre, which is in use for the LIVEr disease in HIV Cohort. G. S. is supported by a Junior 1 and 2 Salary Award from Fonds de Recherche Santé du Québec (award numbers 27127 and 267806) and research salary from the Department of Medicine of McGill University. C. B. received funding from Dt. Leberstiftung, German Center for Infection Research (DZIF), Hector Stiftung, The European treatment network for HIV, hepatitis and global infectious diseases. This study was supported by the Consejería de Salud de la Junta de Andalucía (grant number PI-0014/2014); the Servicio Andaluz de Salud (grant number SAS/111239); the Fondo de Investigaciones Sanitarias ISCIII (grant number PI13/01621); and Project PI16/01443, funded by Instituto de Salud Carlos III, integrated in the national I + D+i 2013–2016 and co-funded by the European Union (European Regional Development Fund/European Social Fund, “Investing in your future”). A. R.-J. is the recipient of a Miguel Servet Research Contract by the Ministerio de Ciencia, Promoción y Universidades of Spain (grant number CP18/00111). J. A. P. is the recipient of an intensification grant from the Instituto de Salud Carlos III (grant number Programa-I3SNS). This work has been partially funded by the Spanish AIDS Research Network RD16/0025/0010 as part of the Plan Nacional R + D + + I and cofinanced by the Instituto de Salud Carlos III Subdirección General de Evaluación y el Fondo Europeo de Desarrollo Regional.
Published: 2020

87. A standardized gnotobiotic mouse model harboring a minimal 15-member mouse gut microbiota recapitulates SOPF/SPF phenotypes

Author: Jennifer Yansouni, Filipe De Vadder, Martin Schwarzer, Dagmar Šrůtková, Ana Delgado, Alban Mathieu, Anne-Laure Bulteau, François Leulier, Andrei Bunescu, Céline Elie, Severine Planel, Bärbel Stecher, Lilia Boucinha, Djomangan Adama Ouattara, Céline Couturier, Andrea Tamellini, Tereza Novotná, Marion Darnaud, Adrien Saliou, Pascaline Bogeat, Helene Dugua, Institut de Génomique Fonctionnelle de Lyon (IGFL), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), BIOASTER Microbiology Technology Institute [Lyon], Institut de Génomique Fonctionnelle (IGF), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institute of Microbiology of the Czech Academy of Sciences [Prague, Czech Republic] (MBU / CAS), Czech Academy of Sciences [Prague] (CAS), Ludwig-Maximilians University [Munich] (LMU), German Center for Infection Research, Partnersite Munich (DZIF), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), and Leulier, François
Subjects: Male, Physiology, Science, [SDV]Life Sciences [q-bio], General Physics and Astronomy, Computational biology, Gut flora, digestive system, General Biochemistry, Genetics and Molecular Biology, Article, Feces, 03 medical and health sciences, 0302 clinical medicine, Species Specificity, [SDV.BA.ZV]Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, Animals, Germ-Free Life, [SDV.MP] Life Sciences [q-bio]/Microbiology and Parasitology, 030304 developmental biology, Genetics, 2. Zero hunger, 0303 health sciences, Multidisciplinary, Bacteria, Whole Genome Sequencing, biology, 030302 biochemistry & molecular biology, Body Weight, Laboratory mouse, Robustness (evolution), General Chemistry, Fecal microbiota, biology.organism_classification, Confounding effect, Phenotype, Gut microbiome, Gastrointestinal Microbiome, Specific Pathogen-Free Organisms, Mice, Inbred C57BL, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Metagenomics, [SDV.BA.ZV] Life Sciences [q-bio]/Animal biology/Vertebrate Zoology, Female, Microbiome, 030217 neurology & neurosurgery, Microbiota composition
Abstract: Mus musculus is the classic mammalian model for biomedical research. Despite global efforts to standardize breeding and experimental procedures, the undefined composition and interindividual diversity of the microbiota of laboratory mice remains a limitation. In an attempt to standardize the gut microbiome in preclinical mouse studies, here we report the development of a simplified mouse microbiota composed of 15 strains from 7 of the 20 most prevalent bacterial families representative of the fecal microbiota of C57BL/6J Specific (and Opportunistic) Pathogen-Free (SPF/SOPF) animals and the derivation of a standardized gnotobiotic mouse model called GM15. GM15 recapitulates extensively the functionalities found in the C57BL/6J SOPF microbiota metagenome, and GM15 animals are phenotypically similar to SOPF or SPF animals in two different facilities. They are also less sensitive to the deleterious effects of post-weaning malnutrition. In this work, we show that the GM15 model provides increased reproducibility and robustness of preclinical studies by limiting the confounding effect of fluctuation in microbiota composition, and offers opportunities for research focused on how the microbiota shapes host physiology in health and disease., Here, the authors develop and characterize a mouse microbiota composed of 15 strains representative of the intestinal microbiota found in C57BL/6J specific opportunistic- and pathogen-free (C57Bl/6J SOPF) mice and derive a new standardized gnotobiotic mouse model, called GM15, which recapitulates the phenotypes of SOPF or SPF animals in different animal facilities with improved reproducibility.
Published: 2019

88. Regulation of the Ebola Virus VP24 Protein by SUMO

Author: Santiago Vidal, Dolores Rodríguez, César Muñoz-Fontela, María Teresa Rejas, Carmen San Martín, Rosa Barrio, Viktorija Preitakaite, Maite Baz-Martínez, James D. Sutherland, Sergio Gómez-Medina, Rocío Seoane, Yanis Hichem Bouzaher, Ahmed El Motiam, Carmen Rivas, Manuel S. Rodriguez, Ministerio de Economía y Competitividad (España), Xunta de Galicia, German Center for Infection Research, European Commission, CIMUS Biomedical Research Institute [Santiago de Compostela], Functional Genomics, CIC Biogune, Environmental Engineering Research Centre, Universidad de los Andes [Bogota] (UNIANDES), Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, and Molecular and Cellular Biology
Subjects: Models, Molecular, Protein Conformation, [SDV]Life Sciences [q-bio], viruses, medicine.disease_cause, Deubiquitinating enzyme, Ubiquitin-Specific Peptidase 7, Ebola virus, Ubiquitin, Interferon, Chlorocebus aethiops, Monoubiquitination, 0303 health sciences, biology, SUMO, USP7, VP24, ubiquitin, 030302 biochemistry & molecular biology, Ebolavirus, Virus-Cell Interactions, 3. Good health, Cell biology, Protein Transport, STAT1 Transcription Factor, Host-Pathogen Interactions, Interferon Type I, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Protein Binding, Signal Transduction, medicine.drug, alpha Karyopherins, Viral protein, SUMO-1 Protein, Immunology, Microbiology, Virus, Viral Proteins, 03 medical and health sciences, VP40, Protein Domains, Virology, medicine, Animals, Humans, Vero Cells, 030304 developmental biology, Binding Sites, Sumoylation, Immunity, Innate, HEK293 Cells, Gene Expression Regulation, Insect Science, Mutation, biology.protein, HeLa Cells
Abstract: Some viruses take advantage of conjugation of ubiquitin or ubiquitin-like proteins to enhance their own replication. One example is Ebola virus, which has evolved strategies to utilize these modification pathways to regulate the viral proteins VP40 and VP35 and to counteract the host defenses. Here, we show a novel mechanism by which Ebola virus exploits the ubiquitin and SUMO pathways. Our data reveal that minor matrix protein VP24 of Ebola virus is a bona fide SUMO target. Analysis of a SUMOylation-defective VP24 mutant revealed a reduced ability to block the type I interferon (IFN) pathway and to inhibit IFN-mediated STAT1 nuclear translocation, exhibiting a weaker interaction with karyopherin 5 and significantly diminished stability. Using glutathione S-transferase (GST) pulldown assay, we found that VP24 also interacts with SUMO in a noncovalent manner through a SIM domain. Mutation of the SIM domain in VP24 resulted in a complete inability of the protein to downmodulate the IFN pathway and in the monoubiquitination of the protein. We identified SUMO deubiquitinating enzyme ubiquitin-specific-processing protease 7 (USP7) as an interactor and a negative modulator of VP24 ubiquitination. Finally, we show that mutation of one ubiquitination site in VP24 potentiates the IFN modulatory activity of the viral protein and its ability to block IFN-mediated STAT1 nuclear translocation, pointing to the ubiquitination of VP24 as a negative modulator of the VP24 activity. Altogether, these results indicate that SUMO interacts with VP24 and promotes its USP7-mediated deubiquitination, playing a key role in the interference with the innate immune response mediated by the viral protein.IMPORTANCE The Ebola virus VP24 protein plays a critical role in escape of the virus from the host innate immune response. Therefore, deciphering the molecular mechanisms modulating VP24 activity may be useful to identify potential targets amenable to therapeutics. Here, we identify the cellular proteins USP7, SUMO, and ubiquitin as novel interactors and regulators of VP24. These interactions may represent novel potential targets to design new antivirals with the ability to modulate Ebola virus replication., Funding at the laboratory of C.R. is provided by Ministry of Science, Innovation and Universities and FEDER (BFU-2017-88880-P). C.R. also acknowledges grants GRC GI-2119 (Xunta de Galicia) and SAF2017-90900-REDT (UBIRed Program). S.V. is a predoctoral fellow funded by Xunta de Galicia. M.B.-M. is a postdoctoral fellow funded by Xunta de Galicia (Consellería de Cultura, Educación e Ordenación Universitaria). A.E.M. is the recipient of a fellowship of the Spanish FPI program. This work was partially funded by the German Center for Infection Research (DZIF TTU 01.702_00 to C.M.-F.). R.B. and J.D.S. acknowledge grants BFU2017-84653-P (MINECO/FEDER, EU), SEV-2016-0644 (Severo Ochoa Excellence Program), 765445-EU (UbiCODE Program), and SAF2017- 90900-REDT (UBIRed Program). C.S.M. acknowledges grant BFU2016-74868-P.
Published: 2019

89. Detection of rat hepatitis E virus in wild Norway rats (Rattus norvegicus) and Black rats (Rattus rattus) from 11 European countries

Author: Johannes Lang, Daniel Bajomi, Gerald Heckel, Sebastian Guenther, Chrysostomos I. Dovas, J. Freise, Elisa Heuser, Martin H. Groschup, Rainer G. Ulrich, Samuel Bernstein, Michel Pépin, Sandro Wolf, Stefania Zanet, Kristof Baert, Gabi Müller, Francisco Ruiz-Fons, Hermann Ansorge, Jiri Pikula, Paul Dremsek, Nataša Knap, Ann-Charlotte Heiberg, René Ryll, Maxi Zumpe, Christian Imholt, Ιoannis Tsakmakidis, Mathias Schlegel, Reimar Johne, Carina Spahr, Friedrich-Loeffler-Institut (FLI), Institute for Medical Microbiology and Hygiene, Faculty of Medicine 'Carl Gustav Carus', Technische Universität Dresden = Dresden University of Technology (TU Dresden), Virpath-Grippe, de l'émergence au contrôle -- Virpath-Influenza, from emergence to control (Virpath), Centre International de Recherche en Infectiologie - UMR (CIRI), École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Bábolna Bio Ltd., Stadt Zürich, Umwelt- und Gesundheitsschutz Zürich, AC Heiberg Rådgivning, German Federal Institute for Risk Assessment [Berlin] (BfR), Institut für Medizinische Mikrobiologie - Institute of Medical Microbiology, Justus-Liebig-Universität Gießen (JLU), Senckenberg Museum of Natural History Görlitz, Senckenberg Museum [Frankfurt], Task-Force Veterinärwesen, Institute of Microbiology and Epizootics, INBO, Research Institute for Nature and Forest (INBO), Institut de recherche sur l'environnement (IREC), Ecole Polytechnique Fédérale de Lausanne (EPFL), University of Veterinary and Pharmaceutical Sciences [Brno] (VFU), CEITEC - Central European Institute of Technology [Brno, Czech Republic], Zaloška 4, Aristotle University of Thessaloniki, Università degli studi di Torino (UNITO), Julius Kühn-Institute, Institute of Ecology & Evolution (IEE), University of Bern, Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), German Centre for Infection Research (DZIF), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Justus-Liebig-Universität Gießen = Justus Liebig University (JLU), Senckenberg – Leibniz Institution for Biodiversity and Earth System Research - Senckenberg Gesellschaft für Naturforschung, Leibniz Association-Leibniz Association, Università degli studi di Torino = University of Turin (UNITO), Université de Lausanne = University of Lausanne (UNIL), and German Center for Infection Research
Subjects: Male, 0301 basic medicine, 030106 microbiology, Wild, Zoology, Animals, Wild, Black rat, medicine.disease_cause, Microbiology, Population density, 03 medical and health sciences, Species Specificity, Hepatitis E virus, Environmental protection, Phylogenetics, Genotype, medicine, Animals, Humans, Phylogeny, Population Density, General Veterinary, biology, Phylogenetic tree, General Medicine, Genotype 3, biology.organism_classification, Hepatitis E, medicine.disease, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Hepeviridae, Rats, 3. Good health, Europe, 030104 developmental biology, Norway rat, Animal Distribution, Female, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology
Abstract: Rat hepatitis E virus (HEV) is genetically only distantly related to hepeviruses found in other mammalian reservoirs and in humans. It was initially detected in Norway rats (Rattus norvegicus) from Germany, and subsequently in rats from Vietnam, the USA, Indonesia, China, Denmark and France. Here, we report on a molecular survey of Norway rats and Black rats (Rattus rattus) from 12 European countries for ratHEV and human pathogenic hepeviruses. RatHEV-specific real-time and conventional RT-PCR investigations revealed the presence of ratHEV in 63 of 508 (12.4%) rats at the majority of sites in 11 of 12 countries. In contrast, a real-time RT-PCR specific for human pathogenic HEV genotypes 1–4 and a nested broad-spectrum (NBS) RT-PCR with subsequent sequence determination did not detect any infections with these genotypes. Only in a single Norway rat from Belgium a rabbit HEV-like genotype 3 sequence was detected. Phylogenetic analysis indicated a clustering of all other novel Norway and Black rat-derived sequences with ratHEV sequences from Europe, the USA and a Black rat-derived sequence from Indonesia within the proposed ratHEV genotype 1. No difference in infection status was detected related to age, sex, rat species or density of human settlements and zoological gardens. In conclusion, our investigation shows a broad geographical distribution of ratHEV in Norway and Black rats from Europe and its presence in all settlement types investigated., The investigations in the laboratory of Rainer G. Ulrich were supported by the German Center for Infection Research (DZIF).
Published: 2017

90. Structure-Based Design, Synthesis, and Biological Evaluation of Triazole-Based smHDAC8 Inhibitors

Author: Dmitrii V. Kalinin, Maxim Pfafenrot, Jelena Melesina, Manfred Jung, Raymond J. Pierce, Sunit Kumar Jana, Wolfgang Sippl, Alokta Chakrabarti, Ralph Holl, Julien Lancelot, Tajith B. Shaik, Christophe Romier, Universität Hamburg (UHH), German Centre for Infection Research - partner site Hamburg-Lübeck-Borstel-Riems (DZIF), Westfälische Wilhelms-Universität Münster (WWU), Albert-Ludwigs-Universität Freiburg, Martin-Luther-Universität Halle Wittenberg (MLU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), WS, MJ, and CR received funding from the European Union's Seventh Framework Program for research, technological development and demonstration under grant agreement no. 602080. WS was supported by the European Regional Development Fund of the European Commission. Testing on human subtypes was in part supported by the Deutsche Forschungsgemeinschaft (DFG, MJ: Ju 295/13-1, WS: Si 846/13-1). RJP and JL were supported by institutional funds from the Centre National de la Recherche Scientifique (CNRS), the Institut National de la Santé et de la Recherche Médicale (INSERM), the Institut Pasteur de Lille and the Université de Lille. RH was supported by the German Center for Infection Research (DZIF), DVK by the Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), and SKJ by the NRW International Graduate School of Chemistry, which is gratefully acknowledged., European Project: 602080,EC:FP7:HEALTH,FP7-HEALTH-2013-INNOVATION-1,A-PARADDISE(2014), Westfälische Wilhelms-Universität Münster = University of Münster (WWU), Institut Pasteur de Lille, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS)
Subjects: Models, Molecular, Antiparasitic, medicine.drug_class, triazole derivatives, Triazole, 01 natural sciences, Biochemistry, Histone Deacetylases, chemistry.chemical_compound, crystal structures, [SDV.SP.MED]Life Sciences [q-bio]/Pharmaceutical sciences/Medication, molecular docking studies, Drug Discovery, medicine, Animals, Humans, Schistosomiasis, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, General Pharmacology, Toxicology and Pharmaceutics, Vorinostat, Schistosoma, Pharmacology, biology, [SDV.BBM.BS]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Structural Biology [q-bio.BM], Molecular Structure, Full Paper, 010405 organic chemistry, Organic Chemistry, Active site, HDAC8, Schistosoma mansoni, Triazoles, Full Papers, biology.organism_classification, Small molecule, 3. Good health, 0104 chemical sciences, Histone Deacetylase Inhibitors, Repressor Proteins, 010404 medicinal & biomolecular chemistry, chemistry, Drug Design, biology.protein, Molecular Medicine, medicine.drug
Abstract: Schistosomiasis is a neglected tropical disease caused by parasitic flatworms of the genus Schistosoma, which affects over 200 million people worldwide and leads to at least 300,000 deaths every year. In this study, initial screening revealed the triazole‐based hydroxamate 2 b (N‐hydroxy‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxamide) exhibiting potent inhibitory activity toward the novel antiparasitic target Schistosoma mansoni histone deacetylase 8 (smHDAC8) and promising selectivity over the major human HDACs. Subsequent crystallographic studies of the 2 b/smHDAC8 complex revealed key interactions between the inhibitor and the enzyme's active site, thus explaining the unique selectivity profile of the inhibitor. Further chemical modifications of 2 b led to the discovery of 4‐fluorophenoxy derivative 21 (1‐[5‐chloro‐2‐(4‐fluorophenoxy)phenyl]‐N‐hydroxy‐1H‐1,2,3‐triazole‐4‐carboxamide), a nanomolar smHDAC8 inhibitor (IC50=0.5 μM), exceeding the smHDAC8 inhibitory activity of 2 b and SAHA (vorinostat), while exhibiting an improved selectivity profile over the investigated human HDACs. Collectively, this study reveals specific interactions between smHDAC8 and the synthesized triazole‐based inhibitors and demonstrates that these small molecules represent promising lead structures, which could be further developed in the search for novel drugs for the treatment of schistosomiasis., Triazole‐based smHDAC8 inhibitors exhibiting an improved selectivity profile over human HDACs were synthesized, evaluated in in vitro inhibition assays, and tested for their effects on the viability of Schistosoma mansoni larvae. Crystallographic as well as molecular docking studies revealed key interactions between smHDAC8 and the developed triazole derivatives, thus explaining their unique selectivity profile.
Published: 2019

91. The use of genomic DNA sequences as type material for valid publication of bacterial species names will have severe implications for clinical microbiology and related disciplines

Author: Magne Bisgaard, J. Michael Janda, Niels Nørskov-Lauritsen, Henrik Christensen, Alexandr Nemec, Dominique Clermont, Frans A. G. Reubsaet, Jörg Overmann, Edward R. B. Moore, Lenie Dijkshoorn, Bisgaard Consulting, Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU), Collection de l'Institut Pasteur (CIP), Institut Pasteur [Paris], Leiden University Medical Center (LUMC), Kern County Public Health Laboratory [Bakersfield], University of Gothenburg (GU), Laboratory of Bacterial Genetics, National Institute of Public Health, Department of Clinical Microbiology, Aarhus University Hospital, Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH / Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures (DSMZ), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Braunschweig University of Technology, National Institute of Public Health and the Environment (NIPHE), University of Copenhagen = Københavns Universitet (UCPH), Institut Pasteur [Paris] (IP), and Universiteit Leiden
Subjects: DNA, Bacterial, Microbiology (medical), MESH: Terminology as Topic, MESH: Bacterial Infections, [SDV]Life Sciences [q-bio], Computational biology, Biology, MESH: Genome, Bacterial, 03 medical and health sciences, Type (biology), Terminology as Topic, MESH: Publishing, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, Publishing, 0303 health sciences, Bacteria, 030306 microbiology, Bacterial Infections, General Medicine, MESH: DNA, Bacterial, 3. Good health, genomic DNA, Clinical microbiology, MESH: Bacteria, Infectious Diseases, [SDE]Environmental Sciences, Genome, Bacterial
Abstract: International audience
Published: 2019

92. Comparative Loss-of-Function Screens Reveal ABCE1 as an Essential Cellular Host Factor for Efficient Translation of Paramyxoviridae and Pneumoviridae

Author: Kristmundur Sigmundsson, Danielle E. Anderson, So Young Kim, Zhen Zhen Joanna Yeo, Sharon F. Jamison, Kristin Pfeffermann, James L. Pearson, Bevan Sawatsky, Mikhail Kovtun, Lin-Fa Wang, Pierre J. Talbot, Veronika von Messling, Mariano A. Garcia-Blanco, Yvonne Krebs, David L. Corcoran, Linda J. Rennick, W. Paul Duprex, Duke-NUS Medical School [Singapore], Paul-Ehrlich-Institute - Federal Institute for Vaccines and Biomedicines (EPI), Duke University [Durham], National Emerging Infectious Diseases Laboratories (NEIDL), Boston University [Boston] (BU), Institut Armand Frappier (INRS-IAF), Institut National de la Recherche Scientifique [Québec] (INRS)-Réseau International des Instituts Pasteur (RIIP), The University of Texas Medical Branch (UTMB), This work was supported by grants CIHR MOP-66989 of the Canadian Institutes of Health Research, CFI 9488 Canada Foundation for Innovation, DZIF TTU Emerging Infections SFB1021 of the German Center for Infection Research, and intramural funding of the German Ministry of Health to V.V.M., NMRC/BNIG/2030/2015 (Singapore) to D.E.A., and USA NIH R01-AI089526 and R01-AI101431 to M.A.G.-B. and R01-AI099100 to W.P.D., and We thank members of our laboratories, past and present, for constructive comments throughout this project. We thank the Duke Functional Genomics Shared Resource for work related to the primary siRNA screens. We are grateful to Jaisri Lingappa for sharing the ABCE1 antibody and peptide sequence during our preliminary studies. We thank Ian Mendenhall for his assistance in the construction of the phylogenetic tree and Kevin Wittwer and Oliver Siering for technical assistance. We greatly appreciate the help provided by Robert Tampé, Ralph Wieneke, and Simon Trowitzsch with the phosphorimager and Andrea Maisner and Marc Ringel with the confocal microscope. We thank Stephan Becker for critical comments on the manuscript.
Subjects: MESH: Gene Expression, Paramyxoviridae, ABCE1, respiratory syncytial virus, [SDV]Life Sciences [q-bio], host factor, MESH: Pneumovirus/pathogenicity, RNA-binding protein, Computational biology, Microbiology, 03 medical and health sciences, Virology, MESH: RNA, Small Interfering, MESH: RNA-Binding Proteins/genetics, MESH: ATP-Binding Cassette Transporters/genetics, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, Pneumoviridae, RNAi screen, MESH: RNA, Messenger, 030304 developmental biology, Host factor, 0303 health sciences, MESH: Humans, biology, MESH: Paramyxoviridae/pathogenicity, 030302 biochemistry & molecular biology, Translation (biology), Pneumovirus, biology.organism_classification, QR1-502, MESH: Host Microbial Interactions/genetics, 3. Good health, Vesicular transport protein, biology.protein, MESH: A549 Cells, MESH: Computational Biology
Abstract: International audience; Paramyxoviruses and pneumoviruses have similar life cycles and share the respiratory tract as a point of entry. In comparative genome-scale siRNA screens with wild-type-derived measles, mumps, and respiratory syncytial viruses in A549 cells, a human lung adenocarcinoma cell line, we identified vesicular transport, RNA processing pathways, and translation as the top pathways required by all three viruses. As the top hit in the translation pathway, ABCE1, a member of the ATP-binding cassette transporters, was chosen for further study. We found that ABCE1 supports replication of all three viruses, confirming its importance for viruses of both families. More detailed characterization revealed that ABCE1 is specifically required for efficient viral but not general cellular protein synthesis, indicating that paramyxoviral and pneumoviral mRNAs exploit specific translation mechanisms. In addition to providing a novel overview of cellular proteins and pathways that impact these important pathogens, this study highlights the role of ABCE1 as a host factor required for efficient paramyxovirus and pneumovirus translation.IMPORTANCE The Paramyxoviridae and Pneumoviridae families include important human and animal pathogens. To identify common host factors, we performed genome-scale siRNA screens with wild-type-derived measles, mumps, and respiratory syncytial viruses in the same cell line. A comparative bioinformatics analysis yielded different members of the coatomer complex I, translation factors ABCE1 and eIF3A, and several RNA binding proteins as cellular proteins with proviral activity for all three viruses. A more detailed characterization of ABCE1 revealed its essential role for viral protein synthesis. Taken together, these data sets provide new insight into the interactions between paramyxoviruses and pneumoviruses and host cell proteins and constitute a starting point for the development of broadly effective antivirals.
Published: 2019

93. Revised interpretation of the Hain Lifescience GenoType MTBC to differentiate $Mycobacterium\ canettii$ and members of the $Mycobacterium\ tuberculosis$ Complex

Author: Stefan Niemann, Sebastien Gagneux, Chloé Loiseau, Claudio U. Köser, Silke Feuerriegel, Christine Pourcel, Suelee Robbe-Austerman, Irmgard Moser, Vincent E. Escuyer, Thomas Kohl, Kimberlee A. Musser, Daniela Brites, Sharon J. Peacock, Francesc Coll, Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), Friedrich-Loeffler-Institut (FLI), Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine (LSHTM), Institut de Biologie Intégrative de la Cellule (I2BC), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), United States Department of Agriculture (USDA), Wadsworth Center, New York State Department of Health [Albany], University of Cambridge [UK] (CAM), German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), and Department of Genetics [Cambridge]
Subjects: Tuberculosis, pyrazinamide, intrinsic antibiotic resistance, [SDV]Life Sciences [q-bio], Mycobacterium tuberculosis, 03 medical and health sciences, Genotype, medicine, Pharmacology (medical), Genotyping, 030304 developmental biology, Pharmacology, Genetics, 0303 health sciences, Mycobacterium bovis, biology, 030306 microbiology, orygis, assay, medicine.disease, biology.organism_classification, 3. Good health, Infectious Diseases, Mycobacterium tuberculosis complex, genotyping, polymorphisms, Mycobacterium africanum, Mycobacterium
Abstract: Using 894 phylogenetically diverse genomes of the Mycobacterium tuberculosis complex (MTBC), we simulated in silico the ability of the Hain Lifescience GenoType MTBC assay to differentiate the causative agents of tuberculosis. Here, we propose a revised interpretation of this assay to reflect its strengths (e.g., it can distinguish some strains of Mycobacterium canettii and variants of Mycobacterium bovis that are not intrinsically resistant to pyrazinamide) and limitations (e.g., Mycobacterium orygis cannot be differentiated from Mycobacterium africanum ).
Published: 2019

94. Burden and Characteristics of the Comorbidity Tuberculosis-Diabetes in Europe: TBnet Prevalence Survey and Case-Control Study

Author: Simon Tiberi, Lorenzo Guglielmetti, Pier Francesco Giorgetti, Emanuele Pontali, Jaime Esteban, Monica Rios Prego, Christoph Lange, Gina Gualano, Zorica Nanovic, Anne Margarita Dyrhol-Riise, Jalal Miah, Fabrizio Palmieri, Andrii Dudnyk, Berit Lange, Enrico Girardi, Ivan Solovic, Katerina Manika, Jan Heyckendorf, M. Nieves Altet Gomez, Assunta Navarra, Monica Sañé Schepisi, Anna Kaluzhenina, Istituto Nazionale di Malattie Infettive 'Lazzaro Spallanzani' (INMI), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Oslo University Hospital [Oslo], University of Oslo (UiO), Azienda Socio Sanitaria Territoriale Spedali Civili di Brescia [Brescia], Università degli Studi di Brescia [Brescia], Centre National de Référence des Mycobactéries et de la Résistance aux Antituberculeux [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre d'Immunologie et de Maladies Infectieuses (CIMI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), University of Freiburg [Freiburg], Aristotle University of Thessaloniki, Barts Health NHS Trust [London, UK], Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), UAM. Departamento de Medicina Preventiva y Salud Pública y Microbiología, and Instituto de Investigación Sanitaria Fundación Jiménez Díaz (IIS-FJD)
Subjects: 0301 basic medicine, Pediatrics, medicine.medical_specialty, Tuberculosis, Referral, Medicina, 030106 microbiology, TB-DM patients, Major Articles, 03 medical and health sciences, 0302 clinical medicine, Foreign born, Diabetes mellitus, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Foreign-born, Burden diabetes mellitus, Medicine, Case-control analysis, 030212 general & internal medicine, business.industry, Prevalence of DM, Case-control study, Prevalence survey, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, medicine.disease, Comorbidity, 3. Good health, Europe, Infectious Diseases, Oncology, tuberculosis, diabetes mellitus, CHUP, foreign-born, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract: Background. The growing burden of diabetes mellitus (DM) is posing a threat to global tuberculosis (TB) control. DM triples the risk of developing TB, modifies the presenting features of pulmonary TB, and worsens TB treatment outcomes. We aimed to analyze the prevalence of DM among TB patients and to describe the characteristics and clinical presentation of TB-DM patients in Europe. Methods. We performed a cross-sectional survey on the prevalence of DM among consecutively diagnosed adult TB patients in 11 European TB referral centers located in France, Germany, Greece, Italy, Russia, Slovakia, Spain, and the United Kingdom over the period 2007-2015. We also selected DM-TB cases and TB only controls with a 1:3 ratio to perform a case-control analysis, including patients selected from the countries mentioned above plus Norway and Ukraine. Results. Among 3143 TB enrolled patients, DM prevalence overall was 10.7% and ranged from 4.4% in Greece to 28.5% in the United Kingdom. Patients' median ages ranged from 36 to 49 years, and all centers had >60% males; the proportion of foreign-born patients varied widely across sites. In the case-control study, DM was independently associated with older age and, among older patients, with being foreign-born. Among patients with pulmonary involvement, cavities on chest imaging were more frequently observed among those with DM. Conclusions. Diabetes mellitus represents a challenge for TB control in Europe, especially in foreign-born and in elderly patients. Specific screening strategies should be evaluated., This work was supported in part by Fondi 5x1000 and Ricerca Corrente to National Institute for Infectious Diseases L. Spallanzani – Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS).
Published: 2019

95. GloPID-R report on chikungunya, o'nyong-nyong and Mayaro virus, part 3: Epidemiological distribution of Mayaro virus

Author: Pezzi, L., Rodriguez-Morales, A.J., Reusken, C.B., Ribeiro, G.S., Labeaud, A.D., Lourenço-De-Oliveira, R., Brasil, P., Lecuit, M., Failloux, Anna-Bella, Gallian, P., Jaenisch, T., Simon, F., Siqueira, A.M., Rosa-Freitas, M.G., Vega Rua, A., Weaver, S.C., Drexler, J.F., Vasilakis, N., de Lamballerie, Xavier, Boyer, Sébastien, Busch, M., Diallo, M., Diamond, M.S., Drebot, M.A., Kohl, A., Neyts, J., Ng, L.F.P., Rios, M., Sall, A., Simmons, G., Virology, Unité des Virus Emergents (UVE), Institut de Recherche pour le Développement (IRD)-Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Virologie [UNIV Corse-Inserm] (EA7310), Université Pascal Paoli (UPP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universidad Tecnológica de Pereira [Colombie] (UTP), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Universidade Federal da Bahia (UFBA), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, Fundação Oswaldo Cruz (FIOCRUZ), Réseau International des Instituts Pasteur (RIIP), Biologie des Infections - Biology of Infection, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Descartes - Paris 5 (UPD5), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Arbovirus et Insectes Vecteurs - Arboviruses and Insect Vectors, Institut Pasteur [Paris] (IP), Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Heidelberg University Hospital [Heidelberg], Hôpital d'Instruction des Armées Laveran, Service de Santé des Armées, Institut Pasteur de la Guadeloupe, The University of Texas Medical Branch (UTMB), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Humboldt University Of Berlin, Berlin Institute of Health (BIH), Institut Pasteur du Cambodge, University of California [San Francisco] (UC San Francisco), University of California (UC), Institut Pasteur de Dakar, Washington University in Saint Louis (WUSTL), Public Health Agency of Canada, MRC - University of Glasgow Centre for Virus Research, Laboratory of Virology and Chemotherapy [KU Leuven], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven)-Rega Institute of Medical Research [Leuven, Belgium], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Agency for science, technology and research [Singapore] (A*STAR), U.S. Food and Drug Administration (FDA), Publication fees were covered by the Global Research Collaboration for Infectious Disease Preparedness (GloPID-R)., DEMESLAY GOUGAM, MARIE, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Pascal Paoli (UPP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris], Humboldt-Universität zu Berlin, University of California [San Francisco] (UCSF), University of California, and Fundação Oswaldo Cruz / Oswaldo Cruz Foundation (FIOCRUZ)
Subjects: Primates, GloPID-R chikungunya, o'nyong-nyong and Mayaro virus Working Group, 030231 tropical medicine, Alphavirus, Genome, Viral, Mosquito Vectors, Disease Outbreaks, 03 medical and health sciences, 0302 clinical medicine, Seroepidemiologic Studies, Virology, Zoonoses, Animals, Humans, O'nyong-nyong Virus, Serologic Tests, 030212 general & internal medicine, Pathology, Molecular, ComputingMilieux_MISCELLANEOUS, Phylogeny, Disease Reservoirs, Pharmacology, [SDV.MP.VIR] Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Alphavirus Infections, 3. Good health, Caribbean Region, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Chikungunya Fever, Americas, Chikungunya virus
Abstract: ispartof: ANTIVIRAL RESEARCH vol:172 ispartof: location:Netherlands status: published
Published: 2019

96. Whole genome sequencing of Mycobacterium tuberculosis: current standards and open issues

Author: Meehan CJ, Goig GA, Kohl TA, Verboven L, Dippenaar A, Ezewudo M, Farhat MR, Guthrie JL, Laukens K, Miotto P, Ofori-Anyinam B, Dreyer V, Supply P, Suresh A, Utpatel C, van Soolingen D, Zhou Y, Ashton PM, Brites D, Cabibbe AM, de Jong BC, de Vos M, Menardo F, Gagneux S, Gao Q, Heupink TH, Liu Q, Loiseau C, Rigouts L, Rodwell TC, Tagliani E, Walker TM, Warren RM, Zhao Y, Zignol M, Schito M, Gardy J, Cirillo DM, Niemann S, Comas I, Van Rie A, European Research Council, National Institutes of Health (US), University of British Columbia, German Center for Infection Research, German Research Foundation, Research Foundation - Flanders, Comas, Iñaki, and Goig, Galo A.
Abstract: 13 páginas, 4 figuras. Contiene material suplementario., Whole genome sequencing (WGS) of Mycobacterium tuberculosis has rapidly progressed from a research tool to a clinical application for the diagnosis and management of tuberculosis and in public health surveillance. This development has been facilitated by drastic drops in cost, advances in technology and concerted efforts to translate sequencing data into actionable information. There is, however, a risk that, in the absence of a consensus and international standards, the widespread use of WGS technology may result in data and processes that lack harmonization, comparability and validation. In this Review, we outline the current landscape of WGS pipelines and applications, and set out best practices for M. tuberculosis WGS, including standards for bioinformatics pipelines, curated repositories of resistance-causing variants, phylogenetic analyses, quality control and standardized reporting., C.J.M., B.O.-A., L.R. and B.C.d.J. are supported by a European Research Council grant (INTERRUPTB; no. 311725). I.C. and G.A.G. are supported by a European Research Council grant (TB-ACCELERATE; no. 638553). T.C.R. receives salary support from the not-for-profit organization Foundation for Innovative New Diagnostics (the terms of this arrangement have been reviewed and approved by the University of California, San Diego). T.M.W. is an NIHR Academic Clinical Lecturer. J.L.G. and J.G. receive funding from the University of British Columbia, Vancouver, Canada. T.A.K., C.U., V.D. and S.N. receive funding from the German Center for Infection Research (DZIF) and are funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) under Germany’s Excellence Strategy (EXC 22167–390884018). L.V., T.H.H. and A.V.R. are funded by FWO Odysseus G0F8316N. M.R.F. is supported by the US National Institutes of Health BD2K K01 (MRF ES026835). P.S. is supported by the Agence Nationale de la Recherche (ANR-16-CE35-0009).
Published: 2019

97. Immunogenic particles with a broad antigenic spectrum stimulate cytolytic T cells and offer increased protection against EBV infection ex vivo and in mice

Author: Ming Han Tsai, Dwain G. van Zyl, Viktor Schneidt, Henri Jacques Delecluse, Anatoliy Shumilov, Herbert Fluhr, Josef Mautner, B. Schlehe, Remy Poirey, Unit F100 [Heidelberg, Allemagne], German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Faculty of Biosciences [Heidelberg, Allemagne], Heidelberg University, Microbiology and infectious diseases, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ)-Institut National de la Santé et de la Recherche Médicale (INSERM), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Frauenklinik [Heidelberg, Allemagne], Heidelberg University Hospital [Heidelberg], Children's Hospital [Munich, Allemagne], Helmholtz-Zentrum München (HZM)-Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Funding has been received from the German Cancer Research Center (Project number F100), Inserm (Project number U1074) and Deutsche Krebshilfe (70110621)., Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, and Bodescot, Myriam
Subjects: 0301 basic medicine, Epstein-Barr Virus Infections, Herpesvirus 4, Human, B Cells, Physiology, medicine.disease_cause, Biochemistry, Mice, White Blood Cells, 0302 clinical medicine, Spectrum Analysis Techniques, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Immune Physiology, hemic and lymphatic diseases, Virus latency, Medicine and Health Sciences, Cytotoxic T cell, Public and Occupational Health, Biology (General), Antigens, Viral, Pathology and laboratory medicine, Immune System Proteins, T Cells, Medical microbiology, Flow Cytometry, Vaccination and Immunization, 3. Good health, Virus Latency, Lytic cycle, Spectrophotometry, Viruses, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytophotometry, Cellular Types, Pathogens, Research Article, Herpesviruses, [SDV.IMM] Life Sciences [q-bio]/Immunology, QH301-705.5, Immune Cells, Immunology, Cytotoxic T cells, Herpesvirus Vaccines, Biology, Research and Analysis Methods, Microbiology, Virus, Antibodies, 03 medical and health sciences, Immune system, Antigen, Virology, Genetics, medicine, Animals, Epstein-Barr virus, Antigens, Antibody-Producing Cells, Molecular Biology, Blood Cells, Organisms, Viral pathogens, Biology and Life Sciences, Proteins, Cell Biology, RC581-607, medicine.disease, Epstein–Barr virus, Microbial pathogens, 030104 developmental biology, Humanized mouse, Parasitology, Preventive Medicine, Immunologic diseases. Allergy, DNA viruses, 030215 immunology, T-Lymphocytes, Cytotoxic
Abstract: The ubiquitous Epstein-Barr virus (EBV) is the primary cause of infectious mononucleosis and is etiologically linked to the development of several malignancies and autoimmune diseases. EBV has a multifaceted life cycle that comprises virus lytic replication and latency programs. Considering EBV infection holistically, we rationalized that prophylactic EBV vaccines should ideally prime the immune system against lytic and latent proteins. To this end, we generated highly immunogenic particles that contain antigens from both these cycles. In addition to stimulating EBV-specific T cells that recognize lytic or latent proteins, we show that the immunogenic particles enable the ex vivo expansion of cytolytic EBV-specific T cells that efficiently control EBV-infected B cells, preventing their outgrowth. Lastly, we show that immunogenic particles containing the latent protein EBNA1 afford significant protection against wild-type EBV in a humanized mouse model. Vaccines that include antigens which predominate throughout the EBV life cycle are likely to enhance their ability to protect against EBV infection., Author summary Human herpesviruses are tremendously successful pathogens that establish lifelong infection in a substantial proportion of the population. The oncogenic γ-herpesvirus EBV, like other herpesviruses, expresses a plethora of open-reading frames throughout its multifaceted life cycle. We have developed a prophylactic vaccine candidate in the form of immunogenic particles that contain several EBV antigens. This is in stark contrast to the vast majority of EBV vaccines candidates that contain only one or two EBV antigens. Our immunogenic particles were shown capable of stimulating several EBV-specific T-cell clones in vitro. The immunogenic particles were also capable of expanding cytolytic EBV-specific T cells ex vivo and provided a protective benefit in vivo when used as a prophylactic vaccine.
Published: 2018

98. Dynamic Growth and Shrinkage of the Salmonella-Containing Vacuole Determines the Intracellular Pathogen Niche

Author: Quentin Giai Gianetto, Yoann Le Toquin, Virginie Stévenin, Norbert Reiling, Magalie Duchateau, Chak Hon Luk, Audrey Salles, Mariette Matondo, Yuen-Yan Chang, Jost Enninga, Victoria Sohst, Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Spectrométrie de Masse pour la Biologie – Mass Spectrometry for Biology (UTechS MSBio), Institut Pasteur [Paris] (IP)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, BioImagerie Photonique – Photonic BioImaging (UTechS PBI), Institut Pasteur [Paris] (IP), Research group Microbial Interface Biology [Borstel Center, Germany] (RG-MIB), Research Center Borstel - Leibniz Lung Center [Germany], German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), V. Stévenin was supported by a PhD fellowship from the University Paris Diderot allocated by the ENS Paris-Saclay, a grant from the Fondation pour la Recherche Médicale (FRM, FDT20170436843), and an extension grant from the BCI Department of Institut Pasteur. V. Sohst and N.R. were supported by a grant of the Deutsche Forschungsgemeinschaft (DFG) Excellence Cluster 306 'Inflammation at Interfaces' (MTP2). J.E. is a member of the LabEx consortia IBEID and MilieuInterieur. J.E. also acknowledges support from the ANR (grant StopBugEntry and AutoHostPath) and the ERC (CoG EndoSubvert). N.R. is very grateful for funding within the DFG priority program (SPP1580) (NR: Re1228 5-1, Re1228 5-2) and also thanks the German Center for Infection (DZIF) for financial support. UTechS PBI is part of the France–BioImaging infrastructure network (FBI) supported by the Agence Nationale pour la Recherche (ANR-10–INSB–04, Investments for the Future), and acknowledges support from ANR/FBI and the Région Ile-de-France (program 'Domaine d’Intérêt Majeur-Malinf') for the use of the Zeiss LSM 780 Elyra PS1 microscope., The authors acknowledge T. Galli, E. Boucrot, L. Johannes, and F. Garcia-del Portillo for providing tools and scientific feedback. The authors are deeply grateful to Sjaak Neefjes and his group for providing equipment, reagents, and scientific feedback to V. Stévenin during the revision period., ANR-15-CE15-0017,StopBugEntry,Identification des nouvelles molécules cellulaires cibles pour combattre les infections bactériennes(2015), ANR-15-CE15-0018,AutoHostPath,Rôles alternatifs pour les récepteurs de l'autophagie dans les interactions hôte-pathogène(2015), ANR-10-INBS-0004,France-BioImaging,Développment d'une infrastructure française distribuée coordonnée(2010), European Project: 682809,EndoSubvert(2017), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]
Subjects: Salmonella typhimurium, magnetic extraction, 0301 basic medicine, Salmonella, Vesicle fusion, Synaptosomal-Associated Protein 25, spacious vacuole-associated tubules (SVAT), [SDV]Life Sciences [q-bio], Salmonella enterica serovar Typhimurium, Vacuole, Biology, medicine.disease_cause, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Cytosol, proteomics, 0302 clinical medicine, medicine, Humans, Macropinosome, lcsh:QH301-705.5, Pathogen, membrane rupture, Qa-SNARE Proteins, membrane trafficking, vesicle fusion, biology.organism_classification, Cell biology, Salmonella-containing vacuole, 030104 developmental biology, macropinosome, lcsh:Biology (General), SNARE, Salmonella Infections, Vacuoles, Caco-2 Cells, compartmental size control, 030217 neurology & neurosurgery, Intracellular, Bacteria, HeLa Cells
Abstract: Summary Salmonella is a human and animal pathogen that causes gastro-enteric diseases. The key to Salmonella infection is its entry into intestinal epithelial cells, where the bacterium resides within a Salmonella-containing vacuole (SCV). Salmonella entry also induces the formation of empty macropinosomes, distinct from the SCV, in the vicinity of the entering bacteria. A few minutes after its formation, the SCV increases in size through fusions with the surrounding macropinosomes. Salmonella also induces membrane tubules that emanate from the SCV and lead to SCV shrinkage. Here, we show that these antipodal events are utilized by Salmonella to either establish a vacuolar niche or to be released into the cytosol by SCV rupture. We identify the molecular machinery underlying dynamic SCV growth and shrinkage. In particular, the SNARE proteins SNAP25 and STX4 participate in SCV inflation by fusion with macropinosomes. Thus, host compartment size control emerges as a pathogen strategy for intracellular niche regulation., Graphical Abstract, Highlights • The early SCV simultaneously grows and shrinks through fusion and tubule formation • SCV shrinkage promotes vacuolar rupture and cytosolic release • IAMs are enriched in the host SNAREs SNAP25 and STX4, enabling IAM-SCV fusion • Promoting SNX1-mediated tubule formation, SopB fosters SCV ruptures, When infecting epithelial cells, Salmonella can reside and replicate within vacuolar or cytosolic niches. These co-existing lifestyles provide alternative survival strategies for the bacteria. Stévenin et al. show that the balance between dynamic growth and shrinkage of the Salmonella-containing vacuole determines vacuolar maintenance or rupture and controls the pathogen niche.
Published: 2019

99. SIVcol Nef counteracts SERINC5 by promoting its proteasomal degradation but does not efficiently enhance HIV-1 replication in human CD4+ T cells and lymphoid tissue

Author: Frank Kirchhoff, Dominik Hotter, Daniel Sauter, Martine Peeters, Christine Goffinet, Oliver T. Fackler, Konstantin M. J. Sparrer, Zhong Yao, Birthe Trautz, Ahidjo Ayouba, Bengisu Akbil, Thomas Zillinger, Igor Stagljar, Christina M. Stürzel, Swetha Ananth, Vânia Passos, Dorota Kmiec, Institute of Molecular Virology [Ulm, Allemagne], Universitätsklinikum Ulm - University Hospital of Ulm, Department of Infectious Diseases, Integrative Virology [Heidelberg, Allemagne], Center for Integrative Infectious Diseases Research [Heidelberg, Allemagne] (CIID), Heidelberg University Hospital [Heidelberg]-Heidelberg University Hospital [Heidelberg], German Center for Infection Research, Partner Site Heidelberg [Allemagne] (DZIF), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques er émergentes (TransVIHMI), Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Donnelly Centre [Toronto, ON, Canada], University of Toronto, Department of Biochemistry [University of Toronto], Department of Molecular Genetics [Toronto], Institute of Virology [Hannover], Hannover Medical School [Hannover] (MHH), Institute of Clinical Chemistry and Clinical Pharmacology [Bonn, Allemagne], University of Bonn, This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG, European Project: 323035,EC:FP7:ERC,ERC-2012-ADG_20120314,ANTI-VIROME(2013), Bodescot, Myriam, A combined evolutionary and proteomics approach to the discovery, induction and application of antiviral immunity factors - ANTI-VIROME - - EC:FP7:ERC2013-04-01 - 2018-03-31 - 323035 - VALID, Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Universität Bonn = University of Bonn, and Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Institut de Recherche pour le Développement (IRD)-Université de Yaoundé I-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM)-Université Montpellier 1 (UM1)
Subjects: 0301 basic medicine, RNA viruses, CD4-Positive T-Lymphocytes, viruses, Xenopus, Monkeys, Pathology and Laboratory Medicine, Virus Replication, Gene Products, nef, Virions, White Blood Cells, Database and Informatics Methods, Jurkat Cells, Immunodeficiency Viruses, Animal Cells, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Medicine and Health Sciences, lcsh:QH301-705.5, Cells, Cultured, Infectivity, Mammals, T Cells, CD28, Eukaryota, virus diseases, Transfection, 3. Good health, Cell biology, medicine.anatomical_structure, Infectious Diseases, Medical Microbiology, Viral Pathogens, Viruses, Vertebrates, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, [SDV.IMM]Life Sciences [q-bio]/Immunology, Simian Immunodeficiency Virus, Pathogens, Cellular Types, Sequence Analysis, Research Article, Primates, lcsh:Immunologic diseases. Allergy, Proteasome Endopeptidase Complex, Infectious Disease Control, [SDV.IMM] Life Sciences [q-bio]/Immunology, Bioinformatics, Lymphoid Tissue, T cell, Immune Cells, Immunology, Biology, Viral Structure, Colobus, Research and Analysis Methods, Microbiology, 03 medical and health sciences, Sequence Motif Analysis, Virology, Retroviruses, Old World monkeys, Genetics, medicine, Animals, Humans, Molecular Biology, Microbial Pathogens, Blood Cells, Lentivirus, Organisms, Actin remodeling, Biology and Life Sciences, HIV, Membrane Proteins, Cell Biology, biology.organism_classification, Viral Replication, 030104 developmental biology, HEK293 Cells, Viral replication, lcsh:Biology (General), Amniotes, Proteolysis, Tetherin, HIV-1, Parasitology, lcsh:RC581-607
Abstract: SERINC5 is a host restriction factor that impairs infectivity of HIV-1 and other primate lentiviruses and is counteracted by the viral accessory protein Nef. However, the importance of SERINC5 antagonism for viral replication and cytopathicity remained unclear. Here, we show that the Nef protein of the highly divergent SIVcol lineage infecting mantled guerezas (Colobus guereza) is a potent antagonist of SERINC5, although it lacks the CD4, CD3 and CD28 down-modulation activities exerted by other primate lentiviral Nefs. In addition, SIVcol Nefs decrease CXCR4 cell surface expression, suppress TCR-induced actin remodeling, and counteract Colobus but not human tetherin. Unlike HIV-1 Nef proteins, SIVcol Nef induces efficient proteasomal degradation of SERINC5 and counteracts orthologs from highly divergent vertebrate species, such as Xenopus frogs and zebrafish. A single Y86F mutation disrupts SERINC5 and tetherin antagonism but not CXCR4 down-modulation by SIVcol Nef, while mutation of a C-proximal di-leucine motif has the opposite effect. Unexpectedly, the Y86F change in SIVcol Nef had little if any effect on viral replication and CD4+ T cell depletion in preactivated human CD4+ T cells and in ex vivo infected lymphoid tissue. However, SIVcol Nef increased virion infectivity up to 10-fold and moderately increased viral replication in resting peripheral blood mononuclear cells (PBMCs) that were first infected with HIV-1 and activated three or six days later. In conclusion, SIVcol Nef lacks several activities that are conserved in other primate lentiviruses and utilizes a distinct proteasome-dependent mechanism to counteract SERINC5. Our finding that evolutionarily distinct SIVcol Nefs show potent anti-SERINC5 activity supports a relevant role of SERINC5 antagonism for viral fitness in vivo. Our results further suggest this Nef function is particularly important for virion infectivity under conditions of limited CD4+ T cell activation., Author summary The accessory protein Nef promotes primate lentiviral replication and enhances the pathogenicity of HIV-1 by mechanisms of immune evasion and enhancing viral infectivity and replication. Here, we show that the evolutionarily most isolated primate lentivirus SIVcol lacks several otherwise conserved Nef functions. Nevertheless, SIVcol Nef potently antagonizes SERINC5, a recently discovered inhibitor of viral infectivity, by down-modulating it from the cell surface and inducing its proteasomal degradation. We identified Y86 in SIVcol Nef as a key determinant of SERINC5 antagonism. Efficient counteraction of SERINC5 did not increase HIV-1 replication in preactivated CD4+ T cells and in ex vivo infected lymphoid tissue but had modest enhancing effects when resting PBMCs were first infected and activated six days later. Evolution of high anti-SERINC5 activity by SIVcol Nef supports a relevant role of this antagonism in vivo, for instance by enhancing virion infectivity under conditions of limited T cell activation.
Published: 2018

100. Evolutionary diversification of the HAP2 membrane insertion motifs to drive gamete fusion across eukaryotes

Author: Thomas Krey, Ahmed Haouz, Mark A. Johnson, Félix A. Rey, Juliette Fedry, Gérard Pehau-Arnaudet, Pierre Legrand, Jennifer Forcina, Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Université Paris Descartes - Paris 5 (UPD5), Hannover Medical School [Hannover] (MHH), Brown University, Synchrotron SOLEIL (SSOLEIL), Centre National de la Recherche Scientifique (CNRS), Microscopie ultrastructurale - Ultrapole (CITECH), Institut Pasteur [Paris] (IP), Protéopole, German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), ERC Advanced grant CelCelFus (grant number 340371) received by FAR. Recurrent funding from the CNRS received by FAR. Recurrent funding from the Institut Pasteur received by FAR. Allocation ministerielle pour l’Ecole Polytechnique AMX received by JFe. National Science Foundation (NSF) (grant number IOS-1353798). Received by MJ. National Science Foundation (NSF) (grant number IOS-1540019). Received by MJ. National Institutes of Health Training Grant (grant number #T32-GM007601). Received by JFo., and European Project: 340371,EC:FP7:ERC,ERC-2013-ADG,CELCELFUS(2014)
Subjects: Protein Structure Comparison, 0301 basic medicine, MESH: Sequence Homology, Amino Acid, [SDV]Life Sciences [q-bio], Cell Membranes, Arabidopsis, Chlamydomonas reinhardtii, MESH: Chlamydomonas, Membrane Fusion, Biochemistry, Macromolecular Structure Analysis, MESH: Arabidopsis, MESH: Genetic Variation, Biology (General), Flowering Plants, Fusion, General Neuroscience, Eukaryota, Plants, Biological Evolution, Transmembrane protein, Cell biology, MESH: Eukaryota, Experimental Organism Systems, Cellular Structures and Organelles, General Agricultural and Biological Sciences, Research Article, Protein Structure, QH301-705.5, Arabidopsis Thaliana, MESH: Biological Evolution, MESH: Carrier Proteins, Brassica, MESH: Arabidopsis Proteins, Viral Structure, Biology, Research and Analysis Methods, MESH: Membrane Fusion, Microbiology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Model Organisms, Plant and Algal Models, Virology, Vesicles, Molecular Biology, Sequence Homology, Amino Acid, General Immunology and Microbiology, Arabidopsis Proteins, Chlamydomonas, Organisms, Biology and Life Sciences, Membrane Proteins, Proteins, Genetic Variation, Lipid bilayer fusion, Cell Biology, biology.organism_classification, Fusion protein, MESH: Germ Cells, Germ Cells, 030104 developmental biology, Membrane protein, Liposomes, Helix, Carrier Proteins
Abstract: HAPLESS2 (HAP2) is a broadly conserved, gamete-expressed transmembrane protein that was shown recently to be structurally homologous to viral class II fusion proteins, which initiate fusion with host cells via insertion of fusion loops into the host membrane. However, the functional conformation of the HAP2 fusion loops has remained unknown, as the reported X-ray structure of Chlamydomonas reinhardtii HAP2 lacked this critical region. Here, we report a structure-guided alignment that reveals diversification of the proposed HAP2 fusion loops. Representative crystal structures show that in flowering plants, HAP2 has a single prominent fusion loop projecting an amphipathic helix at its apex, while in trypanosomes, three small nonpolar loops of HAP2 are poised to interact with the target membrane. A detailed structure-function analysis of the Arabidopsis HAP2 amphipathic fusion helix defines key residues that are essential for membrane insertion and for gamete fusion. Our study suggests that HAP2 may have evolved multiple modes of membrane insertion to accommodate the diversity of membrane environments it has encountered during eukaryotic evolution., Author summary The fusion of gamete plasma membranes is the fundamental cellular event that brings two parental cells together to form a new individual, yet we know surprisingly little about this process at the molecular level. HAPLESS 2 (HAP2) is a conserved sperm plasma membrane protein that is essential for gamete fusion in a diverse array of eukaryotes. It was recently shown to share a common ancestor with viral proteins that drive fusion of the viral envelope with host membranes, but its mechanism of action remained elusive, since the reported structure did not resolve the proposed membrane interaction surface. Here, we report two new HAP2 structures revealing that HAP2 has evolved diverse membrane interaction surfaces. In the flowering plants, HAP2 uses an amphipathic helix that presents nonpolar residues to the target membrane; in trypanosomes, the membrane interaction surface comprises three shallow nonpolar loops.
Published: 2018

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