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2. Study on Infectious Mononucleosis in Munich (IMMUC)

Author

Helmholtz Zentrum München, German Cancer Research Center, Ludwig-Maximilians - University of Munich, Hannover Medical School, University Hospital Freiburg, and German Center for Infection Research

Published
2024

4. Platform Assessing Regimens and Durations In a Global Multisite Consortium for TB (PARADIGM4TB)

Author

Radboud University Medical Center, London School of Hygiene and Tropical Medicine, University of Oxford, Research Center Borstel, Lygature, TASK Applied Science, Vita-Salute San Raffaele University, Helmholtz Zentrum Munchen, KNCV Tuberculosis Foundation, Critical Path Institute, European Lung Foundation, Instituto de Saude Publica da Universidade do Porto, University of Liverpool, Institut de Recherche Pour le Developpment, University of Hamburg-Eppendorf, University of California, San Francisco, TB Alliance, Find, University of Milano, University of St Andrews, Uppsala University, European Respiratory Society, Tuberculosis Network European Trialsgroup, Janssen, LP, Otsuka Pharmaceutical Development & Commercialization, Inc., German Center for Infection Research, LMU University Hospital Munich, University of Cambridge, and GlaxoSmithKline

Published
2024

9. HIV and STIs Clinical Study in Germany

Author

US Military HIV Research Program, United States Army Medical Materiel Development Activity, Federal Ministry of Health, Germany, German Center for Infection Research, and Hendrik Streeck, Prof. Dr. med. Hendrik Streeck

Published
2022

17. A Single Ascending Dose Study of BTZ043

Author

German Center for Infection Research, German Federal Ministry of Education and Research, Hans Knöll Institute (HKI), and Michael Hoelscher, Director

Published
2019

24. The transplant cohort of the German center for infection research (DZIF Tx-Cohort): study design and baseline characteristics

Author

Karch, A., Schindler, D., Kühn-Steven, A., Blaser, R., Kuhn, K.A., Sandmann, L., Sommerer, C., Guba, M., Heemann, U., Strohäker, J., Glöckner, S., Mikolajczyk, R., Busch, D.H., Schulz, T.F., Transplant Cohort of the German Center for Infection Research (DZIF Transplant Cohort) Consortium (Anton, G.), Transplant Cohort of the German Center for Infection Research (DZIF Transplant Cohort) Consortium (Wichmann, H.-E.), and HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany.

Subjects
Adult, Male, medicine.medical_specialty, Adolescent, Epidemiology, medicine.medical_treatment, 030230 surgery, Organ transplantation, Clinical cohort study, Cohort Studies, Young Adult, 03 medical and health sciences, Postoperative Complications, 0302 clinical medicine, Internal medicine, medicine, Humans, 030212 general & internal medicine, Child, Prospective cohort study, Aged, Biological Specimen Banks, Aged, 80 and over, Immunosuppression Therapy, Cohort Profile, Clinical Cohort Study, Immunosuppression, Infection, Organ Transplantation, business.industry, Public health, Bacterial Infections, Middle Aged, ddc, Transplantation, Research Design, Child, Preschool, Cohort, Female, business, Cohort study
Abstract

Infectious complications are the major cause of morbidity and mortality after solid organ and stem cell transplantation. To better understand host and environmental factors associated with an increased risk of infection as well as the effect of infections on function and survival of transplanted organs, we established the DZIF Transplant Cohort, a multicentre prospective cohort study within the organizational structure of the German Center for Infection Research. At time of transplantation, heart-, kidney-, lung-, liver-, pancreas- and hematopoetic stem cell- transplanted patients are enrolled into the study. Follow-up visits are scheduled at 3, 6, 9, 12 months after transplantation, and annually thereafter; extracurricular visits are conducted in case of infectious complications. Comprehensive standard operating procedures, web-based data collection and monitoring tools as well as a state of the art biobanking concept for blood, purified PBMCs, urine, and faeces samples ensure high quality of data and biosample collection. By collecting detailed information on immunosuppressive medication, infectious complications, type of infectious agent and therapy, as well as by providing corresponding biosamples, the cohort will establish the foundation for a broad spectrum of studies in the field of infectious diseases and transplant medicine. By January 2020, baseline data and biosamples of about 1400 patients have been collected. We plan to recruit 3500 patients by 2023, and continue follow-up visits and the documentation of infectious events at least until 2025. Information about the DZIF Transplant Cohort is available at https://www.dzif.de/en/working-group/transplant-cohort.

Published
2020

25. COVID19 Disease Map, a computational knowledge repository of virus–host interaction mechanisms

Author

Fonds National de la Recherche Luxembourg, European Commission, Federal Ministry of Education and Research (Germany), Ministry of Science, Research and Art Baden-Württemberg, German Center for Infection Research, Netherlands Organisation for Health Research and Development, National Institutes of Health (US), European Molecular Biology Laboratory, Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta-Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Schreiber, Falk, Montagud, Arnau, Ponce de León, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G., Dräger, Andreas, Renz, Alina, Naveez, Muhammad, Orlic-Milacic, Marija, Bocskei, Zsolt, Messina, Francesco, Börnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Senff Ribeiro, Andrea, Ackerman, Emily E., Shoemaker, Jason E., Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, Gökçe Yagmu, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Rothfels, Karen, Eijssen, Lars, Ehrhart, Friederike, Arokia Balaya Rex, Devasahayam, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Shamovsky, Veronic, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean-Marie, Fraser, Rupsha, Ortseifen, Vera, Soliman, Sylvain, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Valdeolivas, Alberto, Hu, Xiaoming, Overall, Rupert W., Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Vega, Carlos, Groues, Valentin, Vázquez, Miguel, Porras, Pablo, Esteban-Medina, Marina, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, Waard, Anita de, Turei, Denes, Luna, Augustín, Babur, Ozgun, Peña-Chilet, María, Rian, Kinza, Helikar, Tomas, Lal Puniya, Bhanwar, Modos, Dezso, Treveil, Agatha, Olbe, Marton, Fobo, Gisela, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aurelien, Naldi, Aurelien, Noël, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C., Montrone, Corinna, Auge, Franck, Beckmann, Jacques S., Hasenauer, Jan, Wolkenhauer, Olaf, Wilighagen, Egon L ., Pico, Alexander R., Evelo, Chris T., Gillespie, Marc E., Stein, Lincoln D., Hermjakob, Henning, Brauner, Barbara, D’Eustachio, Peter, Sáez-Rodríguez, Julio, Dopazo, Joaquín, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, Frishman, Goar, Monraz Gómez, Luis Cristóbal, Somers, Julia, Hoch, Matti, Gupta, Shailendra Kumar, Scheel, Julia, Borlinghaus, Hanna, Czauderna, Tobias, Fonds National de la Recherche Luxembourg, European Commission, Federal Ministry of Education and Research (Germany), Ministry of Science, Research and Art Baden-Württemberg, German Center for Infection Research, Netherlands Organisation for Health Research and Development, National Institutes of Health (US), European Molecular Biology Laboratory, Ostaszewski, Marek, Niarakis, Anna, Mazein, Alexander, Kuperstein, Inna, Phair, Robert, Orta-Resendiz, Aurelio, Singh, Vidisha, Aghamiri, Sara Sadat, Acencio, Marcio Luis, Glaab, Enrico, Ruepp, Andreas, Schreiber, Falk, Montagud, Arnau, Ponce de León, Miguel, Funahashi, Akira, Hiki, Yusuke, Hiroi, Noriko, Yamada, Takahiro G., Dräger, Andreas, Renz, Alina, Naveez, Muhammad, Orlic-Milacic, Marija, Bocskei, Zsolt, Messina, Francesco, Börnigen, Daniela, Fergusson, Liam, Conti, Marta, Rameil, Marius, Nakonecnij, Vanessa, Vanhoefer, Jakob, Schmiester, Leonard, Wang, Muying, Senff Ribeiro, Andrea, Ackerman, Emily E., Shoemaker, Jason E., Zucker, Jeremy, Oxford, Kristie, Teuton, Jeremy, Kocakaya, Ebru, Summak, Gökçe Yagmu, Hanspers, Kristina, Kutmon, Martina, Coort, Susan, Rothfels, Karen, Eijssen, Lars, Ehrhart, Friederike, Arokia Balaya Rex, Devasahayam, Slenter, Denise, Martens, Marvin, Pham, Nhung, Haw, Robin, Jassal, Bijay, Matthews, Lisa, Shamovsky, Veronic, Stephan, Ralf, Sevilla, Cristoffer, Varusai, Thawfeek, Ravel, Jean-Marie, Fraser, Rupsha, Ortseifen, Vera, Soliman, Sylvain, Marchesi, Silvia, Gawron, Piotr, Smula, Ewa, Heirendt, Laurent, Satagopam, Venkata, Wu, Guanming, Riutta, Anders, Golebiewski, Martin, Owen, Stuart, Goble, Carole, Valdeolivas, Alberto, Hu, Xiaoming, Overall, Rupert W., Maier, Dieter, Bauch, Angela, Gyori, Benjamin M., Bachman, John A., Vega, Carlos, Groues, Valentin, Vázquez, Miguel, Porras, Pablo, Esteban-Medina, Marina, Licata, Luana, Iannuccelli, Marta, Sacco, Francesca, Nesterova, Anastasia, Yuryev, Anton, Waard, Anita de, Turei, Denes, Luna, Augustín, Babur, Ozgun, Peña-Chilet, María, Rian, Kinza, Helikar, Tomas, Lal Puniya, Bhanwar, Modos, Dezso, Treveil, Agatha, Olbe, Marton, Fobo, Gisela, De Meulder, Bertrand, Ballereau, Stephane, Dugourd, Aurelien, Naldi, Aurelien, Noël, Vincent, Calzone, Laurence, Sander, Chris, Demir, Emek, Korcsmaros, Tamas, Freeman, Tom C., Montrone, Corinna, Auge, Franck, Beckmann, Jacques S., Hasenauer, Jan, Wolkenhauer, Olaf, Wilighagen, Egon L ., Pico, Alexander R., Evelo, Chris T., Gillespie, Marc E., Stein, Lincoln D., Hermjakob, Henning, Brauner, Barbara, D’Eustachio, Peter, Sáez-Rodríguez, Julio, Dopazo, Joaquín, Valencia, Alfonso, Kitano, Hiroaki, Barillot, Emmanuel, Auffray, Charles, Balling, Rudi, Schneider, Reinhard, Frishman, Goar, Monraz Gómez, Luis Cristóbal, Somers, Julia, Hoch, Matti, Gupta, Shailendra Kumar, Scheel, Julia, Borlinghaus, Hanna, and Czauderna, Tobias

Abstract

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.

Published
2021

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

Author

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), European Commission, Atamna-Mawassi, Heyam, Huberman-Samuel, Maayan, Hershcovitz, , Shimrit, Karny-Epstein, Nitzan, Kola, Axel, López-Cortés, Luis Eduardo, Leibovici, Leonard, Yahav, Dafna, 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), European Commission, Atamna-Mawassi, Heyam, Huberman-Samuel, Maayan, Hershcovitz, , Shimrit, Karny-Epstein, Nitzan, Kola, Axel, López-Cortés, Luis Eduardo, Leibovici, Leonard, and Yahav, Dafna

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.

Published
2021

27. Incidences of Infectious Events in a Renal Transplant Cohort of the German Center of Infectious Diseases (DZIF).

Author

Sommerer, Claudia, Schröter, Iris, Gruneberg, Katrin, Schindler, Daniela, Behnisch, Rouven, Morath, Christian, Renders, Lutz, Heemann, Uwe, Schnitzler, Paul, Melk, Anette, Penna, Andrea Della, Nadalin, Silvio, Heeg, Klaus, Meuer, Stefan, Zeier, Martin, Giese, Thomas, and Consortium, for the Transplant Cohort of the German Center for Infection Research (DZIF Transplant Cohort)

Subjects
KIDNEY transplantation, COMMUNICABLE diseases, ESCHERICHIA coli, OPPORTUNISTIC infections, MYCOSES, PNEUMOCYSTIS jiroveci, ENTEROCOCCAL infections
Abstract

Background Infectious complications are a major cause of morbidity and mortality after kidney transplantation. Methods In this transplant cohort study at the German Center of Infectious Diseases (DZIF), we evaluated all infections occurring during the first year after renal transplantation. We assessed microbial etiology, incidence rates, and temporal occurrence of these infections. Results Of 804 renal transplant recipients (65.2% male, 51 ± 14 years), 439 (54.6%) had 972 infections within the first year after transplantation. Almost half of these infections (47.8%) occurred within the first 3 months. Bacteria were responsible for 66.4% (645/972) of all infections, followed by viral (28.9% [281/972]) and fungal (4.7% [46/972]) pathogens. The urinary tract was the most common site of infection (42.4%). Enterococcus was the most frequently isolated bacterium (20.9%), followed by E. coli (17.6%) and Klebsiella (12.5%). E. coli was the leading pathogen in recipients <50 years of age, whereas Enterococcus predominated in older recipients. Resistant bacteria were responsible for at least 1 infection in 9.5% (76/804) of all recipients. Viral infections occurred in 201 recipients (25.0%). Of these, herpes viruses predominated (140/281 [49.8%]), and cytomegalovirus had the highest incidence rate (12.3%). In the 46 fungal infections, Candida albicans (40.8%) was the most commonly isolated. Other fungal opportunistic pathogens, including Aspergillus fumigatus and Pneumocystis , were rare. Conclusions Renal allograft recipients in Germany experience a high burden of infectious complications in the first year after transplantation. Bacteria were the predominating pathogen, followed by opportunistic infections such as cytomegalovirus. Microbial etiology varied between age groups, and resistant bacteria were identified in 10% of recipients. [ABSTRACT FROM AUTHOR]

Published
2022
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28. Regulation of the Ebola Virus VP24 Protein by SUMO

Author

Ministerio de Economía y Competitividad (España), Xunta de Galicia, German Center for Infection Research, European Commission, Vidal, Santiago, Motiam, Ahmed El, Seoane, Rocío, Preitakaite, Viktorija, Hichem Bouzaher, Yanis, Gómez-Medina, Sergio, San Martín, Carmen, Rodríguez, Dolores, Rejas, M. Teresa, Baz-Martínez, Maite, Barrio, Rosa, Sutherland, James D., Rodríguez, Manuel S., Muñoz-Fontela, César, Rivas, Carmen, Ministerio de Economía y Competitividad (España), Xunta de Galicia, German Center for Infection Research, European Commission, Vidal, Santiago, Motiam, Ahmed El, Seoane, Rocío, Preitakaite, Viktorija, Hichem Bouzaher, Yanis, Gómez-Medina, Sergio, San Martín, Carmen, Rodríguez, Dolores, Rejas, M. Teresa, Baz-Martínez, Maite, Barrio, Rosa, Sutherland, James D., Rodríguez, Manuel S., Muñoz-Fontela, César, and Rivas, Carmen

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

Published
2020

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

Author

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 [0000-0001-5504-9408], Goig, Galo A. [0000-0002-4136-6610], Meehan, Conor J., Goig, Galo A., Kohl, Thomas A., Verboven, Lennert, Dippenaar, Anzaan, Ezewudo, Matthew, Farhat, Maha R., Guthrie, Jennifer L., Laukens, Kris, Miotto, Paolo, Ofori-Anyinam, Boatema, Dreyer, Viola, Supply, Philip, Suresh, Anita, Utpatel, Christian, van Soolingen, Dick, Zhou, Yang, Ashton, Philip M., Brites, Daniela, Cabibbe, Andrea M., de Jong, Bouke C., de Vos, Margaretha, Menardo, Fabrizio, Gagneux, Sebastien, Gao, Qian, Heupink, Tim H., Liu, Qingyun, Loiseau, Chloé, Rigouts, Leen, Rodwell, Timothy C., Tagliani, Elisa, Walker, Timothy M., Warren, Robin M., Zhao, Yanlin, Zignol, Matteo, Schito, Marco, Gardy, Jennifer, Cirillo, Daniela M., Niemann, Stefan, Comas, Iñaki, Van Rie, Annelies, 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 [0000-0001-5504-9408], Goig, Galo A. [0000-0002-4136-6610], Meehan, Conor J., Goig, Galo A., Kohl, Thomas A., Verboven, Lennert, Dippenaar, Anzaan, Ezewudo, Matthew, Farhat, Maha R., Guthrie, Jennifer L., Laukens, Kris, Miotto, Paolo, Ofori-Anyinam, Boatema, Dreyer, Viola, Supply, Philip, Suresh, Anita, Utpatel, Christian, van Soolingen, Dick, Zhou, Yang, Ashton, Philip M., Brites, Daniela, Cabibbe, Andrea M., de Jong, Bouke C., de Vos, Margaretha, Menardo, Fabrizio, Gagneux, Sebastien, Gao, Qian, Heupink, Tim H., Liu, Qingyun, Loiseau, Chloé, Rigouts, Leen, Rodwell, Timothy C., Tagliani, Elisa, Walker, Timothy M., Warren, Robin M., Zhao, Yanlin, Zignol, Matteo, Schito, Marco, Gardy, Jennifer, Cirillo, Daniela M., Niemann, Stefan, Comas, Iñaki, and Van Rie, Annelies

Abstract

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.

Published
2019

30. The transplant cohort of the German center for infection research (DZIF Tx-Cohort): study design and baseline characteristics.

Author

Karch, André, Schindler, Daniela, Kühn-Steven, Andrea, Blaser, Rainer, Kuhn, Klaus A., Sandmann, Lisa, Sommerer, Claudia, Guba, Markus, Heemann, Uwe, Strohäker, Jens, Glöckner, Stephan, Mikolajczyk, Rafael, Busch, Dirk H., Schulz, Thomas F., for the Transplant Cohort of the German Center for Infection Research (DZIF Transplant Cohort) Consortium, Lehmann, Andreas, Ganser, Arnold, Lange, Berit, Maecker-Kolhoff, Britta, and Tönshoff, Burkhard

Subjects
STEM cell transplantation, TRANSPLANTATION of organs, tissues, etc., RESEARCH institutes, EXPERIMENTAL design, STANDARD operating procedure, ARTIFICIAL pancreases, ARTIFICIAL hearts
Abstract

Infectious complications are the major cause of morbidity and mortality after solid organ and stem cell transplantation. To better understand host and environmental factors associated with an increased risk of infection as well as the effect of infections on function and survival of transplanted organs, we established the DZIF Transplant Cohort, a multicentre prospective cohort study within the organizational structure of the German Center for Infection Research. At time of transplantation, heart-, kidney-, lung-, liver-, pancreas- and hematopoetic stem cell- transplanted patients are enrolled into the study. Follow-up visits are scheduled at 3, 6, 9, 12 months after transplantation, and annually thereafter; extracurricular visits are conducted in case of infectious complications. Comprehensive standard operating procedures, web-based data collection and monitoring tools as well as a state of the art biobanking concept for blood, purified PBMCs, urine, and faeces samples ensure high quality of data and biosample collection. By collecting detailed information on immunosuppressive medication, infectious complications, type of infectious agent and therapy, as well as by providing corresponding biosamples, the cohort will establish the foundation for a broad spectrum of studies in the field of infectious diseases and transplant medicine. By January 2020, baseline data and biosamples of about 1400 patients have been collected. We plan to recruit 3500 patients by 2023, and continue follow-up visits and the documentation of infectious events at least until 2025. Information about the DZIF Transplant Cohort is available at https://www.dzif.de/en/working-group/transplant-cohort. [ABSTRACT FROM AUTHOR]

Published
2021
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31. Proposed primary endpoints for use in clinical trials that compare treatment options for bloodstream infection in adults: a consensus definition

Author

University of Queensland, National Institutes of Health (US), National Institute of Allergy and Infectious Diseases (US), National Health and Medical Research Council (Australia), German Center for Infection Research, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Red Española de Investigación en Patología Infecciosa, Innovative Medicines Initiative, Harris, P. N. A., McNamara, J. F., Lye, D. C., Davis, J. S., Bernard, Louis, Cheng, A. C., Doi, Y., Fowler, Vance G., Kaye, K. S., Leibovici, Leonard, Lipman, Jeffrey, Llewelyn, Martin J., Muñoz-Price, S., Paul, Mical, Peleg, A. Y., Rodríguez-Baño, Jesús, Rogers, B. A., Seifert, Harald, Thamlikitkul, V., Thwaites, Guy, Tong, S. Y. C., Turnidge, J., Utili, R., Webb, S. A. R., Paterson, David L., University of Queensland, National Institutes of Health (US), National Institute of Allergy and Infectious Diseases (US), National Health and Medical Research Council (Australia), German Center for Infection Research, Ministerio de Economía y Competitividad (España), Instituto de Salud Carlos III, European Commission, Red Española de Investigación en Patología Infecciosa, Innovative Medicines Initiative, Harris, P. N. A., McNamara, J. F., Lye, D. C., Davis, J. S., Bernard, Louis, Cheng, A. C., Doi, Y., Fowler, Vance G., Kaye, K. S., Leibovici, Leonard, Lipman, Jeffrey, Llewelyn, Martin J., Muñoz-Price, S., Paul, Mical, Peleg, A. Y., Rodríguez-Baño, Jesús, Rogers, B. A., Seifert, Harald, Thamlikitkul, V., Thwaites, Guy, Tong, S. Y. C., Turnidge, J., Utili, R., Webb, S. A. R., and Paterson, David L.

Abstract

[Objectives] To define standardized endpoints to aid the design of trials that compare antibiotic therapies for bloodstream infections (BSI)., [Methods] Prospective studies, randomized trials or registered protocols comparing antibiotic therapies for BSI, published from 2005 to 2016, were reviewed. Consensus endpoints for BSI studies were defined using a modified Delphi process., [Results] Different primary and secondary endpoints were defined for pilot (small-scale studies designed to evaluate protocol design, feasibility and implementation) and definitive trials (larger-scale studies designed to test hypotheses and influence clinical practice), as well as for Staphylococcus aureus and Gram-negative BSI. For pilot studies of S. aureus BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever, stable/improved Sequential Organ Failure Assessment (SOFA) score and clearance of blood cultures, with no microbiologically confirmed failure up to 90 days. For definitive S. aureus BSI studies, a primary outcome of success at 90 days was defined by survival and no microbiologically confirmed failure. For pilot studies of Gram-negative BSI, a primary outcome of success at day 7 was defined by: survival, resolution of fever and symptoms related to BSI source, stable or improved SOFA score and negative blood cultures. For definitive Gram-negative BSI studies, a primary outcome of survival at 90 days supported by a secondary outcome of success at day 7 (as previously defined) was agreed., [Conclusions] These endpoints provide a framework to aid future trial design. Further work will be required to validate these endpoints with respect to patient-centred clinical outcomes.

Published
2017

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

Author

German Center for Infection Research, Ryll, René, Bernstein, Samuel, Heuser, Elisa, Schlegel, Mathias, Dremsek, Paul, Zumpe, Maxi, Wolf, Sandro, Pépin, Michel, Bajomi, Daniel, Müller, Gabi, Heiberg, Ann-Charlotte, Spahr, Carina, Lang, Johannes, Groschup, Martin H., Ansorge, Hermann, Freise, Jona, Guenther, Sebastian, Baert, Kristof, Ruiz-Fons, Francisco, Pikula, Jiri, Knap, Nataša, Tsakmakidis, Ioannis., Dovas, Chrysostomos, Zanet, Stefania, Imholt, Christian, Heckel, Gerald, Johne, Reimar, Ulrich, Rainer G., German Center for Infection Research, Ryll, René, Bernstein, Samuel, Heuser, Elisa, Schlegel, Mathias, Dremsek, Paul, Zumpe, Maxi, Wolf, Sandro, Pépin, Michel, Bajomi, Daniel, Müller, Gabi, Heiberg, Ann-Charlotte, Spahr, Carina, Lang, Johannes, Groschup, Martin H., Ansorge, Hermann, Freise, Jona, Guenther, Sebastian, Baert, Kristof, Ruiz-Fons, Francisco, Pikula, Jiri, Knap, Nataša, Tsakmakidis, Ioannis., Dovas, Chrysostomos, Zanet, Stefania, Imholt, Christian, Heckel, Gerald, Johne, Reimar, and Ulrich, Rainer G.

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.

Published
2017

33. A G-quadruplex-binding macrodomain within the >SARS-unique domain> is essential for the activity of the SARS-coronavirus replication-transcription complex

Author

German Center for Infection Research, European Commission, Ministerio de Ciencia e Innovación (España), National Institutes of Health (US), Sino-German Center for Research Promotion, Kusov, Yuri, Tan, Jinzhi, Álvarez, Enrique, Enjuanes Sánchez, Luis, Hilgenfeld, Rolf, German Center for Infection Research, European Commission, Ministerio de Ciencia e Innovación (España), National Institutes of Health (US), Sino-German Center for Research Promotion, Kusov, Yuri, Tan, Jinzhi, Álvarez, Enrique, Enjuanes Sánchez, Luis, and Hilgenfeld, Rolf

Abstract

The multi-domain non-structural protein 3 of SARS-coronavirus is a component of the viral replication/transcription complex (RTC). Among other domains, it contains three sequentially arranged macrodomains: the X domain and subdomains SUD-N as well as SUD-M within the >SARS-unique domain>. The X domain was proposed to be an ADP-ribose-1>-phosphatase or a poly(ADP-ribose)-binding protein, whereas SUD-NM binds oligo(G)-nucleotides capable of forming G-quadruplexes. Here, we describe the application of a reverse genetic approach to assess the importance of these macrodomains for the activity of the SARS-CoV RTC. To this end, Renilla luciferase-encoding SARS-CoV replicons with selectively deleted macrodomains were constructed and their ability to modulate the RTC activity was examined. While the SUD-N and the X domains were found to be dispensable, the SUD-M domain was crucial for viral genome replication/transcription. Moreover, alanine replacement of charged amino-acid residues of the SUD-M domain, which are likely involved in G-quadruplex-binding, caused abrogation of RTC activity.

Published
2015

34. Antiviral immunity via RIG-I-mediated recognition of RNA bearing 5'-diphosphates

Author

Cancer Research UK, European Research Council, Fondation Bettencourt Schueller, Department of Health and Human Services (US), Vanderbilt University, Fundación Ramón Areces, German Research Foundation, German Center for Infection Research, Goubau, Delphine, Fujimura, Tsutomu, Reis e Sousa, Caetano, Cancer Research UK, European Research Council, Fondation Bettencourt Schueller, Department of Health and Human Services (US), Vanderbilt University, Fundación Ramón Areces, German Research Foundation, German Center for Infection Research, Goubau, Delphine, Fujimura, Tsutomu, and Reis e Sousa, Caetano

Abstract

Mammalian cells possess mechanisms to detect and defend themselves from invading viruses. In the cytosol, the RIG-I-like receptors (RLRs), RIG-I (retinoic acid-inducible gene I; encoded by DDX58) and MDA5 (melanoma differentiation-associated gene 5; encoded by IFIH1) sense atypical RNAs associated with virus infection. Detection triggers a signalling cascade via the adaptor MAVS that culminates in the production of type I interferons (IFN-¿ and ß; hereafter IFN), which are key antiviral cytokines. RIG-I and MDA5 are activated by distinct viral RNA structures and much evidence indicates that RIG-I responds to RNAs bearing a triphosphate (ppp) moiety in conjunction with a blunt-ended, base-paired region at the 5'-end (reviewed in refs 1, 2, 3). Here we show that RIG-I also mediates antiviral responses to RNAs bearing 5'-diphosphates (5'pp). Genomes from mammalian reoviruses with 5'pp termini, 5'pp-RNA isolated from yeast L-A virus, and base-paired 5'pp-RNAs made by in vitro transcription or chemical synthesis, all bind to RIG-I and serve as RIG-I agonists. Furthermore, a RIG-I-dependent response to 5'pp-RNA is essential for controlling reovirus infection in cultured cells and in mice. Thus, the minimal determinant for RIG-I recognition is a base-paired RNA with 5'pp. Such RNAs are found in some viruses but not in uninfected cells, indicating that recognition of 5'pp-RNA, like that of 5'ppp-RNA, acts as a powerful means of self/non-self discrimination by the innate immune system.

Published
2014

35. Phages against Noncapsulated Klebsiella pneumoniae: Broader Host range, Slower Resistance

Author

Lourenço, Marta, Osbelt, Lisa, Passet, Virginie, Gravey, François, Megrian, Daniela, Strowig, Till, Rodrigues, Carla, Brisse, Sylvain, Biodiversité et Epidémiologie des Bactéries pathogènes - Biodiversity and Epidemiology of Bacterial Pathogens, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Helmholtz Centre for Infection Research (HZI), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), Dynamique Microbienne associée aux Infections Urinaires et Respiratoires (DYNAMICURE), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Université de Rouen Normandie (UNIROUEN), Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Microbiologie structurale - Structural Microbiology (Microb. Struc. (UMR_3528 / U-Pasteur_5)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was mainly supported by the Joint Programming Initiative on Antimicrobial Resistance (JPIAMR) project CRISPR-ATTACK (Advancing CRISPR antimicrobials to combat the bacterial pathogen Klebsiella pneumoniae) under the French Agence Nationale de la Recherche grant ANR-18-JAM2-0004-04, S.B. and 01KI1824 to T.S. C.R. was also supported financially by a Pasteur-Roux fellowship by the Institut Pasteur. The BEBP laboratory is supported by the French Government Investissement d’Avenir Program Laboratoire d’Excellence, Integrative Biology of Emerging Infectious Diseases (ANR10LABX62IBEID). T.S. was also supported by the Federal Ministry of Science under the project DF-AMR2:DECOLONIZE (01KI2131), JPI-AMR Germany (01KI1824) as well as by the German Center for Infection Research (DZIF, TTU 06.826)., We thank Olaya Rendueles Garcia and Eduardo Rocha for sharing the mutant strains that were used for the anti-Kd phage isolation. We thank the Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09) and IBISA, especially Marc Monot, Elodie Turc, Laure Lemée and Georges Haustant, for the sequencing project management, the preparation of the genomic libraries, and the sequencing. We thank Melanie Hennart for the bioinformatics methodological input and Anne-Marie Wehenkel for the help with the protein analyses. We are grateful to Jin-Town Wang for sharing the strain NTUH-K2044. We thank Quentin Lamy-Besnier, Chiara Crestani, and Olaya Rendueles Garcia for the critical reading of the manuscript., ANR-18-JAM2-0004,CRISPRattacK(2018), and ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010)

Subjects
Klebsiella pneumoniae, in vivo, bacteriophages, phage therapy, bacteriophage-bacteria interactions, phage resistance, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, genomics, host range, bacteriophage therapy, antimicrobial resistance, noncapsulated mutants, phage-bacteria interactions
Abstract

International audience; Klebsiella pneumoniae (Kp), a human gut colonizer and opportunistic pathogen, is a major contributor to the global burden of antimicrobial resistance. Virulent bacteriophages represent promising agents for decolonization and therapy. However, the majority of anti-Kp phages that have been isolated thus far are highly specific to unique capsular types (anti-K phages), which is a major limitation to phage therapy prospects due to the highly polymorphic capsule of Kp. Here, we report on an original anti-Kp phage isolation strategy, using capsule-deficient Kp mutants as hosts (anti-Kd phages). We show that anti-Kd phages have a broad host range, as the majority are able to infect noncapsulated mutants of multiple genetic sublineages and O-types. Additionally, anti-Kd phages induce a lower rate of resistance emergence in vitro and provide increased killing efficiency when in combination with anti-K phages. In vivo, anti-Kd phages are able to replicate in mouse guts colonized with a capsulated Kp strain, suggesting the presence of noncapsulated Kp subpopulations. The original strategy proposed here represents a promising avenue that circumvents the Kp capsule host restriction barrier, offering promise for therapeutic development.IMPORTANCE Klebsiella pneumoniae (Kp) is an ecologically generalist bacterium as well as an opportunistic pathogen that is responsible for hospital-acquired infections and a major contributor to the global burden of antimicrobial resistance. In the last decades, limited advances have been made in the use of virulent phages as alternatives or complements to antibiotics that are used to treat Kp infections. This work demonstrates the potential value of an anti-Klebsiella phage isolation strategy that addresses the issue of the narrow host range of anti-K phages. Anti-Kd phages may be active in infection sites in which capsule expression is intermittent or repressed or in combination with anti-K phages, which often induce the loss of capsule in escape mutants.

Published
2023

36. Access and benefit-sharing by the European Virus Archive in response to COVID-19

Author

Jan Felix Drexler, Thomas C. Mettenleiter, Antonio Di Caro, Amber Hartman Scholz, Christian Drosten, Carrie Batten, Sven Reiche, Anthony R. Fooks, Bruno Coutard, Boris Klempa, Hervé Bourhy, Carolina dos S. Ribeiro, Florence Komurian-Pradel, Thomas Klimkait, Jean-Louis Romette, George B. Haringhuizen, Marion Koopmans, Christine M.A. Prat, Jean-Claude Manuguerra, Stephan Günther, Maria Serena Beato, Ali Mirazimi, Scarlett Sett, Rémi N. Charrel, David Williams, Chantal Reusken, Tatjana Avšič, Sylvie van der Werf, Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH / Leibniz Institute DSMZ-German Collection of Microorganisms and Cell Cultures (DSMZ), Netherlands Center for Infectious Disease Control, 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), University of Ljubljana, The Pirbright Institute, Biotechnology and Biological Sciences Research Council (BBSRC), Istituto Zooprofilattico Sperimentale delle Venezie (IZSVe), Lyssavirus, épidémiologie et neuropathologie - Lyssavirus Epidemiology and Neuropathology, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Istituto Nazionale di Malattie Infettive 'Lazzaro Spallanzani' (INMI), German Center for Infection Research, Partnersite Munich (DZIF), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Animal and Plant Health Agency [Addlestone, UK] (APHA), Slovak Academy of Science [Bratislava] (SAS), Erasmus University Medical Center [Rotterdam] (Erasmus MC), University of Basel (Unibas), Bernhard Nocht Institute for Tropical Medicine - Bernhard-Nocht-Institut für Tropenmedizin [Hamburg, Germany] (BNITM), German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Cellule d'Intervention Biologique d'Urgence (Centre National de Référence) - Laboratory for Urgent Response to Biological Threats (National Reference Center) (CIBU), Université Paris Cité (UPCité)-Environnement et Risques infectieux - Environment and Infectious Risks (ERI), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité)-Institut Pasteur [Paris] (IP), Environnement et Risques infectieux - Environment and Infectious Risks (ERI), Public Health Agency of Sweden, Friedrich-Loeffler-Institut (FLI), Fondation Mérieux, National Institute for Public Health and the Environment [Bilthoven] (RIVM), Aix Marseille Université (AMU), 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), Australian Centre for Disease Preparedness, Commonwealth Scientific and Industrial Research Organisation [Canberra] (CSIRO), This publication was supported by the European Virus Archive-GLOBAL project that has received funding from the EU Horizon 2020 research and innovation programme (grantagreement number 871029), The manuscript was written by the European Virus Archive access and benefit-sharing compliance team but would not have been possible without the front-line scientists that built up the European Virus Archive infrastructure and have worked tirelessly over the past year to support the global pandemic response. We welcome the European Virus Archive signatory authors who endorse this publication and its call for a multilateral pathogen genetic resources mechanism tied to a distributed biobanking infrastructure., European Virus Archive principal investigators Slovenia T Avšič (University of Ljubljana, Ljubljana). UK C Batten (The Pirbright Institute, Pirbright), A R Fooks (The Animal and Plant Health Agency, Addlestone). Italy M S Beato (Istituto Zooprofilattico Sperimentale delle Venezie, Legnaro), A Di Caro (Istituto Nazionale Malattie Infettive Lazzaro Spallanzani, Rome). France H Bourhy, J-C Manuguerra, S van der Werf (Institute Pasteur, Paris), R Charrel, J-L Romette, B Coutard (Aix Marseille University, Marseille), F Komurian-Pradel (Fondation Mérieux, Lyon). Germany J F Drexler, C Drosten (Charité–Universitätsmedizin Berlin, Berlin), S Günther (Bernhard Nocht Institute for Tropical Medicine, Hamburg), T C Mettenleiter, S Reiche (Friedrich Loeffler Institute, Greifswald). Slovakia B Klempa (Biomedical Research Center of the Slovak Academy of Sciences, Bratislava). Switzerland T Klimkait (University of Basel, Basel). Sweden A Mirazimi (The Public Health Agency of Sweden, Solna). Netherlands C Reusken (Dutch National Institute for Public Health and the Environment, Bilthoven), M Koopmans (Erasmus Medical Center, Rotterdam). Australia D Williams (Australian Centre for Disease Preparedness, East Geelong, VIC)., and European Project: 871029,H2020,H2020-INFRAIA-2019-1,EVA-GLOBAL(2020)

Subjects
Microbiology (medical), 2019-20 coronavirus outbreak, Coronavirus disease 2019 (COVID-19), Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), [SDV]Life Sciences [q-bio], Internet privacy, Microbiology, Corrections, SDG 3 - Good Health and Well-being, Genetic resources, Virology, Pandemic, Humans, Pandemics, Biological Specimen Banks, Personal View, Benefit sharing, business.industry, SARS-CoV-2, DNA Viruses, COVID-19, Biobank, Infectious Diseases, Viruses, Viruses, Unclassified, Business
Abstract

Erratum in Correction to Lancet Microbe 2021; published online Nov 16. https://doi.org/10.1016/S2666-5247(21)00211-1. [No authors listed] Lancet Microbe. 2022 Jan;3(1):e8. doi: 10.1016/S2666-5247(21)00325-6. Epub 2021 Nov 26. PMID: 34870252 Free PMC article.; International audience; Biobanking infrastructures, which are crucial for responding early to new viral outbreaks, share pathogen genetic resources in an affordable, safe, and impartial manner and can provide expertise to address access and benefit-sharing issues. The European Virus Archive has had a crucial role in the global response to the COVID-19 pandemic by distributing EU-subsidised (free of charge) viral resources to users worldwide, providing non-monetary benefit sharing, implementing access and benefit-sharing compliance, and raising access and benefit-sharing awareness among members and users. All currently available SARS-CoV-2 material in the European Virus Archive catalogue, including variants of concern, are not access and benefit-sharing cases per se, but multilateral benefit-sharing has nevertheless occurred. We propose and discuss how a multilateral system enabling access and benefit-sharing from pathogen genetic resources, based on the European Virus Archive operational model, could help bridge the discrepancies between the current bilateral legal framework for pathogen genetic resources and actual pandemic response practices.

Published
2021

37. MDR M. tuberculosis outbreak clone in Eswatini missed by Xpert has elevated bedaquiline resistance dated to the pre-treatment era

Author

Elisabeth Sanchez-Padilla, Nazir Ahmed Ismail, Thomas Kohl, Christian Utpatel, Patrick Beckert, Stefan Niemann, Claudio U. Köser, Harald Hoffmann, Sönke Andres, Robin M. Warren, Bouke C. de Jong, Marisa Klopper, Matthias Merker, Florian P. Maurer, Shaheed V. Omar, Katharina Kranzer, Maryline Bonnet, Bernhard Kerschberger, Viola Dreyer, Ivan Barilar, Elisa Ardizzoni, Birgit Schramm, Gugu Maphalala, Forschungszentrum Borstel - Research Center Borstel, German Center for Infection Research (DZIF), Heidelberg University, Epicentre [Paris] [Médecins Sans Frontières], University of Cambridge [UK] (CAM), National Institute for Communicable Diseases [Johannesburg] (NICD), University of Pretoria [South Africa], University of the Witwatersrand [Johannesburg] (WITS), Stellenbosch University, Institute of Tropical Medicine [Antwerp] (ITM), London School of Hygiene and Tropical Medicine (LSHTM), Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Recherches Translationnelles sur le VIH et les maladies infectieuses endémiques et émergentes (TransVIHMI), Université Montpellier 1 (UM1)-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), 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), University of Namibia (UNAM), Parts of this work have been supported by the European Union TB-PAN-NET (FP7-223681) project, by Médecins Sans Frontières-Switzerland, and by German Center for Infection Research, Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germanys Excellence Strategy – EXC 2167, and Leibniz Science Campus Evolutionary Medicine of the LUNG (EvoLUNG). The funders had no role in the study design, in the collection, analysis, and interpretation of the data, in the writing of the report, and in the decision to submit the paper for publication., European Project: 223681,EC:FP7:HEALTH,FP7-HEALTH-2007-B,TB PAN-NET(2009), Niemann, Stefan [0000-0002-6604-0684], and Apollo - University of Cambridge Repository

Subjects
0301 basic medicine, MESH: Mycobacterium tuberculosis, Antitubercular Agents, Drug resistance, Multidrug resistance, Disease Outbreaks, Clofazimine, chemistry.chemical_compound, Tuberculosis, Multidrug-Resistant, MESH: Disease Outbreaks, Diarylquinolines, MESH: Bacterial Proteins, Genetics (clinical), MESH: Microbial Sensitivity Tests, Resistance mutation, MESH: Diarylquinolines, Mycobacterium tuberculosis complex, Molecular Medicine, medicine.drug, MESH: Mutation, Tuberculosis, 030106 microbiology, Microbial Sensitivity Tests, Biology, 03 medical and health sciences, Bacterial Proteins, MESH: Eswatini, Genetics, medicine, Humans, Molecular Biology, MESH: Tuberculosis, Multidrug-Resistant, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, Diagnostice escape, Research, MESH: Clone Cells, Resistance evolution, Treatment escape, Mycobacterium tuberculosis, rpoB, medicine.disease, biology.organism_classification, MESH: Antitubercular Agents, Virology, Clone Cells, Multiple drug resistance, MDR outbreak strains, 030104 developmental biology, chemistry, Treatment failure, Mutation, Bedaquiline, Eswatini
Abstract

Background Multidrug-resistant (MDR) Mycobacterium tuberculosis complex strains not detected by commercial molecular drug susceptibility testing (mDST) assays due to the RpoB I491F resistance mutation are threatening the control of MDR tuberculosis (MDR-TB) in Eswatini. Methods We investigate the evolution and spread of MDR strains in Eswatini with a focus on bedaquiline (BDQ) and clofazimine (CFZ) resistance using whole-genome sequencing in two collections ((1) national drug resistance survey, 2009–2010; (2) MDR strains from the Nhlangano region, 2014–2017). Results MDR strains in collection 1 had a high cluster rate (95%, 117/123 MDR strains) with 55% grouped into the two largest clusters (gCL3, n = 28; gCL10, n = 40). All gCL10 isolates, which likely emerged around 1993 (95% highest posterior density 1987–1998), carried the mutation RpoB I491F that is missed by commercial mDST assays. In addition, 21 (53%) gCL10 isolates shared a Rv0678 M146T mutation that correlated with elevated minimum inhibitory concentrations (MICs) to BDQ and CFZ compared to wild type isolates. gCL10 isolates with the Rv0678 M146T mutation were also detected in collection 2. Conclusion The high clustering rate suggests that transmission has been driving the MDR-TB epidemic in Eswatini for three decades. The presence of MDR strains in Eswatini that are not detected by commercial mDST assays and have elevated MICs to BDQ and CFZ potentially jeopardizes the successful implementation of new MDR-TB treatment guidelines. Measures to limit the spread of these outbreak isolates need to be implemented urgently.

Published
2020

38. The Spatial Heterogeneity of the Gut Limits Predation and Fosters Coexistence of Bacteria and Bacteriophages

Author

Luisa De Sordi, Thierry Pedron, Claudia Eberl, Lorenzo Chaffringeon, Quentin Lamy-Besnier, Pascal Campagne, Marion Bérard, Laurent Debarbieux, Bärbel Stecher, Marta Lourenço, Bactériophage, bactérie, hôte - Bacteriophage, bacterium, host, Institut Pasteur [Paris], Collège doctoral [Sorbonne universités], Sorbonne Université (SU), Centre de Recherche Saint-Antoine (CR Saint-Antoine), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Université Paris Descartes - Paris 5 (UPD5), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Max von Pettenkofer-Institut for Hygiene and Medical Microbiology, Ludwig-Maximilians-Universität München (LMU), Animalerie centrale (Plate-forme), German Center for Infection Research, Partnersite Munich (DZIF), Institut Carnot Pasteur Maladie Infectieuse ANR-11-CARN-017-01, M.L. is part of the Pasteur - Paris University (PPU) International PhD Program. M.L. is funded by Institut Carnot Pasteur Maladie Infectieuse (ANR 11-CARN 017-01). L.D.S. is funded by a Roux-Cantarini fellowship from the Institut Pasteur (Paris, France). L.C. is funded by a PhD fellowships from the Ministère de l’Enseignement Supérieur et de la Recherche, France, École Doctorale n°394. Q.L.-B. is funded by École Doctorale FIRE - Program Bettencourt. B.S. is supported by the German Center of Infection Research (DZIF), the Center for Gastrointestinal Microbiome Research (CEGIMIR), the DFG, Germany, Priority Programme SPP1656 (STE 1971/4-2 and STE 1971/6-1), and the Collaborative Research Center CRC 1371., We thank Harald Brüssow for critically reading the manuscript and Jorge Moura de Sousa for valuable discussion and opinion on early versions of the manuscript. We thank Dwayne Roach and Anne Chevallereau for valuable discussions. We thank Sean Benler for kindly sharing the comprehensive HMM database of Ig-like domains identified on Pfam database. We thank the members of the Centre for Gnotobiology Platform of the Institut Pasteur (Thierry Angélique, Eddie Maranghi, Martine Jacob, and Marisa Gabriela Lopez Dieguez) for their help with the animal work. We thank Cédric Fund for 16S libraries and sequencing from the Biomics Platform, C2RT, Institut Pasteur, Paris, France, supported by France Génomique (ANR-10-INBS-09-09) and IBISA., Institut Pasteur [Paris] (IP), Collège Doctoral, Centre de Recherche Saint-Antoine (CRSA), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Cova Rodrigues, Ana

Subjects
Male, Phage therapy, enteroaggregative, medicine.medical_treatment, viruses, [SDV]Life Sciences [q-bio], murine intestine, Gut flora, medicine.disease_cause, gnotobiotic mice, Microbiology, Predation, 03 medical and health sciences, Feces, Mice, 0302 clinical medicine, Virology, medicine, Escherichia coli, microbiota, Animals, Germ-Free Life, Bacteriophages, mucosa, Ecosystem, intestinal microbes, 030304 developmental biology, 0303 health sciences, Mucous Membrane, Oligo mouse microbiota, biology, Bacteria, Ecological dynamics, gut biogeography, biology.organism_classification, Spatial heterogeneity, Gastrointestinal Microbiome, [SDV] Life Sciences [q-bio], Gastrointestinal Tract, Mice, Inbred C57BL, Models, Animal, Microbial Interactions, Parasitology, Female, 030217 neurology & neurosurgery
Abstract

International audience; The ecological dynamics underlying the coexistence between antagonistic populations of bacteria and their viruses, bacteriophages (phages), in the mammalian gut microbiota remain poorly understood. We challenged a murine synthetic bacterial community with phages to study the factors allowing phages-bacteria coexistence. Coexistence was not dependent on the development of phage-resistant clones nor on the ability of phages to extend their host range. Instead, our data suggest that phage-inaccessible sites in the mucosa serve as a spatial refuge for bacteria. From there, bacteria disseminate in the gut lumen where they are predated by luminal phages fostering the presence of intestinal phage populations. The heterogeneous biogeography of microbes contributes to the long-term coexistence of phages with phage-susceptible bacteria. This observation could explain the persistence of intestinal phages in humans as well as the low efficiency of oral phage therapy against enteric pathogens in animal models and clinical trials.

Published
2020

39. HIV DNA reservoir and elevated PD-1 expression of CD4 T-cell subsets particularly persist in the terminal ileum of HIV-positive patients despite cART

Author

Meryem S. Ercanoglu, Darragh Duffy, M Müller-Trutwin, C Vivaldi, J Anderson, Jan Rybniker, Florian Klein, Max Augustin, D Nierhoff, Eva Heger, Mark Oette, S-H Chon, H Schäfer, Christof Geldmacher, V Bondet, Isabelle Suárez, Elena Knops, Carola Horn, Kathrin Held, Clara Lehmann, Gerd Fätkenheuer, Universität zu Köln, German Centre for Infection Research (DZIF), Faculty of Medicine [Cologne], University Hospital of Cologne [Cologne]-University of Cologne, Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), University Hospital of Cologne [Cologne], PAN Klinik [Köln], Klinikum der Universität [München], German Center for Infection Research, Partnersite Munich (DZIF), HIV, Inflammation et persistance, Institut Pasteur [Paris], This work was supported by the German Center for Infection Research (grant nos 80185MDCAH to CH and 8018804915 to CL) and the French Agency for Research on AIDS and Viral Hepatitis (ANRS) (grant no. 17066 to MMT)., Universität zu Köln = University of Cologne, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), and Vougny, Marie-Christine

Subjects
0301 basic medicine, Cart, CD4-Positive T-Lymphocytes, [SDV.IMM] Life Sciences [q-bio]/Immunology, medicine.medical_treatment, Programmed Cell Death 1 Receptor, Rectum, HIV Infections, In situ hybridization, Peripheral blood mononuclear cell, HIV reservoir, Flow cytometry, 03 medical and health sciences, immune dysfunction, 0302 clinical medicine, Ileum, T-Lymphocyte Subsets, PD-1, Medicine, Humans, Pharmacology (medical), 030212 general & internal medicine, medicine.diagnostic_test, business.industry, Health Policy, virus diseases, HIV, Immunotherapy, DNA, 030112 virology, 3. Good health, Infectious Diseases, medicine.anatomical_structure, Real-time polymerase chain reaction, Immunology, memory CD4 T-cell subsets, HIV-1, Immunohistochemistry, [SDV.IMM]Life Sciences [q-bio]/Immunology, business
Abstract

International audience; Despite its importance as an HIV anatomic sanctuary, little is known about the characteristics of the HIV reservoir in the terminal ileum (TI). In blood, the immune checkpoint inhibitor programmed-death-1 (PD-1) has been linked to the HIV reservoir and T-cell immune dysfunction. We thus evaluated PD-1 expression and cell-associated HIV DNA in memory CD4 T-cell subsets from TI, peripheral blood (PB) and rectum (RE) of untreated and treated HIV-positive patients to identify associations between PD-1 and HIV reservoir in other sites.MethodsUsing mononuclear cells from PB, TI and RE of untreated HIV-positive (N = 6), treated (n = 18) HIV-positive and uninfected individuals (n = 16), we identified and sorted distinct memory CD4 T-cell subsets by flow cytometry, quantified their cell-associated HIV DNA using quantitative PCR and assessed PD-1 expression levels using geometric mean fluorescence intensity. Combined HIV-1 RNA in situ hybridization and immunohistochemistry was performed on ileal biopsy sections.ResultsCombined antiretroviral therapy (cART)-treated patients with undetectable HIV RNA and significantly lower levels of HIV DNA in PB showed particularly high PD-1 expression in PB and TI, and high HIV DNA levels in TI, irrespective of clinical characteristics. By contrast, in treatment-naïve patients HIV DNA levels in memory CD4 T-cell subsets were high in PB and TI.ConclusionElevated PD-1 expression on memory CD4 T-cells in PB and TI despite treatment points to continuous immune dysfunction and underlines the importance of evaluating immunotherapy in reversing HIV latency and T-cell reconstitution. As HIV DNA particularly persists in TI despite cART, investigating samples from TI is crucial in understanding HIV immunopathogenesis.

Published
2020

40. De novo protein design enables the precise induction of RSV-neutralizing antibodies

Author

Sean Ervin, Jean-François Eléouët, Sabrina Vollers, Marie-Anne Rameix-Welti, Marie Galloux, Stéphane Rosset, Jean-Philippe Julien, Xiaolin Wen, Yuxing Li, Johannes T. Cramer, Che Yang, Jaume Bonet, Thomas Krey, Theodore S. Jardetzky, Patricia Corthésy, Yimeng Wang, Sabine Riffault, Chi-I Chiang, Iga Kucharska, Delphyne Descamps, Elie Dheilly, Sandrine Georgeon, Giacomo Castoro, Mélanie Villard, Charles-Adrien Richard, Teresa C. Delgado, Fabian Sesterhenn, Elisa Oricchio, Vicente Mas, Luciano A. Abriata, Bruno E. Correia, John T. Bates, Instituto de Salud Carlos III, European Research Council, Swiss National Science Foundation, Stavros Niarchos Foundation, EPFL Postdoctoral Fellows, German Center for Infection Research (Alemania), Deutsche Forschungsgemeinschaft (Alemania), Federal Ministry of Education & Research (Alemania), Canada Research Chairs, NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), Ecole Polytechnique Fédérale de Lausanne (EPFL), Swiss Institute of Bioinformatics [Lausanne] (SIB), Université de Lausanne (UNIL), Hannover Medical School [Hannover] (MHH), Stanford School of Medicine [Stanford], Stanford Medicine, Stanford University-Stanford University, University of Maryland [Baltimore], The Hospital for sick children [Toronto] (SickKids), Department of Biochemistry [University of Toronto], University of Toronto, 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), Swiss Institute for Experimental Cancer Research - Lausanne (ISREC), Swiss Institute for Experimental Cancer Research, Centro Nacional de Microbiología [ISCIII, Madrid, Spain] (CNM), Instituto de Salud Carlos III [Madrid] (ISC), Infection et inflammation (2I), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Institut National de la Santé et de la Recherche Médicale (INSERM), Wake Forest Baptist Medical Center, University of Mississippi Medical Center (UMMC), University of Maryland School of Medicine, University of Maryland System, German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), University of Luebeck, INSTITUT FUR ANGEWANDTE BODENBIOLOGIE GMBH HAMBURG DEU, Partenaires IRSTEA, Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA)-Institut national de recherche en sciences et technologies pour l'environnement et l'agriculture (IRSTEA), European Project: 716058,DeNovoImmunoDesign, Université de Lausanne = University of Lausanne (UNIL), and European Project: 716058,EXCELLENT SCIENCE - European Research Council (ERC),ERC-2016-STG - ERC Starting Grant,DeNovoImmunoDesign(2017)

Subjects
Immunogen, medicine.drug_class, Protein Conformation, Recombinant Fusion Proteins, Protein design, Amino Acid Motifs, computational design, Computational biology, Biology, Monoclonal antibody, Protein Engineering, Epitope, Article, Affinity maturation, 03 medical and health sciences, 0302 clinical medicine, Antigen, backbone, medicine, Respiratory Syncytial Virus Vaccines, Humans, b-cells, 030304 developmental biology, affinity maturation, 0303 health sciences, epitope, Multidisciplinary, dengue virus, Immunodominant Epitopes, Computational Biology, fusion-glycoprotein vaccine, Single-Domain Antibodies, [SHS.ECO]Humanities and Social Sciences/Economics and Finance, Fusion protein, Antibodies, Neutralizing, 3. Good health, nmr structure determination, Respiratory Syncytial Virus, Human, biology.protein, potent, Antibody, influenza, 030217 neurology & neurosurgery
Abstract

De novo protein design has been successful in expanding the natural protein repertoire. However, most de novo proteins lack biological function, presenting a major methodological challenge. In vaccinology, the induction of precise antibody responses remains a cornerstone for next-generation vaccines. Here, we present a protein design algorithm called TopoBuilder, with which we engineered epitope-focused immunogens displaying complex structural motifs. In both mice and nonhuman primates, cocktails of three de novo-designed immunogens induced robust neutralizing responses against the respiratory syncytial virus. Furthermore, the immunogens refocused preexisting antibody responses toward defined neutralization epitopes. Overall, our design approach opens the possibility of targeting specific epitopes for the development of vaccines and therapeutic antibodies and, more generally, will be applicable to the design of de novo proteins displaying complex functional motifs. This work was supported by the swiss initiative for systems biology (SystemsX.ch), the European Research Council (Starting grant - 716058), the Swiss National Science Foundation (310030_163139) and the EPFL’s Catalyze4Life initiative. F.S. was supported by an SNF/Innosuisse BRIDGE Proof-of-Concept grant. J.B. was supported by the EPFL Fellows postdoctoral fellowship. T.K. received funding from the German Center of Infection Research (DZIF) and the Cluster of Excellence RESIST (EXC 2155) of the German Research foundation. J.T.C. was funded by the ERA-Net PrionImmunity project 01GM1503 (Federal Ministry of Education and Research, Germany). V.M. received funding from “AESI-18” (Instituto de Salud Carlos III), grant MPY 375/18. J.PJ. was funded by the Canada Research Chairs program (J.P.J.), T.J. and X.W. were funded by the NIH NIAID (R01 AI137523). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Sí

Published
2020

41. Comparison of four PCR methods for efficient detection of Trypanosoma cruzi in routine diagnostics

Author

Michael Pritsch, Thomas Löscher, Edoardo Marchisio, Stefan Hohnerlein, Carolin Mengele, Gisela Bretzel, Kerstin Helfrich, Peter Seiringer, Nicole Berens-Riha, Michael Hoelscher, María Flores-Chávez, German Center for Infection Research, University of Munich, German Center for Infection Research (Alemania), and Ludwig Maximilian University of Munich (Alemania)

Subjects
Adult, Male, 0301 basic medicine, Microbiology (medical), Chagas disease, Conventional, Adolescent, Trypanosoma cruzi, 030231 tropical medicine, 030106 microbiology, Comparison, Minicircle, Polymerase Chain Reaction, Sensitivity and Specificity, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Diagnosis, parasitic diseases, medicine, Humans, Chagas Disease, Positive serology, biology, General Medicine, Middle Aged, biology.organism_classification, medicine.disease, Leishmania, Trypanosoma cruzi DNA, PCR, Blood, Infectious Diseases, Molecular Diagnostic Techniques, Child, Preschool, Immunology, biology.protein, Female, Pcr method, Antibody, Real-time
Abstract

Due to increased migration, Chagas disease has become an international health problem. Reliable diagnosis of chronically infected people is crucial for prevention of non-vectorial transmission as well as treatment. This study compared four distinct PCR methods for detection of Trypanosoma cruzi DNA for the use in well-equipped routine diagnostic laboratories. DNA was extracted of T. cruzi-positive and negative patients' blood samples and cultured T. cruzi, T. rangeli as well as Leishmania spp. One conventional and two real-time PCR methods targeting a repetitive Sat-DNA sequence as well as one conventional PCR method targeting the variable region of the kDNA minicircle were compared for sensitivity, intra- and interassay precision, limit of detection, specificity and cross-reactivity. Considering the performance, costs and ease of use, an algorithm for PCR-diagnosis of patients with a positive serology for T. cruzi antibodies was developed. This research was supported by the German Center for InfectionResearch through the MD program (to MH, MP and PS). Overall,the project wasfinanced by the University of Munich (LMU). Sí

Published
2017

42. Repertoire characterization and validation of gB-specific human IgGs directly cloned from humanized mice vaccinated with dendritic cells and protected against HCMV

Author

Torsten Witte, Martin Messerle, Andreas Schneider, Johannes Koenig, Sebastian J. Theobald, Michael Mach, Matthias Ballmaier, Simon Danisch, Henning Olbrich, Renata Stripecke, Agnes Bonifacius, Lutz Gieselmann, Constanca Figueiredo, Michael Meyer-Hermann, Meryem S. Ercanoglu, Constantin von Kaisenberg, Frank Klawonn, Britta Eiz-Vesper, Florian Klein, Marija Backovic, Christoph Kreer, Sahamoddin Khailaie, Valery Volk, Hannover Medical School [Hannover] (MHH), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), University of Cologne, University Hospital of Cologne [Cologne], Helmholtz Centre for Infection Research (HZI), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), German Center for Infection Research - Partner Site Bonn-Cologne (DZIF), Ostfalia University of Applied Sciences, Technische Universität Braunschweig = Technical University of Braunschweig [Braunschweig], R.S./S.T./V.V./H.O. Hannover: This work was financed by grants of the German Center for Infections Research (DZIF-TTU07.803 and DZIF-TTU07.805 to R.S.), by a research collaboration grant of 'The Jackson Laboratory' and by the German Research Council (DFG/SFB738 Project A6 to R.S. and MM, DFG/REBIRTH Unit 6.4 to R.S.). S.T. received a RegSci Ph.D. fellowship, H.O. received a DZIF-Strucmed fellowship and V.V. received a DAAD/ZIB Ph.D. fellowship. F.K./C.K./ Univ. Cologne: This work was funded by grants from the German Center for Infection Research (DZIF, F.K.), the German Research Foundation (CRC 1279, F.K., CRC 1310, C.K. and F.K., Heisenberg-Program KL2389/2-1, F.K.) and the European Research Council (ERC-StG639961, F.K.). M.M.-H./ S.K./ Braunschweig: S.K. was supported by the German Federal Ministry of Education and Research (BMBF) for the eMED project SYSIMIT and by the Helmholtz-Gemeinschaft, Zukunftsthema 'Immunology and Inflammation' (ZT-0027)., European Project: 639961,H2020,ERC-2014-STG,HIV1ABTHERAPY(2016), BRICS, Braunschweiger Zentrum für Systembiologie, Rebenring 56,38106 Braunschweig, Germany, HZI,Helmholtz-Zentrum für Infektionsforschung GmbH, Inhoffenstr. 7,38124 Braunschweig, Germany., and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
B Cells, Pathology and Laboratory Medicine, Antibodies, Viral, Biochemistry, MESH: Antibodies, Monoclonal, MESH: Antibodies, Neutralizing, Mice, Animal Cells, Cytotoxic T cell, MESH: Animals, Biology (General), Enzyme-Linked Immunoassays, Immune Response, MESH: Immunoglobulin G, 0303 health sciences, 030302 biochemistry & molecular biology, Antibodies, Monoclonal, 3. Good health, Medical Microbiology, Viral Pathogens, MESH: Immunization, Passive, Antibody, Blood cells, QH301-705.5, T cell, Immunology, Cytotoxic T cells, Microbiology, 03 medical and health sciences, Antigen, Genetics, Humans, Antibody-Producing Cells, Immunoassays, Molecular Biology, Microbial Pathogens, MESH: Humans, Organisms, Immunization, Passive, Proteins, Correction, MESH: Cytomegalovirus Infections, Dendritic Cells, biochemical phenomena, metabolism, and nutrition, medicine.disease, Virology, Antibodies, Neutralizing, Animal Studies, Parasitology, Immunologic diseases. Allergy, MESH: Disease Models, Animal, MESH: Antibodies, Viral, Human cytomegalovirus, Physiology, [SDV]Life Sciences [q-bio], Cytomegalovirus, White Blood Cells, Cytomegalovirus Vaccines, Medizinische Fakultät, Immune Physiology, Cellular types, Medicine and Health Sciences, Antigens, Viral, Immune System Proteins, biology, MESH: Dendritic Cells, T Cells, Immune cells, Animal Models, medicine.anatomical_structure, Experimental Organism Systems, Viruses, Cytomegalovirus Infections, Human Cytomegalovirus, Pathogens, MESH: Antigens, Viral, Research Article, MESH: Cytomegalovirus, Cell biology, Herpesviruses, Somatic hypermutation, Mouse Models, Research and Analysis Methods, Antibodies, Immune system, Model Organisms, MESH: Cytomegalovirus Vaccines, medicine, Animals, ddc:610, MESH: Mice, 030304 developmental biology, Biology and life sciences, RC581-607, Disease Models, Animal, Immunization, Immunoglobulin G, biology.protein, Immunologic Techniques, DNA viruses
Abstract

Human cytomegalovirus (HCMV) causes serious complications to immune compromised hosts. Dendritic cells (iDCgB) expressing granulocyte-macrophage colony-stimulating factor, interferon-alpha and HCMV-gB were developed to promote de novo antiviral adaptive responses. Mice reconstituted with a human immune system (HIS) were immunized with iDCgB and challenged with HCMV, resulting into 93% protection. Immunization stimulated the expansion of functional effector memory CD8+ and CD4+ T cells recognizing gB. Machine learning analyses confirmed bone marrow T/CD4+, liver B/IgA+ and spleen B/IgG+ cells as predictive biomarkers of immunization (≈87% accuracy). CD8+ and CD4+ T cell responses against gB were validated. Splenic gB-binding IgM-/IgG+ B cells were sorted and analyzed at a single cell level. iDCgB immunizations elicited human-like IgG responses with a broad usage of various IgG heavy chain V gene segments harboring variable levels of somatic hypermutation. From this search, two gB-binding human monoclonal IgGs were generated that neutralized HCMV infection in vitro. Passive immunization with these antibodies provided proof-of-concept evidence of protection against HCMV infection. This HIS/HCMV in vivo model system supported the validation of novel active and passive immune therapies for future clinical translation., Author summary Human cytomegalovirus (HCMV) is a ubiquitous pathogen. As long as the immune system is functional, T and B cells can control HCMV. Yet, for patients who have debilitated immune functions, HCMV infections and reactivations cause major complications. Vaccines or antibodies to prevent or treat HCMV are not yet approved. Novel animal models for testing new immunization approaches are emerging and are important tools to identify biomedical products with a reasonable chance to work in patients. Here, we used a model based on mice transplanted with human immune cells and infected with a traceable HCMV. We tested a cell vaccine (iDCgB) carrying gB, a potent HCMV antigen. The model showed that iDCgB halted the HCMV infection in more than 90% of the mice. We found that antibodies were key players mediating protection. Using state-of-the-art methods, we were able to use the sequences of the human antibodies generated in the mice to construct and produce monoclonal antibodies in the laboratory. Proof-of-concept experiments indicated that administration of these monoclonal antibodies into mice protected them against HCMV infection. In summary, this humanized mouse model was useful to test a vaccine and to generate and test novel antibodies that can be further developed for human use.

Published
2019

43. Vulnerability to reservoir reseeding due to high immune activation after allogeneic hematopoietic stem cell transplantation in individuals with HIV-1

Author

Elena Knops, Gero Hütter, Jan van Lunzen, Asier Sáez-Cirión, Valérie Monceaux, Carolina Martínez-Laperche, José Luis Díez-Martín, Pascual Balsalobre, Johanna M. Eberhard, Maria Cristina O. Salgado, Annemarie M. J. Wensing, Kavita Raj, Alessandra Bandera, Nicolaus Kröger, Jürgen Kuball, Guido Kobbe, Javier Martinez-Picado, Mathieu Angin, Jon Badiola, Maximilian Christopeit, Björn Jensen, Linos Vandekerckhove, Caroline Passaes, Mi Kwon, Julian Schulze zur Wiesch, Monique Nijhuis, 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), HIV, Inflammation et persistance, Institut Pasteur [Paris], IrsiCaixa (Institut de Recerca de la Sida), Institute of Virology [Cologne], Universitätsklinikum Köln (Uniklinik Köln)-University of Cologne, University Hospital Düsseldorf, Department of Stem Cell Transplantation, HIV Cure Research Center [Ghent, Belgium], Universiteit Gent = Ghent University [Belgium] (UGENT)-Ghent University Hospital, Hospital Universitario Virgen de las Nieves (Granada), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), King's College Hospital (KCH), ViiV Healthcare [Brentford, UK], Cellex Patient Treatment GmbH, University Medical Center [Utrecht], Hospital General Universitario 'Gregorio Marañón' [Madrid], Universidad Complutense de Madrid = Complutense University of Madrid [Madrid] (UCM), Institució Catalana de Recerca i Estudis Avançats (ICREA), Universitat de Vic, This study was funded by the amfAR (The Foundation for AIDS Research) through the amfAR Research Consortium on HIV Eradication (ARCHE) program (grants 108930-56-RGRL, 109293-59-RGRL, and 109552-61-RGRL). J.M.E. and J.S.z.W. were supported by the German Center for Infection Research (DZIF) and the European HIV Alliance (EHVA). J.S.z.W. got additional funding from the German Research Agency (DFG SFB1328 A12)., We thank all individuals who participated in this study and the IciStem study group (www.icistem.org) for constant support and discussion of results. We also thank the participants and investigators of the ANRS CODEX cohort and ANRS TRANSbioHIV study, European Project: 681032,H2020,H2020-PHC-2015-single-stage_RTD,EHVA(2016), HIV, Inflammation et persistance - HIV, Inflammation and Persistence, Institut Pasteur [Paris] (IP), Universiteit Gent = Ghent University (UGENT)-Ghent University Hospital, and Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB)

Subjects
0301 basic medicine, medicine.medical_treatment, T cell, Priming (immunology), Hematopoietic stem cell transplantation, Biology, CD8-Positive T-Lymphocytes, 03 medical and health sciences, 0302 clinical medicine, Immune system, Antigen, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, medicine, Humans, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation, virus diseases, [SDV.MHEP.HEM]Life Sciences [q-bio]/Human health and pathology/Hematology, General Medicine, 3. Good health, 030104 developmental biology, medicine.anatomical_structure, HIV Antigens, surgical procedures, operative, Hematologic Neoplasms, Immunology, HIV-1, [SDV.IMM]Life Sciences [q-bio]/Immunology, Bone marrow, CD8, 030215 immunology
Abstract

International audience; Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only medical intervention that has led to an HIV cure. Whereas the HIV reservoir sharply decreases after allo-HSCT, the dynamics of the T cell reconstitution has not been comprehensively described. We analyzed the activation and differentiation of CD4+ and CD8+ T cells, and the breadth and quality of HIV- and CMV-specific CD8+ T cell responses in 16 patients with HIV who underwent allo-HSCT (including five individuals who received cells from CCR5Δ32/Δ32 donors) to treat their underlying hematological malignancy and who remained on antiretroviral therapy (ART). We found that reconstitution of the T cell compartment after allo-HSCT was slow and heterogeneous with an initial expansion of activated CD4+ T cells that preceded the expansion of CD8+ T cells. Although HIV-specific CD8+ T cells disappeared immediately after allo-HSCT, weak HIV-specific CD8+ T cell responses were detectable several weeks after transplant and could still be detected at the time of full T cell chimerism, indicating that de novo priming, and hence antigen exposure, occurred during the time of T cell expansion. These HIV-specific T cells had limited functionality compared with CMV-specific CD8+ T cells and persisted years after allo-HSCT. In conclusion, immune reconstitution was slow, heterogeneous, and incomplete and coincided with de novo detection of weak HIV-specific T cell responses. The initial short phase of high T cell activation, in which HIV antigens were present, may constitute a window of vulnerability for the reseeding of viral reservoirs, emphasizing the importance of maintaining ART directly after allo-HSCT.

Published
2019

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

Author

Jennifer L. Guthrie, Sebastien Gagneux, Tim H. Heupink, Timothy M Walker, Annelies Van Rie, Philip Ashton, Maha R. Farhat, Daniela Brites, Galo A. Goig, Lennert Verboven, Dick van Soolingen, Christian Utpatel, Elisa Tagliani, Robin M. Warren, Qian Gao, Viola Dreyer, Philip Supply, Thomas Kohl, Fabrizio Menardo, Yanlin Zhao, Anzaan Dippenaar, Leen Rigouts, Andrea M. Cabibbe, Kris Laukens, Qingyun Liu, Marco Schito, Matteo Zignol, Margaretha de Vos, Iñaki Comas, Matthew Ezewudo, Stefan Niemann, Chloé Loiseau, Timothy C. Rodwell, Anita Suresh, Boatema Ofori-Anyinam, Daniela Maria Cirillo, Yang Zhou, Jennifer L. Gardy, Bouke C. de Jong, Conor J. Meehan, Paolo Miotto, Institute of Tropical Medicine [Antwerp] (ITM), Instituto de biomedicina [Valencia] (IBV), Consejo Superior de Investigaciones Científicas [Madrid] (CSIC), Forschungszentrum Borstel - Research Center Borstel, German Center for Infection Research - Partner Site Hamburg-Lübeck-Borstel-Riems, German Centre for Infection Research (DZIF), Universiteit Antwerpen [Antwerpen], Stellenbosch University, Critical Path Institute [Tucson, AZ], Harvard Medical School [Boston] (HMS), Massachusetts General Hospital [Boston], University of British Columbia (UBC), IRCCS San Raffaele Scientific Institute [Milan, Italie], Center for Global Health Security and Diplomacy [Ottawa] (CGHSD), Food and Drugs Authority [Accra, Ghana] (FDA Ghana), 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), Foundation for Innovative New Diagnostics (FIND), National Institute for Public Health and the Environment [Bilthoven] (RIVM), Chinese Center for Disease Control and Prevention, University of Oxford [Oxford], Swiss Tropical and Public Health Institute [Basel], University of Basel (Unibas), Fudan University [Shanghai], John Radcliffe Hospital [Oxford University Hospital], Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), 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)., ANR-16-CE35-0009,TBemerg,Naissance d'un tueur: facteurs génétiques et adaptations métaboliques impliquées dans l'émergence des bacilles tuberculeux épidémiques(2016), European Project: 311725,EC:FP7:ERC,ERC-2012-StG_20111109,INTERRUPTB(2013), European Project: 638553,H2020,ERC-2014-STG,TB-ACCELERATE(2015), Universiteit Antwerpen = University of Antwerpen [Antwerpen], 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), and University of Oxford

Subjects
Tuberculosis, Best practice, Sequencing data, Harmonization, Biology, Microbiology, Mycobacterium tuberculosis, 03 medical and health sciences, Public health surveillance, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], Drug Resistance, Bacterial, medicine, Humans, Phylogeny, Whole genome sequencing, Computer. Automation, 0303 health sciences, Molecular Epidemiology, General Immunology and Microbiology, Whole Genome Sequencing, 030306 microbiology, Computational Biology, medicine.disease, biology.organism_classification, Data science, 3. Good health, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, Molecular Diagnostic Techniques, Practice Guidelines as Topic, Human medicine
Abstract

International audience; 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.

Published
2019

45. Relevance of Assembly-Activating Protein for Adeno-associated Virus Vector Production and Capsid Protein Stability in Mammalian and Insect Cells

Author

Manuel Gunkel, Kathleen Börner, Stefanie Grosse, Lucie Ménard, Ellen Wiedtke, Eduard Ayuso, Chiara Krämer, Julia Fakhiri, Anne-Kathrin Herrmann, Magalie Penaud-Budloo, Dirk Grimm, Vibor Laketa, Department of Infectious Diseases/Virology [Heidelberg, Germany] (Cluster of Excellence CellNetworks), Universität Heidelberg [Heidelberg], BioQuant Center [Heidelberg, Germany], 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), German Center for Infection Research [Heidelberg, Germany] (DZIF), Heidelberg University, CellNetworks Advanced Biological Screening Facility [Heidelberg, Germany], A.-K.H. and D.G. gratefully acknowledge support from Collaborative Research Center SFB1129 (project TP2, Deutsche Forschungsgemeinschaft [DFG]). D.G. and his lab are further thankful for support from Collaborative Research Center TRR179 (project TP18, DFG). S.G., A.-K.H., E.W., and D.G. are grateful for funding from the Cluster of Excellence CellNetworks at Heidelberg University (funded by the DFG [EXC81]). J.F. appreciates a PhD stipend from the Hartmut Hoffmann-Berling International Graduate School (HBIGS) at Heidelberg University. M.P.-B. and E.A. acknowledge support from Institut National de la Santé et la Recherche Médicale (INSERM), CHU Nantes, University of Nantes, and the Association Française contre les Myopathies (AFM). K.B., V.L. and D.G. gratefully acknowledge funding through the German Center for Infection Research (DZIF, TTU HIV). S.G., C.K., and D.G. further acknowledge support through a research collaboration with the company Baxalta Inc./Shire., JAULIN, Nicolas, Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), and Université de Nantes (UN)-Université de Nantes (UN)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
0301 basic medicine, Proteasome Endopeptidase Complex, Insecta, viruses, [SDV]Life Sciences [q-bio], Genetic Vectors, Immunology, adeno-associated virus, Biology, medicine.disease_cause, Microbiology, Virus, law.invention, Gene Delivery, 03 medical and health sciences, Plasmid, law, Virology, Sf9 Cells, medicine, Animals, Humans, Vector (molecular biology), capsid assembly, Adeno-associated virus, Mammals, AAP, Protein Stability, Virus Assembly, parvovirus, Virion, AAV, Dependovirus, assembly-activating protein, [SDV] Life Sciences [q-bio], Open reading frame, 030104 developmental biology, Capsid, Insect Science, Recombinant DNA, Capsid Proteins, Proteasome Inhibitors, Nuclear localization sequence, HeLa Cells
Abstract

The discovery that adeno-associated virus 2 (AAV2) encodes an eighth protein, called assembly-activating protein (AAP), transformed our understanding of wild-type AAV biology. Concurrently, it raised questions about the role of AAP during production of recombinant vectors based on natural or molecularly engineered AAV capsids. Here, we show that AAP is indeed essential for generation of functional recombinant AAV2 vectors in both mammalian and insect cell-based vector production systems. Surprisingly, we observed that AAV2 capsid proteins VP1 to -3 are unstable in the absence of AAP2, likely due to rapid proteasomal degradation. Inhibition of the proteasome led to an increase of intracellular VP1 to -3 but neither triggered assembly of functional capsids nor promoted nuclear localization of the capsid proteins. Together, this underscores the crucial and unique role of AAP in the AAV life cycle, where it rapidly chaperones capsid assembly, thus preventing degradation of free capsid proteins. An expanded analysis comprising nine alternative AAV serotypes (1, 3 to 9, and rh10) showed that vector production always depends on the presence of AAP, with the exceptions of AAV4 and AAV5, which exhibited AAP-independent, albeit low-level, particle assembly. Interestingly, AAPs from all 10 serotypes could cross-complement AAP-depleted helper plasmids during vector production, despite there being distinct intracellular AAP localization patterns. These were most pronounced for AAP4 and AAP5, congruent with their inability to rescue an AAV2/AAP2 knockout. We conclude that AAP is key for assembly of genuine capsids from at least 10 different AAV serotypes, which has implications for vectors derived from wild-type or synthetic AAV capsids. IMPORTANCE Assembly of adeno-associated virus 2 (AAV2) is regulated by the assembly-activating protein (AAP), whose open reading frame overlaps with that of the viral capsid proteins. As the majority of evidence was obtained using virus-like particles composed solely of the major capsid protein VP3, AAP's role in and relevance for assembly of genuine AAV capsids have remained largely unclear. Thus, we established a trans -complementation assay permitting assessment of AAP functionality during production of recombinant vectors based on complete AAV capsids and derived from any serotype. We find that AAP is indeed a critical factor not only for AAV2, but also for generation of vectors derived from nine other AAV serotypes. Moreover, we identify a new role of AAP in maintaining capsid protein stability in mammalian and insect cells. Thereby, our study expands our current understanding of AAV/AAP biology, and it concomitantly provides insights into the importance of AAP for AAV vector production.

Published
2017

46. Helicobacter pylori Adapts to Chronic Infection and Gastric Disease via pH-Responsive BabA-Mediated Adherence

Author

Verena Königer, D. Scott Merrell, Roman Andriiovych Moskalenko, Rainer Haas, Thomas Borén, Sara Henriksson, Jafar Mahdavi, Abhijit Chowdhury, Johan Ögren, Anders Hofer, Jay V. Solnick, Dan Danielsson, Sara K. Lindén, Dag Ilver, Konstantinos S. Papadakos, Susanne Vikström, Jörgen Ådén, Jan Holgersson, Gerhard Gröbner, Alexej Schmidt, Jeanna Bugaytsova, Oscar Björnham, Göran O. Bylund, Rolf Sjöström, Stefan Oscarson, Dionyssios N. Sgouras, Lori M. Hansen, Yevgen A Chernov, Anders Esberg, Kristof Moonens, Christopher Aisenbrey, Charles Kelly, Ludmilla A. Morozova-Roche, Jeannette M. Whitmire, Beatriz Martinez-Gonzalez, Asish K. Mukhopadhyay, Angela Eldridge, Nicklas Strömberg, Robert H. Gilman, Andre Dubois, Lars Engstrand, Staffan Schedin, Brett A. Chromy, Justine Younson, Matthew Goldman, Anna Shevtsova, Macarena P. Quintana-Hayashi, Hui Liu, Magnus Unemo, Lena Rakhimova, Anna Åberg, Sebastian Suerbaum, Anna Arnqvist, Pär Gideonsson, Maréne Landström, Douglas E. Berg, Kristoffer Brännström, Anders Olofsson, Melissa Mendez, G. Balakrish Nair, Han Remaut, Umeå University, School of Life Sciences, University of Nottingham, UK (UON), Sahlgrenska Academy at University of Gothenburg [Göteborg], Université libre de Bruxelles (ULB), VIB-VUB Center for Structural Biology [Bruxelles], VIB [Belgium], Sumy State University, Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), Uniformed Services University of the Health Sciences (USUHS), King‘s College London, Johns Hopkins Bloomberg School of Public Health [Baltimore], Johns Hopkins University (JHU), School of Digestive and Liver Diseases [Kolkata] (SDLD), National Institute of Cholera and Enteric Diseases, Translational Health Science and Technology Institute [Faridabad] (THSTI), Institut Pasteur Hellénique, Réseau International des Instituts Pasteur (RIIP), Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Karolinska Institutet [Stockholm], Örebro University Hospital [Örebro, Sweden], Hannover Medical School [Hannover] (MHH), German Center for Infection Research - partner site Hannover-Braunschweig (DZIF), School of Chemistry and Chemical Biology (UCD), University College Dublin [Dublin] (UCD), University of California [Davis] (UC Davis), University of California, German Center for Infection Research, Partnersite Munich (DZIF), Département d'Informatique [Bruxelles] (ULB), Faculté des Sciences [Bruxelles] (ULB), Université libre de Bruxelles (ULB)-Université libre de Bruxelles (ULB), University of California [San Diego] (UC San Diego), This work was supported by grants from Vetenskapsrådet (VR/M) to T.B. and S.K.L., Cancerfonden to T.B. and A.A., VR/NT to A.A. and S. Schedin, Formas to S.K.L., the J.C. Kempe and Seth M. Kempe Memorial Foundation, the Knut and Alice Wallenberg Foundation (2012.0090) to T.B. and M.L., European Union Seventh Framework Program GastricGlycoExplorer ITN grant number 316929 to T.B. and Y.A.C., Magn. Bergvall’s Foundation to S. Schedin, DFG (SFB 900/A1) to S. Suerbaum, DFG (HA2697/16-1) to R.H., FP6 ANR-06-PATHO-00701 ERA-NET and Actions Concertées Inter-Pasteuriennes (ACIP) (2006) to D.N.S., NIH R01DK063041 to D.E.B., NIH CA082312 to D.S.M., NIH AI070803 and AI081037 to J.V.S., CSIR project, India (No. 37(1640)/14/EMR –II) to A.K.M., and VIB and FWO (grants: G033717N and 12H8416N) to K.M. and H.R., This paper is dedicated to the memory of our friend, collaborator, and co-author Dr. Andre Dubois, a great scientist who contributed importantly both intellectually and materially to this project. We thank S. Michopoulos and G. Mantzaris for H. pylori clinical isolates and Ö. Furberg (NoPolo.se), N. Ulander (softplanbangkok.com), S. Lindström, and M. Borén for the digital movie, tech, art, and figure work, respectively., Vrije Universiteit Brussel, Basic (bio-) Medical Sciences, Structural Biology Brussels, and Department of Bio-engineering Sciences

Subjects
0301 basic medicine, MESH: Hydrogen-Ion Concentration, Gastric acidity, MESH: Helicobacter Infections/pathology, MESH: Helicobacter pylori/physiology, Disease, adaptation, Bacterial Adhesion, polymorphism, acid responsiveness, MESH: Bacterial Adhesion, Bacterial, Hydrogen-Ion Concentration, gastric acidity, Adhesins, 3. Good health, Cell and molecular biology, medicine.anatomical_structure, Infectious Diseases, MESH: Gastric Mucosa/microbiology, Medical Microbiology, 030106 microbiology, Immunology, Digestive Diseases - (Peptic Ulcer), Biology, blood group antigen-binding adhesion, Microbiology, Helicobacter Infections, diversity, Vaccine Related, 03 medical and health sciences, Virology, ABO blood group system, Biodefense, Gastric mucosa, medicine, MESH: Helicobacter Infections/microbiology, multimerization, Adhesins, Bacterial, subpopulations, Helicobacter pylori, Prevention, gastric cancer, MESH: Adhesins, Bacterial/metabolism, biology.organism_classification, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Gastric Mucosa/pathology, Bacterial adhesin, Chronic infection, 030104 developmental biology, Emerging Infectious Diseases, Gastric Mucosa, Parasitology, Digestive Diseases
Abstract

The BabA adhesin mediates high-affinity binding of Helicobacter pylori to the ABO blood group antigen-glycosylated gastric mucosa. Here we show that BabA is acid responsive-binding is reduced at low pH and restored by acid neutralization. Acid responsiveness differs among strains; often correlates with different intragastric regions and evolves during chronic infection and disease progression; and depends on pH sensor sequences in BabA and on pH reversible formation of high-affinity binding BabA multimers. We propose that BabA's extraordinary reversible acid responsiveness enables tight mucosal bacterial adherence while also allowing an effective escape from epithelial cells and mucus that are shed into the acidic bactericidal lumen andthat bio-selection and changes in BabA bindingproperties through mutation and recombination with babA-related genes are selected by differencesamong individuals and by changes in gastric acidity over time. These processes generate diverse H.pylori subpopulations, in which BabA's adaptive evolution contributes to H.pylori persistence and overt gastric disease.

Published
2017

47. Virological efficacy of 24-week fozivudine-based regimen in ART-naive patients from Tanzania and Cote d'Ivoire

Author

Tessa Lennemann, Pierre-Marie Girard, Alain Pruvost, Raoul Moh, Xavier Anglaret, Lucas Maganga, Friedrich von Massow, Jimson Mgaya, Serge Eholié, Frederic N. Ello, Christine Danel, Michael Hoelscher, Ralph Zuhse, Arne Kroidl, Elmar Saathoff, Division of Infectious Diseases and Tropical Medicine, Ludwig Maximilians University of Munich, German Center for Infection Research (DZIF), Programme PAC Cote Ivoire, Centre Hospitalier Universitaire de Treichville (CHU de Treichville), Service des Maladies Infectieuses et Tropicales, NIMR, Mbeya Medical Research Center, Mbeya Medical Research Center (MMRC), Laboratoire d'Etudes et de Recherches en Immunoanalyses (LERI), Service de Pharmacologie et Immunoanalyse (SPI), Médicaments et Technologies pour la Santé (MTS), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE)-Médicaments et Technologies pour la Santé (MTS), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE), Université Paris-Saclay, Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Department of Infectious Diseases, University of Gothenburg (GU), Chiracon - Biotechnology Park/TGZ I, Helmholtz-Zentrum München (HZM), Institute for Life Sciences and Environment (i-LSE), German Ministry for Science and Education (BMBF) [01KA1201], German Center for Infection Research (DZIF) [TTU 04.703], French Agence Nationale de Recherches sur le Sida (ANRS), European Project: 304786, Ludwig-Maximilians University [Munich] (LMU), and Helmholtz Zentrum München = German Research Center for Environmental Health

Subjects
Male, 0301 basic medicine, Sustained Virologic Response, [SDV]Life Sciences [q-bio], HIV Infections, Tanzania, law.invention, chemistry.chemical_compound, 0302 clinical medicine, Randomized controlled trial, law, Antiretroviral Therapy, Highly Active, Immunology and Allergy, Medicine, Prospective Studies, 030212 general & internal medicine, Lamivudine, Middle Aged, Clinical Science, Lipids, 3. Good health, zidovudine, Treatment Outcome, Infectious Diseases, Anti-Retroviral Agents, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, medicine.drug, Adult, medicine.medical_specialty, Efavirenz, Drug-Related Side Effects and Adverse Reactions, Immunology, antiretroviral therapy, Neutropenia, 03 medical and health sciences, Zidovudine, Internal medicine, Humans, fozivudine, Dosing, business.industry, HIV, medicine.disease, 030112 virology, Clinical trial, Regimen, Cote d'Ivoire, chemistry, Africa, business
Abstract

Supplemental Digital Content is available in the text, Objective: Use of zidovudine (ZDV) in antiretroviral therapy is limited by toxicity and twice daily (b.i.d.) dosing. Fozivudine (FZD) is a ZDV prodrug, which is activated intracellularly to ZDV-monophosphate especially in mononuclear cells but not in bone marrow cells. FZD promises improved myelotoxicity and once daily (o.d.) dosing. Design: Randomized clinical trial. Methods: We conducted an open-label, phase II, proof-of-concept trial investigating three different FZD doses (800 mg o.d., 600 mg b.i.d., 1200 mg o.d.) versus ZDV (300 mg b.i.d.) in combination with lamivudine and efavirenz in HIV-infected, ART-naive patients from Tanzania and Côte d’Ivoire. The primary objective was to demonstrate virological efficacy after 24 weeks in intent-to treat and per-protocol analysis. Secondary endpoints included safety and pharmacokinetic outcomes. Results: Of 119 participants included in the intent-to treat analysis, HIV RNA less than 50 copies/ml at 24 weeks was observed in 64 of 88 (73%) patients in the combined FZD arms versus 24 of 31 (77%) in the ZDV arm (RR 0.94, 95% confidence interval 0.75–1.18). In the per-protocol analysis, responses were 64 of 77 (87%) versus 23 of 29 (79%), respectively (RR 1.09, 95% confidence interval 0.89–1.34). Outcomes were similar between FZD arms. Overall, treatments were well tolerated. Severe or worse anaemia occurred in two cases (one related to FZD, one to ZDV), grade III/IV neutropenia was less frequent in FZD compared with ZDV arms (22 versus 42%, P = 0.035). Pharmacokinetic analysis supported o.d. administration of FZD. Conclusion: Virological 24-week efficacy was demonstrated in b.i.d. and o.d. administered FZD-based regimens. Reduced myelotoxicity of FZD needs to be confirmed in a larger trial.

Published
2017

48. Contribution of alcohol use in HIV/hepatitis C virus co-infection to all-cause and cause-specific mortality: A collaboration of cohort studies

Author

Trickey, Adam, Ingle, Suzanne M, Boyd, Anders, Gill, M John, Grabar, Sophie, Jarrin-Vera, Inmaculada, Obel, Niels, Touloumi, Giota, Zangerle, Robert, Rauch, Andri, Rentsch, Christopher T, Satre, Derek D, Silverberg, Michael J, Bonnet, Fabrice, Guest, Jodie, Burkholder, Greer, Crane, Heidi, Teira, Ramon, Berenguer, Juan, Wyen, Christoph, Abgrall, Sophie, Hessamfar, Mojgan, Reiss, Peter, d'Arminio Monforte, Antonella, McGinnis, Kathleen A, Sterne, Jonathan A C, Wittkop, Linda, Antiretroviral Therapy Cohort Collaboration, NIH - National Institute on Alcohol Abuse and Alcoholism (NIAAA) (Estados Unidos), NIH - National Institute of Allergy and Infectious Diseases (NIAID) (Estados Unidos), United States Department of Veterans Affairs, 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), Swiss National Science Foundation, Ministerio de Sanidad (España), Janssen Cilag, Institut National de la Santé et de la Recherche Médicale (Francia), Wellcome Trust, Gilead Sciences (Spain), Ministère de la Santé (Francia), Austrian Agency for Health and Food Safety, Stichting HIV Monitoring, German Center for Infection Research (Alemania), Ministry of Health Welfare and Sport (Países Bajos), National Institute for Health Research (Reino Unido), Alberta Health (Canadá), Agence Nationale de Recherches sur le sida et les hépatites virales (Francia), ViiV Healthcare, and Integrated Clinical Systems

Subjects
Hepatitis C virus, Cohort, HIV, Mortality, Alcohol, Cause-specific
Abstract

Among persons with HIV (PWH), higher alcohol use and having hepatitis C virus (HCV) are separately associated with increased morbidity and mortality. We investigated whether the association between alcohol use and mortality among PWH is modified by HCV. Data were combined from European and North American cohorts of adult PWH who started antiretroviral therapy (ART). Self-reported alcohol use data, collected in diverse ways between cohorts, were converted to grams/day. Eligible PWH started ART during 2001-2017 and were followed from ART initiation for mortality. Interactions between the associations of baseline alcohol use (0, 0.1-20.0, >20.0 g/day) and HCV status were assessed using multivariable Cox models. Of 58,769 PWH, 29,711 (51%), 23,974 (41%) and 5084 (9%) self-reported alcohol use of 0 g/day, 0.1-20.0 g/day, and > 20.0 g/day, respectively, and 4799 (8%) had HCV at baseline. There were 844 deaths in 37,729 person-years and 2755 deaths in 443,121 person-years among those with and without HCV, respectively. Among PWH without HCV, adjusted hazard ratios (aHRs) for mortality were 1.18 (95% CI: 1.08-1.29) for 0.0 g/day and 1.84 (1.62-2.09) for >20.0 g/day compared with 0.1-20.0 g/day. This J-shaped pattern was absent among those with HCV: aHRs were 1.00 (0.86-1.17) for 0.0 g/day and 1.64 (1.33-2.02) for >20.0 g/day compared with 0.1-20.0 g/day (interaction p

Published
2023

49. Prior flavivirus immunity skews the yellow fever vaccine response to expand cross-reactive antibodies with increased risk of antibody dependent enhancement of Zika and dengue virus infection

Author

Antonio Santos-Peral, Fabian Luppa, Sebastian Goresch, Elena Nikolova, Magdalena Zaucha, Lisa Lehmann, Frank Dahlstroem, Hadi Karimzadeh, Beate M Kummerer, Julia Thorn-Seshold, Elena Winheim, Gerhard Dobler, Michael Hoelscher, Stefan Endres, Anne B Krug, Michael Pritsch, Giovanna Barba-Spaeth, Simon Rothenfusser, Ludwig-Maximilians-Universität München (LMU), Rheinische Friedrich-Wilhelms-Universität Bonn, German Centre for Infection Research (DZIF), Bundeswehr Institute of Microbiology, Fraunhofer Institute for Translational Medicine and Pharmacology (ITMP), Helmholtz Zentrum München (HMGU), Virologie Structurale - Structural Virology, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), This work was supported by FlavImmunity a combined grant of the German Research foundation (DFG) project number 391217598 to SR and ABK and the French National Research Agency (ANR) project number ANR-17-CE15-0031-01 to GBS, by DFG TRR237 grant project number 369799452 to SR and ABK (TRR237 TPB14) and BMK (TRR237 TPA04), by grants of the iMed consortium of the German Helmholtz Societies to SR, by the Einheit für Klinische Pharmakologie (EKLIP), Helmholtz Zentrum München, Neuherberg, Germany to SR and SE, a Stipend (TI 07.003) by the German Center for Infection Research (DZIF) to FL, grants by the Friedrich Baur Foundation (FBS) to JTS, HK and MP, a Metiphys fellowship of the Medical Faculty of the LMU Munich to MP, by the FöFoLe Program of the Medical Faculty of the LMU Munich to SG, EN, LL, FL, the international doctoral program 'iTarget: Immunotargeting of cancer'funded by the Elite Network of Bavaria to ASP, MZ, SG, LL, EN., and 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)

Subjects
vaccine immunogenicity, immunodominance, cross-reactivity, [SDV]Life Sciences [q-bio], pre-existing flavivirus immunity, yellow fever virus
Abstract

Human pathogenic flaviviruses pose a significant health concern and vaccination is the most effective instrument to control their circulation. How pre-existing immunity to antigenically related viruses modulates immunization outcome remains poorly understood. In this study, we evaluated the effect of vaccination against tick-borne encephalitis virus (TBEV) on the epitope immunodominance and immunogenicity of the yellow fever 17D vaccine (YF17D) in a cohort of 250 human vaccinees.Following YF17D vaccination, all study participants seroconverted and generated protective neutralizing antibody titers. At day 28, TBEV pre-immunity did not affect the polyclonal neutralizing response which largely depended on the IgM fraction. We found that sera from TBEV-immunized individuals enhanced YF17D vaccine virus infection via antibody-dependent enhancement (ADE). Upon vaccination, individuals with TBEV pre-immunity had higher concentrations of cross-reactive IgG antibodies with limited neutralizing capacity against YF17D whereas vaccinees without prior flavivirus exposure showed a non-cross-reacting response. Using a set of recombinant YF17D envelope protein mutants displaying different epitopes, we identified quaternary epitopes as the primary target of neutralizing antibodies. Sequential immunizations redirected the IgG response towards the pan-flavivirus fusion loop epitope (FLE) with the potential to mediate enhancement of dengue and Zika virus infections whereas TBEV naïve individuals elicited an IgG response directed towards neutralizing epitopes without an enhancing effect.We propose that the YF17D vaccine effectively conceals the FLE and primes a neutralizing IgG response in individuals with no prior flavivirus exposure. In contrast, the response in TBEV-experienced recipients favors weakly-neutralizing, cross-reactive epitopes potentially increasing the risk of severe dengue and Zika disease due to ADE.

Published
2023

50. Chromosome folding and prophage activation reveal specific genomic architecture for intestinal bacteria

Author

Lamy-Besnier, Quentin, Bignaud, Amaury, Garneau, Julian, Titecat, Marie, Conti, Devon, von Strempel, Alexandra, Monot, Marc, Stecher, Bärbel, Koszul, Romain, Debarbieux, Laurent, Marbouty, Martial, Bactériophage, bactérie, hôte - Bacteriophage, bacterium, host, 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), Régulation spatiale des Génomes - Spatial Regulation of Genomes, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Collège Doctoral, Sorbonne Université (SU), Biomics (plateforme technologique), Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), Institute for Translational Research in Inflammation - U 1286 (INFINITE (Ex-Liric)), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Lille, Max Von Pettenkofer Institute (MVP), Ludwig-Maximilians-Universität München (LMU), German Center for Infection Research, Partnersite Munich (DZIF), This research was supported by funding to BS from DFG-STE-1971/11–1 (PhaStGut project), to BS from the European Research Council under the Horizon 2020 Program (ERC grant agreement 865615), to LD and MMa from PRCI ANR-20-CE92-0048 (PhaStGut project), and to RK from the European Research Council under the Horizon 2020 Program (ERC grant agreement 771813) and from JPI-EC-AMR STARCS ANR-16-JPEC-0003–05. QLB received funding from École Doctorale FIRE-Program Bettencourt. AB is supported by an ENS fellowship from the French Ministry of Higher Education, Research and Innovation. MMo and JRG were supported by JCJC ANR-18-CE35-0011 (project CDPhages). MT received funding from DigestScience. Biomics Platform, C2RT, Institut Pasteur, Paris, France, was supported by France Génomique (ANR-10-INBS-09) and IBISA. AB and DC belong to Ecole Doctorale Complexité du vivant ED515 of Sorbonne Université., ANR-20-CE92-0048,PhaStGut,Etude des mécanismes de la coexistence stable entre bactériophages et bactéries et de ses conséquences sur la fonction du microbiote intestinal(2020), ANR-16-JPEC-0003,STARCS,Selection and Transmission of Antimicrobial Resistance in Complex Systems(2016), ANR-18-CE35-0011,CDPhages,Le role des bactériophages dans l'évolution de la virulence chez Clostridium difficile(2018), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), and European Project: 771813,ERC-2017-COG,SynarchiC(2018)

Subjects
Microbiology (medical), MESH: Humans, Virome, MESH: Genomics, [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Molecular biology, OMM12, Phages Gut HiC Virome OMM12 3D signatures, Microbiology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, MESH: Bacteria, MESH: Prophages, 3D signatures, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Phages, Gut, MESH: Animals, MESH: Ecosystem, MESH: Chromosomes, MESH: Bacteriophages, HiC, MESH: Mice
Abstract

Background Bacteria and their viruses, bacteriophages, are the most abundant entities of the gut microbiota, a complex community of microorganisms associated with human health and disease. In this ecosystem, the interactions between these two key components are still largely unknown. In particular, the impact of the gut environment on bacteria and their associated prophages is yet to be deciphered. Results To gain insight into the activity of lysogenic bacteriophages within the context of their host genomes, we performed proximity ligation-based sequencing (Hi-C) in both in vitro and in vivo conditions on the 12 bacterial strains of the OMM12 synthetic bacterial community stably associated within mice gut (gnotobiotic mouse line OMM12). High-resolution contact maps of the chromosome 3D organization of the bacterial genomes revealed a wide diversity of architectures, differences between environments, and an overall stability over time in the gut of mice. The DNA contacts pointed at 3D signatures of prophages leading to 16 of them being predicted as functional. We also identified circularization signals and observed different 3D patterns between in vitro and in vivo conditions. Concurrent virome analysis showed that 11 of these prophages produced viral particles and that OMM12 mice do not carry other intestinal viruses. Conclusions The precise identification by Hi-C of functional and active prophages within bacterial communities will unlock the study of interactions between bacteriophages and bacteria across conditions (healthy vs disease).

Published
2023

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