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101. Genomic Epidemiology of 2015–2016 Zika Virus Outbreak in Cape Verde

Author

Bram Vrancken, Cecílio Mendes Pires, Jorge Noel Barreto, Ousmane Faye, Maryam Diarra, Silvânia Da Veiga Leal, Mamadou Diop, Ibrahima Socé Fall, Carolina Cardoso da Silva Leite Gomes, Fabiana Gámbaro-Roglia, Mariano Salazar Castellon, Maria de Lourdes Monteiro, Amadou A. Sall, Philippe Lemey, Déborah Delaune, Linete Fernandes, António Lima Moreira, Matthieu Prot, Oumar Faye, Jessica Ramos, Frédéric Lemoine, Cheikh Loucoubar, Sebastian Lequime, Tomás Valdez, Maria da Luz Lima Mendonça, Laurence Ma, Sandra Tavarez, Oumar Ndiaye, Etienne Simon-Loriere, Anavaj Sakuntabhai, Edward C. Holmes, Gamou Fall, Maria do Céu Teixeira, Maria Filomena Tavares, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Ministry of Health [Cape Verde], Catholic University of Leuven - Katholieke Universiteit Leuven (KU Leuven), Institut Pasteur [Paris] (IP), World Health Organisation (WHO), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Sorbonne Université (SU), Université Paris-Sud - Paris 11 (UP11), Institut de Recherche Biomédicale des Armées [Brétigny-sur-Orge] (IRBA), Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, The University of Sydney, This work was supported by Institut Pasteur de Dakar. P.L. received funding by the European Research Council under the European Union’s Horizon 2020 Research and Innovation Programme (grant agreement no. 725422-ReservoirDOCS) and by the Wellcome Trust through project 206298/Z/17/Z. S.L. and B.V. are supported by the Fonds Wetenschappelijk Onderzoek (Belgium). E.S.-L. received funding from the INCEPTION program (Investissements d’Avenir grant ANR-16-CONV-0005) and Institut Pasteur. F.G.-R. is part of the Pasteur-Paris University International doctoral program, BioSPC doctoral school. E.C.H. is funded by an Australian Research Council Australian Laureate Fellowship (FL170100022)., We thank 2 anonymous reviewers whose suggestions helped to improve this manuscript, ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), European Project: 0725422(2007), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche Biomédicale des Armées (IRBA), and Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris]

Subjects
Microcephaly, vector-borne infections, lcsh:Medicine, serology, phylogeography, Zika virus, Disease Outbreaks, 0302 clinical medicine, Epidemiology, Cabo Verde, epidemiologic studies, microcephaly, 030212 general & internal medicine, Cape Verde, biology, Zika Virus Infection, Genomics, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, Africa, Western, Infectious Diseases, Geography, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Synopsis, epidemiology, Brazil, Microbiology (medical), medicine.medical_specialty, Lineage (genetic), 030231 tropical medicine, Asian lineage, Virus, Genomic Epidemiology of 2015–2016 Zika Virus Outbreak in Cape Verde, lcsh:Infectious and parasitic diseases, Cape verde, 03 medical and health sciences, West Africa, genomics, medicine, Humans, lcsh:RC109-216, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, viruses, Western Africa, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], outbreak, lcsh:R, Outbreak, Zika Virus, biology.organism_classification, medicine.disease, Virology, Phylogeography, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, disease outbreaks, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM]
Abstract

During 2015-2016, Cape Verde, an island nation off the coast of West Africa, experienced a Zika virus (ZIKV) outbreak involving 7,580 suspected Zika cases and 18 microcephaly cases. Analysis of the complete genomes of 3 ZIKV isolates from the outbreak indicated the strain was of the Asian (not African) lineage. The Cape Verde ZIKV sequences formed a distinct monophylogenetic group and possessed 1-2 (T659A, I756V) unique amino acid changes in the envelope protein. Phylogeographic and serologic evidence support earlier introduction of this lineage into Cape Verde, possibly from northeast Brazil, between June 2014 and August 2015, suggesting cryptic circulation of the virus before the initial wave of cases were detected in October 2015. These findings underscore the utility of genomic-scale epidemiology for outbreak investigations. ispartof: EMERGING INFECTIOUS DISEASES vol:26 issue:6 pages:1084-1090 ispartof: location:United States status: published

Published
2020
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102. Risk factors for Plasmodium falciparum gametocyte positivity in a longitudinal cohort.

Author

Laura Grange, Cheikh Loucoubar, Olivier Telle, Adama Tall, Joseph Faye, Cheikh Sokhna, Jean-François Trape, Anavaj Sakuntabhai, Jean-François Bureau, and Richard Paul

Subjects
Medicine, Science
Abstract

Malaria transmission intensity is highly heterogeneous even at a very small scale. Implementing targeted intervention in malaria transmission hotspots offers the potential to reduce the burden of disease both locally and in adjacent areas. Transmission of malaria parasites from man to mosquito requires the production of gametocyte stage parasites. Cluster analysis of a 19-year long cohort study for gametocyte carriage revealed spatially defined gametocyte hotspots that occurred during the time when chloroquine was the drug used for clinical case treatment. In addition to known risk factors for gametocyte carriage, notably young age (

Published
2015
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104. Antibody fucosylation predicts disease severity in secondary dengue infection

Author

Heidi Auerswald, Stylianos Bournazos, Tineke Cantaert, Anavaj Sakuntabhai, Sowath Ly, Philippe Dussart, Jeffrey V. Ravetch, Veasna Duong, Hoa Thi My Vo, Rockefeller University [New York], Immunologie [Phnom Penh], Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Unité de Virologie / Virology Unit [Phnom Penh], Réseau International des Instituts Pasteur (RIIP), Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], We acknowledge support from the Howard Hughes Medical Institute (HHMI)–Wellcome Trust (208710/Z/17/Z to T.C.), the National Institute of Allergy and Infectious Diseases (NIAID) (R01AI137276 to S.B., U19AI111825 to J.V.R.), and the Rockefeller University. Sample collection from DENV patients was supported by the EU Seventh Framework Programme (FP7/2007-2011). This manuscript was prepared using samples from ZIKV-infected individuals provided by Blood Systems Research Institute (BSRI) from studies funded in whole or in part by NHLBI (HHSN268201100001I), Roche Molecular Systems, Inc., and the Department of Health and Human Services, Biomedical Advanced Research and Development Authority (HHSO100201600010C). The content is solely the responsibility of the authors and does not necessarily represent the official views of BSRI or the NIH., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Male, viruses, 030231 tropical medicine, Dengue virus, medicine.disease_cause, Antibodies, Viral, Solanum, Severity of Illness Index, Article, Dengue fever, Pathogenesis, Dengue, 03 medical and health sciences, 0302 clinical medicine, Severity of illness, Medicine, Humans, Antibody-dependent enhancement, Severe Dengue, Child, Fucosylation, Fucose, Multidisciplinary, biology, business.industry, Coinfection, Zika Virus Infection, Receptors, IgG, Antibody titer, virus diseases, Dengue Virus, medicine.disease, Antibodies, Neutralizing, Antibody-Dependent Enhancement, 3. Good health, Immunoglobulin Fc Fragments, 030104 developmental biology, Immunoglobulin G, Immunology, biology.protein, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Antibody, business, Sugars
Abstract

IgG fucosylation predicts dengue severity Secondary infections with dengue virus (DENV) can produce life-threatening symptoms, including thrombocytopenia and hemorrhagic disease, when preexisting DENV-reactive immunoglobulin G1 (IgG1) antibodies promote the infection of immune cells. Although severe dengue symptoms are associated with increased levels of afucosylated IgG1 glycoforms, it is unclear whether this is simply a result of the infection or if it is a preexisting phenomenon that can dictate susceptibility to this disease. Bournazos et al. studied the Fab and Fc structures of anti-DENV antibodies from patients before and after infection and with variable disease outcomes (see the Perspective by de Alwis and Ooi). They found that DENV infection induced specific increases in IgG1 afucosylation, and levels of afucosylated IgG1 could indeed predict dengue disease severity, making IgG1 fucosylation status a potentially useful prognostic tool for the treatment of dengue patients. Science , abc7303, this issue p. 1102 ; see also abj0435, p. 1041

Published
2021
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105. Differential transcriptomic response of Anopheles arabiensis to Plasmodium vivax and Plasmodium falciparum infection

Author

Tsapi Mt, Goupeyou-Youmsi J, Etienne Kornobis, Romain Girod, Nicolas Puchot, Anavaj Sakuntabhai, Marie-Agnes-Dillies, Catherine Bourgouin, Milijaona R, English S, Caroline Proux, Mamadou Ousmane Ndiath, Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Biomics (plateforme technologique), Institut Pasteur [Paris], Hub Bioinformatique et Biostatistique - Bioinformatics and Biostatistics HUB, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), St Catharine's College Cambridge [Cambridge, UK], Transcriptome et Epigénome (PF2), Institut Pasteur de Madagascar, Réseau International des Instituts Pasteur (RIIP), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris] (IP)

Subjects
0303 health sciences, biology, [SDV]Life Sciences [q-bio], 030231 tropical medicine, Plasmodium vivax, Anopheles, Plasmodium falciparum, biology.organism_classification, medicine.disease, Virology, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Genotype, parasitic diseases, medicine, Gametocyte, Vector (molecular biology), Gene, Malaria, 030304 developmental biology
Abstract

Plasmodium vivax malaria is now recognized as the second most dangerous parasitic threat to human health with the regular decrease of Plasmodium falciparum worldwide over recent decades. A very limited numbers of studies address the interaction of P. vivax with its Anopheles mosquito vectors. Those studies were conducted in P. vivax endemic countries with P.vivax local major vectors for which limited genomic and genetic tools are available. Despite the presence of P. vivax in several African countries and increasing reports on its occurrence in many others, there is virtually no data on the molecular responses of Anopheles arabiensis, a major African mosquito vector, to P. vivax, which limits the development of further “mosquito-targeted” interventions aimed at reducing P. vivax transmission. Taking advantage of the situation of Madagascar where P. falciparum, P. vivax and An. arabiensis are present, we explore the molecular responses of An. arabiensis towards these two human malaria parasites. RNA sequencing on RNAs isolated from mosquito midguts dissected at the early stage of infection (24 hours) was performed using mosquitoes fed on the blood of P. vivax and P. falciparum gametocyte carriers in a field station. From a de novo assembly of An. arabiensis midgut total RNA transcriptome, the comparative analysis revealed that a greater number of genes were differentially expressed in the mosquito midgut in response to P. vivax (209) than to P. falciparum (81). Among these, 15 common genes were identified to be significantly expressed in mosquito midgut 24 hours after ingesting P. vivax and P. falciparum gametocytes, including immune responsive genes and genes involved in amino-acid detoxification pathways. Importantly, working with both wild mosquitoes and field circulating parasites, our analysis revealed a strong mosquito genotype by parasite genotype interaction. Our study also identified 51 putative long non-coding RNAs differentially expressed in An. arabiensis mosquito infected midgut. Among these, several mapped to the published An. arabiensis genome at genes coding immune responsive genes such as gambicin 1, leucine-rich repeat containing genes, either on sense or antisense strands.This study constitutes the first comparison of An. arabiensis molecular interaction with P. vivax and P. falciparum, investigating both coding and long non-coding RNAs for the identification of potential transcripts, that could lead to the development of novel approaches to simultaneously block the transmission of vivax and falciparum malaria.

Published
2021

107. Genetic association study of exfoliation syndrome identifies a protective rare variant at LOXL1 and five new susceptibility loci

Author

Daniele Cusi, Etsuo Chihara, Leyla Al-Jasim, Ya Xing Wang, Tero Kivelä, Jinghong Sang, Adeyinka O. Ashaye, Bowen Zhao, Tan Do, Susanne Moebus, Ursula Schlötzer-Schrehardt, Shamira A. Perera, Augustine W O Cheong, Afsaneh Naderi Beni, Francisco A. Escudero-Domínguez, Yoshiaki Kiuchi, Tomomi Higashide, DS Klobassa, Friedrich E. Kruse, Nicole Weisschuh, Chunyan Qiao, Muhammad Imran Khan, Martin L. Hibberd, Arthur J. Sit, Jamie E Craig, Akitoshi Yoshida, Periasamy Sundaresan, Humaira Ayub, Kathryn P. Burdon, Jonathan G Crowston, Kazunori Miyata, Marisa Cruz-Aguilar, Markus M. Nöthen, Hasnaa Lamari, Michael A. Hauser, Louis R. Pasquale, Anneke I. den Hollander, Eija Vesti, Ursula Hoja, Raphael Q Soh, Burcu Kasım, Adeola O Onakoya, Rachel W. Kuchtey, Eugeny L. Akopov, Liang Xu, Juan Carlos Zenteno, Chaiwat Teekhasaenee, Saleh A. Al-Obeidan, Eleftherios Anastasopoulos, Anita S Y Chan, Nagahisa Yoshimura, John Kuchtey, Naris Kitnarong, Yaan Fun Chong, Boonsong Wanichwecharugruang, R.R. Fayzrakhmanov, Paul Mitchell, N Kalpana, Unnur Thorsteinsdottir, Kei Tashiro, Rajesh Kumar, Jin Wook Jeoung, Deepak P. Edward, Frederico Martinon-Torres, Bilge Batu, Anavaj Sakuntabhai, Robert N. Weinreb, Héctor González-Iglesias, Sasan Moghimi, Jia Nee Foo, Nkechi J Uche, Karen Curtin, Kenji Inoue, Lingam Vijaya, Makoto Aihara, Dilek Aktas, Norimoto Gotoh, Wasu Supakontanasan, Laura Dallorto, Takako Sugimoto, Jonathan L. Haines, Olusola Olawoye, Janey L. Wiggs, Sripriya Sarangapani, Craig J. Chaya, Theofanis Pappas, Fotis Topouzis, Eranga N. Vithana, Steffen Heegaard, Fridbert Jonasson, Kazuhiko Mori, Idakwo Ugbede, Hongyan Jia, Anthi Chatzikyriakidou, Robert P. Igo, Soon Cheol Cha, Yueming Chen, Su-Ling Ho, Zhenglin Yang, Jost B. Jonas, Francesca Pasutto, Ken Hayashi, Rahat Husain, Georg Mossböck, S Fabian Lerner, R. Rand Allingham, Priti Sahay, Fumihiko Matsuda, Yanin Suwan, Teresa Rolle, Robert Ritch, Peter Kraft, Trevor R. Carmichael, Kar Seng Sim, Raheel Qamar, Gordana Sunaric Megevand, Tomasz Zarnowski, Shazia Micheal, Scott Thomas, Paolo Frezzotti, Vera Vysochinskaya, Linda M. Zangwill, Alina Popa Cherecheanu, Tin Aung, Jessica N. Cooke Bailey, Kyu Hyung Park, Edward Dervan, Suhanya Okeke, Pablo Fornero, Sidi M Ezzouhairi, Pascal Reynier, Gudmar Thorleifsson, Michael V. Dubina, Kazuhisa Sugiyama, Sylvain Roy, Per Kappelgaard, Mineo Ozaki, Vijayan Saravanan, Carlo Lavia, Wenda L. Greer, Takanori Mizoguchi, Alireza Lashay, A. Binder, Daniel Berner, Su Qin Peh, Balram Chowbay, Nino Kobakhidze, Ifeoma N. Asimadu, Delia Sivori, Gopalakrishnan Prakadeeswari, Alexandros Lambropoulos, Michael Coote, Sergei Y. Astakhov, Shahin Yazdani, Dan Milea, Montserrat García, Lydia Álvarez, Kenji Yamashiro, Soumya Raychaudhuri, Pratap Challa, Aparna Rao, Jae H. Kang, Khai Koon Heng, Richard K. Lee, Tien Yin Wong, Alex W. Hewitt, Yoko Ikeda, Kessara Pathanapitoon, Panayiota Founti, Daniella Bach-Holm, Emmanuelle Souzeau, Margaret A. Pericak-Vance, Michèle Ramsay, Nkiru Kizor-Akaraiwe, Yosai Mori, Antonio Maria Fea, Chandrashekaran Shivkumar, Xiao Yu Ng, Jie Jin Wang, Erika Salvi, Giang T T Nguyn, Steffen Uebe, Tamara Zompa, Anne L. Coleman, Werner Zenz, Min Sagong, Luis Fernández-Vega Cueto, Farah Akhtar, Susan Williams, Sarah C. Nelson, Bradford J. Shingleton, Ryuichi Ideta, Leon W. Herndon, Zheng Li, Murat Irkec, M. Roy Wilson, Ewa Kosior-Jarecka, Christian Y. Mardin, Mozhgan Rezaei Kanavi, Tsutomu Ohashi, Abderrahman Rafei, Rengaraj Venkatesh, Stefan Herms, George Chichua, Mohammad Pakravan, Robyn M. Rautenbach, Shi Qi Mok, Trình V Nguyn, Patricio G. Schlottmann, Nassim Khatibi, Daniel Gaston, Masaru Inatani, Morio Ueno, Mukharram M. Bikbov, Eoin Silke, Homa Naderifar, Linda Hansapinyo, Paolo Manunta, Z. Xie, Urszula Lukasik, Eray Atalay, Lulin Huang, Xuyang Liu, Chie Sotozono, Shuang Ru Goh, John H. Fingert, Richard A. Mills, Khaled K. Abu-Amero, Xiao Yin Chen, Matthias Zenkel, Sergo Tabagari, Irma Järvelä, Xueyi Chen, Stéphanie Leruez, Yury S. Astakhov, Sonia Davila, Yildirim Nilgün, Ronnie George, Shin-ichi Manabe, Miguel Coca-Prados, Masahiro Miyake, Ignacio Lischinsky, Rogelio González-Sarmiento, Arkasubhra Ghosh, A. Emelyanov, Çilingir Oguz, Masakazu Nakano, Rohit Shetty, Karen Bedard, Toshiya Sakurai, Yutao Liu, Barbara M Wirostko, Hui Zhang, Ulrich-Christoph Welge-Luessen, Toshiaki Kubota, Vania Castro, Hip X Nguyn, Liyun Jia, Ari Ziskind, Hideki Chuman, Andrew C. Orr, Satoko Nakano, Daniela Paoli, Masahide Yanagi, Aravind Haripriya, Kari Stefansson, Pedro Pablo Rodríguez-Calvo, Hui Meng Soo, Chiea Chuen Khor, Gyulli M. Kazakbaeva, Osvaldo Cuello, Mei Chin Lee, Ki Ho Park, Natalia Porporato, Lourdes de Juan Marcos, Ching-Yu Cheng, Shigeyasu Kazama, Shigeru Kinoshita, Axel M. Hillmer, Alan S. Crandall, Victor H. K. Yong, Ohoud Owaidhah, Rodolfo Perez Grossmann, Jeeyun Ahn, André Reis, Nevbahar Tamçelik, Satoshi Ishiko, Antonio Salas, Ningli Wang, Singapore Eye Research Institute [Singapore] (SERI), Ozaki Eye Hospital [Miyazaki], Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), deCODE genetics [Reykjavik], Mizoguchi Eye Hospital [Sasebo], Case Western Reserve University [Cleveland], Aravind Eye Hospital [Madurai, India], University of the Witwatersrand [Johannesburg] (WITS), Pavlov First Saint Petersburg State Medical University [St. Petersburg], Dalhousie University [Halifax], Flinders University [Adelaide, Australia], Kyoto Prefectural University of Medicine [Kyoto, Japon], King Saud University [Riyadh] (KSU), Genome Institute of Singapore (GIS), Aravind Medical Research Foundation (AMRF), Université de Médecine Carol Davila, Harvard Medical School [Boston] (HMS), University of Washington [Seattle], Hayashi Eye Hospital [Fukuoka], Shinjo Eye Clinic [Nagoya], Medical University of Lublin, Inoue Eye Hospital [Tokyo], Hacettepe University = Hacettepe Üniversitesi, Universidad de Oviedo [Oviedo], Kanazawa University (KU), Department of Medical and Clinical Genetics [Helsinki], Haartman Institute [Helsinki], Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Faculty of Medecine [Helsinki], Helsingin yliopisto = Helsingfors universitet = University of Helsinki-Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Organizacion Medica de Investigacion (OMI BUENOS AIRES), Fundacion para el Estudio del Glaucoma [Buenos Aires], Chercheur indépendant, Eskisehir Osmangazi University, Ufa Eye Research Institute [Bashkortostan], Seoul National University Hospital, Yeungnam University [South Korea], Kyoto University, Universidad Nacional Autónoma de México = National Autonomous University of Mexico (UNAM), Universität Heidelberg [Heidelberg] = Heidelberg University, Birla Institute of Scientific Research (BISR), B. M. Birla Science and Technology Center, Faculty of Computer Science, Department of Pathology and Immunology, Geneva University Hospital (HUG), Key Laboratory for Information System Security, ministry of education, Numerical modeling and high performance computing for evolution problems in complex domains and heterogeneous media (NACHOS), Inria Sophia Antipolis - Méditerranée (CRISAM), Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (LJAD), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA)-Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)-Université Côte d'Azur (UCA), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Institute of Human Genetics [Erlangen, Allemagne], Department of Ophthalmology, School of Medicine [Thessaloniki, Grèce], Aristotle University of Thessaloniki, Università degli Studi di Siena = University of Siena (UNISI), Department of Medicine, Surgery, and Dentistry, University of Milano, Japan Advanced Institute of Science and Technology (JAIST), Etudes génomiques trans-ethniques des maladies multifactorielles, Kyoto University-Institut National de la Santé et de la Recherche Médicale (INSERM), Fondation Ophtalmologique Adolphe de Rothschild [Paris], Archaeogenetics Laboratory, Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Rheinische Friedrich-Wilhelms-Universität Bonn, University of Kentucky (UK), Helsinki University Eye Hospital, Turku University Hospital, Turku, Finland, COMSATS Institute of Information Technology (CIIT), Department of Epidemiology, Harvard School of Public Health, University of Miami Leonard M. Miller School of Medicine (UMMSM), Brigham and Women's Hospital [Boston], Department of Neuroscience and Pharmacology, Section of Eye Pathology, University of Copenhagen, University of Copenhagen = Københavns Universitet (UCPH), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, University of California [San Diego] (UC San Diego), University of California (UC), University of Iceland [Reykjavik], New York Eye and Ear Infirmary of Mount Sinai [New York] (NYEE), Oita University Faculty of Medicine [Oita, Japon], Radboud University Medical Center [Nijmegen], Oogheelkunde, RS: FHML non-thematic output, Kyoto University [Kyoto], Universidad Nacional Autónoma de México (UNAM), Universität Heidelberg [Heidelberg], Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire Jean Alexandre Dieudonné (JAD), Dipartimento di Scienze oftalmologiche e Neurochirurgiche, Universita' degli Studi di Siena, Siena, Kyoto University [Kyoto]-Institut National de la Santé et de la Recherche Médicale (INSERM), Rothschild Hospital, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), University of Kentucky, University of Copenhagen = Københavns Universitet (KU), University of California, Aung, Tin, Ozaki, Mineo, Lee, Mei Chin, Schlötzer Schrehardt, Ursula, Thorleifsson, Gudmar, Mizoguchi, Takanori, Igo, Robert P, Haripriya, Aravind, Williams, Susan E, Astakhov, Yury S, Orr, Andrew C, Burdon, Kathryn P, Nakano, Satoko, Mori, Kazuhiko, Abu Amero, Khaled, Hauser, Michael, Li, Zheng, Prakadeeswari, Gopalakrishnan, Bailey, Jessica N. Cooke, Cherecheanu, Alina Popa, Kang, Jae H, Nelson, Sarah, Hayashi, Ken, Manabe, Shin Ichi, Kazama, Shigeyasu, Zarnowski, Tomasz, Inoue, Kenji, Irkec, Murat, Coca Prados, Miguel, Sugiyama, Kazuhisa, Järvelä, Irma, Schlottmann, Patricio, Lerner, S. Fabian, Lamari, Hasnaa, Nilgün, Yildirim, Bikbov, Mukharram, Park, Ki Ho, Cha, Soon Cheol, Yamashiro, Kenji, Zenteno, Juan C, Jonas, Jost B, Kumar, Rajesh S, Perera, Shamira A, Chan, Anita S. Y, Kobakhidze, Nino, George, Ronnie, Vijaya, Lingam, Do, Tan, Edward, Deepak P, de Juan Marcos, Lourde, Pakravan, Mohammad, Moghimi, Sasan, Ideta, Ryuichi, Bach Holm, Daniella, Kappelgaard, Per, Wirostko, Barbara, Thomas, Samuel, Gaston, Daniel, Bedard, Karen, Greer, Wenda L, Yang, Zhenglin, Chen, Xueyi, Huang, Lulin, Sang, Jinghong, Jia, Hongyan, Jia, Liyun, Qiao, Chunyan, Zhang, Hui, Liu, Xuyang, Zhao, Bowen, Wang, Ya Xing, Xu, Liang, Leruez, Stéphanie, Reynier, Pascal, Chichua, George, Tabagari, Sergo, Uebe, Steffen, Zenkel, Matthia, Berner, Daniel, Mossböck, Georg, Weisschuh, Nicole, Hoja, Ursula, Welge Luessen, Ulrich Christoph, Mardin, Christian, Founti, Panayiota, Chatzikyriakidou, Anthi, Pappas, Theofani, Anastasopoulos, Eleftherio, Lambropoulos, Alexandro, Ghosh, Arkasubhra, Shetty, Rohit, Porporato, Natalia, Saravanan, Vijayan, Venkatesh, Rengaraj, Shivkumar, Chandrashekaran, Kalpana, Narendran, Sarangapani, Sripriya, Kanavi, Mozhgan R, Beni, Afsaneh Naderi, Yazdani, Shahin, Lashay, Alireza, Naderifar, Homa, Khatibi, Nassim, Fea, Antonio, Lavia, Carlo, Dallorto, Laura, Rolle, Teresa, Frezzotti, Paolo, Paoli, Daniela, Salvi, Erika, Manunta, Paolo, Mori, Yosai, Miyata, Kazunori, Higashide, Tomomi, Chihara, Etsuo, Ishiko, Satoshi, Yoshida, Akitoshi, Yanagi, Masahide, Kiuchi, Yoshiaki, Ohashi, Tsutomu, Sakurai, Toshiya, Sugimoto, Takako, Chuman, Hideki, Aihara, Makoto, Inatani, Masaru, Miyake, Masahiro, Gotoh, Norimoto, Matsuda, Fumihiko, Yoshimura, Nagahisa, Ikeda, Yoko, Ueno, Morio, Sotozono, Chie, Jeoung, Jin Wook, Sagong, Min, Park, Kyu Hyung, Ahn, Jeeyun, Cruz Aguilar, Marisa, Ezzouhairi, Sidi M, Rafei, Abderrahman, Chong, Yaan Fun, Ng, Xiao Yu, Goh, Shuang Ru, Chen, Yueming, Yong, Victor H. 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Subjects
0301 basic medicine, Male, Calcium Channels/genetics, Messenger, Medizin, PSEUDOEXFOLIATION SYNDROME, Genome-wide association study, BLOOD-PRESSURE, Disease, Exfoliation Syndrome, Eye, Exfoliation Syndrome/ethnology/genetics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, PARKINSONS-DISEASE, 80 and over, ta319, Missense mutation, Genetics, Aged, 80 and over, Amino Acid Oxidoreductases/genetics/physiology, Alleles, Amino Acid Oxidoreductases, Amino Acid Substitution, Asian Continental Ancestry Group, Calcium Channels, Cell Adhesion, Extracellular Matrix, Female, Gene Expression Profiling, Genetic Predisposition to Disease, Haplotypes, Humans, Molecular Chaperones, RNA, Messenger, Spheroids, Cellular, Genome-Wide Association Study, Mutation, Missense, Point Mutation, Metaanalysis, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], 3. Good health, ALZHEIMERS-DISEASE, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Molecular Chaperones/biosynthesis/genetics, Biology, SYNONYMOUS MUTATIONS, ta3111, Article, 03 medical and health sciences, Asian People, Asian Continental Ancestry Group/genetics, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, Allele, Risk factor, GENOME-WIDE ASSOCIATION, Eye/metabolism, Aged, Genetic association, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Haplotype, Individuals, Glaucoma, Odds ratio, Extracellular Matrix/metabolism, RNA, Messenger/biosynthesis, MACULAR DEGENERATION, RISK LOCI, eye diseases, COMMON SEQUENCE VARIANTS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, 030221 ophthalmology & optometry, RNA, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Cellular, Spheroids, Missense, [INFO.INFO-BI]Computer Science [cs]/Bioinformatics [q-bio.QM], Polymorphisms, purl.org/pe-repo/ocde/ford#1.06.07 [https], INFLAMMATORY-BOWEL-DISEASE
Abstract

International audience; Exfoliation syndrome (XFS) is the commonest known risk factor for secondary glaucoma and a significant cause of blindness worldwide. Variants in two genes, LOXL1 and CACNA1A have been previously associated with XFS. To further elucidate the genetic basis of XFS, we collected a global sample of XFS cases to refine the association at LOXL1, which previously showed inconsistent results between populations,and to identify new variants associated with XFS. We identified a rare, protective allele at LOXL1 (p.407Phe, OR= 25, P=2.9 x 10-14) through deep resequencing of XFS cases and controls from 9 countries. This variant results in increased cellular adhesion strength compared to the wild-type (p.407Tyr) allele. A genome-wide association study (GWAS) of XFS cases and controls from 24 countries followed by replication in 18 countries identified seven genome-wide significant loci (P < 5 x 10-8). Index variants at the new loci map to chromosomes 13q12 (POMP), 11q23.3 (TMEM136), 6p21 (AGPAT1), 3p24 (RBMS3) and 5q23 (near SEMA6A). These findings provide biological insights into the pathology of XFS, and highlight a potential role for naturally occurring rare LOXL1 variants in disease biology.

Published
2017
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108. Autoantibodies neutralizing type I IFNs are present in ~4% of uninfected individuals over 70 years old and account for ~20% of COVID-19 deaths

Author

Bastard, P. Gervais, A. Voyer, T.L. Rosain, J. Philippot, Q. Manry, J. Michailidis, E. Hoffmann, H.-H. Eto, S. Garcia-Prat, M. Bizien, L. Parra-Martínez, A. Yang, R. Haljasmägi, L. Migaud, M. Särekannu, K. Maslovskaja, J. De Prost, N. Tandjaoui-Lambiotte, Y. Luyt, C.-E. Amador-Borrero, B. Gaudet, A. Poissy, J. Morel, P. Richard, P. Cognasse, F. Troya, J. Trouillet-Assant, S. Belot, A. Saker, K. Garçon, P. Rivière, J.G. Lagier, J.-C. Gentile, S. Rosen, L.B. Shaw, E. Morio, T. Tanaka, J. Dalmau, D. Tharaux, P.-L. Sene, D. Stepanian, A. Megarbane, B. Triantafyllia, V. Fekkar, A. Heath, J.R. Franco, J.L. Anaya, J.-M. Solé-Violán, J. Imberti, L. Biondi, A. Bonfanti, P. Castagnoli, R. Delmonte, O.M. Zhang, Y. Snow, A.L. Holland, S.M. Biggs, C.M. Moncada-Vélez, M. Arias, A.A. Lorenzo, L. Boucherit, S. Coulibaly, B. Anglicheau, D. Planas, A.M. Haerynck, F. Duvlis, S. Nussbaum, R.L. Ozcelik, T. Keles, S. Bousfiha, A.A. El Bakkouri, J. Ramirez-Santana, C. Paul, S. Pan-Hammarström, Q. 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Tso, E.Y.K. Tucci, A. Oz, Ş.K.T. Ursini, M.V. Utsumi, T. Uzunhan, Y. Vabres, P. Valencia-Ramos, J. Van Den Rym, A.M. Vandernoot, I. Velez-Santamaria, V. Veliz, S.P.Z. Vidigal, M.C. Viel, S. Vilain, C. Vilaire-Meunier, M.E. Villar-Garcia, J. Vincent, A. Vogt, G. Voiriot, G. Volokha, A. Vuotto, F. Wauters, E. Wu, A.K.L. Wu, T.-C. Yahşi, A. Yesilbas, O. Yildiz, M. Young, B.E. Yukselmiş, U. Zecca, M. Zuccaro, V. Van Praet, J. Lambrecht, B.N. Van Braeckel, E. Bosteels, C. Hoste, L. Hoste, E. Bauters, F. De Clercq, J. Heijmans, C. Slabbynck, H. Naesens, L. Florkin, B. Boulanger, C. Vanderlinden, D. Allavena, C. Andrejak, C. Angoulvant, F. Azoulay, C. Bachelet, D. Bartoli, M. Basmaci, R. Behillill, S. Beluze, M. Benech, N. Benkerrou, D. Bhavsar, K. Bitker, L. Bouadma, L. Bouscambert-Duchamp, M. Paz, P.C. Cervantes-Gonzalez, M. Chair, A. Coelho, A. Cordel, H. Couffignal, C. D'Ortenzio, E. De Montmollin, E. Debard, A. Debray, M.-P. Desvallee, M. Diallo, A. Diouf, A. Dorival, C. Dubos, F. Eloy, P. Epaulard, O. Esposito-Farase, M. Etienne, M. Garot, D. Gault, N. Gaymard, A. Ghosn, J. Gigante, T. Gilg, M. Goehringer, F. Guedj, J. Hoctin, A. Hoffmann, I. Houas, I. Hulot, J.-S. Jaafoura, S. Kaguelidou, F. Kali, S. Kerroumi, Y. Khalil, A. Khan, C. Kimmoun, A. Laouenan, C. Laribi, S. Le, M. Le Bris, C. Le Gac, S. Le Hingrat, Q. Le Mestre, S. Le Nagard, H. Lemaignen, A. Lemee, V. Lescure, F.-X. Levy, Y. Lingas, G. Lucet, J.C. MacHado, M. Mambert, M. Manuel, A. Meziane, A. Mouquet, H. Mullaert, J. Neant, N. Noret, M. Papadopoulos, A. Paul, C. Peiffer-Smadja, N. Peigne, V. Petrov-Sanchez, V. Peytavin, G. Pham, H. Picone, O. Puechal, O. Rosa-Calatrava, M. Rossignol, B. Rossignol, P. Roy, C. Schneider, M. Su, R. Tardivon, C. Tellier, M.-C. Teoule, F. Terrier, O. Timsit, J.F. Tual, C. Vanel, N. Veislinger, A. Wiedemann, A. Danielson, J.J. Dobbs, K. Kashyap, A. Ding, L. Dalgard, C.L. Sottini, A. Quaresima, V. Quiros-Roldan, E. Rossi, C. Bettini, L.R. D'Angio, M. Beretta, I. Montagna, D. Licari, A. Marseglia, G.L. Storgaard, M. Jorgensen, S. Al-Muhsen, S. Al-Mulla, F. Arias, A.A. Bogunovic, D. Bolze, A. Brodin, P. Bryceson, Y. Bustamante, C.D. Butte, M.J. Chakravorty, S. Christodoulou, J. Constantinescu, S.N. Cooper, M.A. Desai, M. Drolet, B.A. El Baghdadi, J. Espinosa-Padilla, S. Froidure, A. Henrickson, S.E. Hsieh, E.W.Y. Husebye, E.S. Imai, K. Itan, Y. Jarvis, E.D. Karamitros, T. Ku, C.-L. Ling, Y. Lucas, C.L. Maniatis, T. Marodi, L. Milner, J.D. Mironska, K. Novelli, A. Novelli, G. Renia, L. Resnick, I. Sancho-Shimizu, V. Seppanen, M.R.J. Shahrooei, M. Slaby, O. Tayoun, A.A. Ramaswamy, S. Turvey, S.E. Furkan Uddin, K.M. Uddin, M.J. Von Bernuth, H. Zawadzki, P. Bigio, B. De La Chapelle, A. Chen, J. Chrabieh, M. Liu, D. Nemirowskaya, Y. Cruz, I.M. Materna, M. Pelet, S. Seeleuthner, Y. Thibault, C. Liu, Z. Foti, G. Bellani, G. Citerio, G. Contro, E. Pesci, A. Valsecchi, M.G. Cazzaniga, M. Batten, I. Reddy, C. McElheron, M. Noonan, C. Connolly, E. Fallon, A. Erikstrup, C. Pedersen, O.B. Sorensen, E. Mikkelsen, S. Dinh, K.M. Larsen, M.A.H. Paulsen, I.W. Von Stemann, J.H. Hansen, M.B. Annereau, J.-P. Briseno-Roa, L. Gribouval, O. Pelet, A. Alcover, A. Aschard, H. Bousso, P. Bruhns, P. Cerf-Bensussan, N. Cumano, A. D'Enfert, C. Deriano, L. Dillies, M.-A. Di Santo, J. Dromer, F. Eberl, G. Enninga, J. Gomperts-Boneca, I. Hasan, M. Hedestam, G.K. Hercberg, S. Ingersoll, M.A. Lantz, O. Kenny, R.A. Menager, M. Michel, F. Patin, E. Pellegrini, S. Rausell, A. Rieux-Laucat, F. Rogge, L. Fontes, M. Sakuntabhai, A. Schwartz, O. Schwikowski, B. Shorte, S. Tangy, F. Toubert, A. Touvier, M. Ungeheuer, M.-N. Zimmer, C. Albert, M.L. Van Agtmael, M. Algera, A.G. Appelman, B. Van Baarle, F. Bax, D. Beudel, M. Bogaard, H.J. Bomers, M. Bonta, P. Bos, L. Botta, M. De Brabander, J. De Bree, G. De Bruin, S. Buis, D.T.P. Bugiani, M. Bulle, E. Chouchane, O. Cloherty, A. Dijkstra, M. Dongelmans, D.A. Dujardin, R.W.G. Elbers, P. Fleuren, L. Geerlings, S. Geijtenbeek, T. Girbes, A. Goorhuis, B. Grobusch, M.P. Hafkamp, F. Hagens, L. Hamann, J. Harris, V. Hemke, R. Hermans, S.M. Heunks, L. Hollmann, M. Horn, J. Hovius, J.W. De Jong, M.D. Lim, E.H.T. Van Mourik, N. Nellen, J. Nossent, E.J. Paulus, F. Peters, E. Pina-Fuentes, D.A.I. Van Der Poll, T. Preckel, B. Prins, J.M. Raasveld, J. Reijnders, T. De Rotte, M.C.F.J. Schinkel, M. Schultz, M.J. Schrauwen, F.A.P. Schuurman, A. Schuurmans, J. Sigaloff, K. Slim, M.A. Smeele, P. Smit, M. Stijnis, C.S. Stilma, W. Teunissen, C. Thoral, P. Tsonas, A.M. Tuinman, P.R. Van Der Valk, M. Veelo, D. Volleman, C. De Vries, H. Vught, L.A. Van Vugt, M. Wouters, D. Zwinderman, A.H. Brouwer, M.C. Joost Wiersinga, W. Vlaar, A.P.J. Nadif, R. Goldberg, M. Ozguler, A. Henny, J. Lemonnier, S. Coeuret-Pellicer, M. Le Got, S. Tzourio, C. Dufouil, C. Soumare, A. Lachaize, M. Fievet, N. Flaig, A. Martin, F. Bonneaudeau, B. Cannet, D. Gallian, P. Jeanne, M. Perroquin, M. Hamzeh-Cognasse, H. CoV-Contact Cohort St James's Hospital, SARS CoV2 Interest group COVID Clinicians French COVID Cohort Study Group NIAID Immune Response to COVID Group Danish CHGE COVID Human Genetic Effort HGID Lab COVID-STORM Clinicians NH-COVAIR Study Group The Danish Blood Donor Study (DBDS) Imagine COVID-Group The Milieu Interieur Consortium Amsterdam UMC Covid-19 Biobank CONSTANCES cohort 3C-Dijon Study Cerba HealthCare Etablissement du Sang study group

Abstract

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases. © 2021 The Authors, some rights reserved.

Published
2021

110. COVID-19 critique et anticorps anti-Interféron : série de 11 cas

Author

Gilardin, L., primary, Nielly, H., additional, Roumier, M., additional, Chauvin, C., additional, Bastard, P., additional, Bousquet, A., additional, Vasse, M., additional, Roth, C., additional, Sakuntabhai, A., additional, Bayry, J., additional, Bourgarit, A., additional, Dubost, C., additional, and Tandjaoui-Lambiotte, Y., additional

Published
2021
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112. High number of previous Plasmodium falciparum clinical episodes increases risk of future episodes in a sub-group of individuals.

Author

Cheikh Loucoubar, Laura Grange, Richard Paul, Augustin Huret, Adama Tall, Olivier Telle, Christian Roussilhon, Joseph Faye, Fatoumata Diene-Sarr, Jean-François Trape, Odile Mercereau-Puijalon, Anavaj Sakuntabhai, and Jean-François Bureau

Subjects
Medicine, Science
Abstract

There exists great disparity in the number of clinical P. falciparum episodes among children of the same age and living in similar conditions. The epidemiological determinants of such disparity are unclear. We used a data-mining approach to explore a nineteen-year longitudinal malaria cohort study dataset from Senegal and identify variables associated with increased risk of malaria episodes. These were then verified using classical statistics and replicated in a second cohort. In addition to age, we identified a novel high-risk group of children in whom the history of P. falciparum clinical episodes greatly increased risk of further episodes. Age and a high number of previous falciparum clinical episodes not only play major roles in explaining the risk of P. falciparum episodes but also are risk factors for different groups of people. Combined, they explain the majority of falciparum clinical attacks. Contrary to what is widely believed, clinical immunity to P. falciparum does not de facto occur following many P. falciparum clinical episodes. There exist a sub-group of children who suffer repeated clinical episodes. In addition to posing an important challenge for population stratification during clinical trials, this sub-group disproportionally contributes to the disease burden and may necessitate specific prevention and control measures.

Published
2013
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113. Innate Lymphoid Cells Activation and Transcriptomic Changes in Response to Human Dengue Infection

Author

Tiraput Poonpanichakul, Wilawan Chan-In, Anunya Opasawatchai, Fabien Loison, Oranart Matangkasombut, Varodom Charoensawan, Ponpan Matangkasombut, DENFREE Thailand, Anavaj Sakuntabhai, Pratap Singhasivanon, Swangjit Suraamornkul, Tawatchai Yingtaweesak, and Khajohnpong Manopwisedjaroen

Subjects
0301 basic medicine, Male, Lymphocyte, medicine.medical_treatment, Immunology, innate lymphoid cells, ILCs, Biology, Dengue virus, medicine.disease_cause, Dengue fever, Dengue, 03 medical and health sciences, Interferon-gamma, 0302 clinical medicine, Immune system, medicine, Immunology and Allergy, Humans, RNA-Seq, immune response to dengue, innate immunity, Original Research, Innate immune system, Innate lymphoid cell, virus diseases, T-Lymphocytes, Helper-Inducer, RC581-607, Dengue Virus, Middle Aged, medicine.disease, Immunity, Innate, 030104 developmental biology, medicine.anatomical_structure, Cytokine, Cytokine secretion, Female, Interleukin-4, viral infection, Immunologic diseases. Allergy, Transcriptome, 030215 immunology
Abstract

BackgroundDengue virus (DENV) infection has a global impact on public health. The clinical outcomes (of DENV) can vary from a flu-like illness called dengue fever (DF), to a more severe form, known as dengue hemorrhagic fever (DHF). The underlying innate immune mechanisms leading to protective or detrimental outcomes have not been fully elucidated. Helper innate lymphoid cells (hILCs), an innate lymphocyte recently discovered, functionally resemble T-helper cells and are important in inflammation and homeostasis. However, the role of hILCs in DENV infection had been unexplored.MethodsWe performed flow cytometry to investigate the frequency and phenotype of hILCs in peripheral blood mononuclear cells from DENV-infected patients of different disease severities (DF and DHF), and at different phases (febrile and convalescence) of infection. Intracellular cytokine staining of hILCs from DF and DHF were also evaluated by flow cytometry after ex vivo stimulation. Further, the hILCs were sorted and subjected to transcriptome analysis using RNA sequencing. Differential gene expression analysis was performed to compare the febrile and convalescent phase samples in DF and DHF. Selected differentially expressed genes were then validated by quantitative PCR.ResultsPhenotypic analysis showed marked activation of all three hILC subsets during the febrile phase as shown by higher CD69 expression when compared to paired convalescent samples, although the frequency of hILCs remained unchanged. Upon ex vivo stimulation, hILCs from febrile phase DHF produced significantly higher IFN-γ and IL-4 when compared to those of DF. Transcriptomic analysis showed unique hILCs gene expression in DF and DHF, suggesting that divergent functions of hILCs may be associated with different disease severities. Differential gene expression analysis indicated that hILCs function both in cytokine secretion and cytotoxicity during the febrile phase of DENV infection.ConclusionsHelper ILCs are activated in the febrile phase of DENV infection and display unique transcriptomic changes as well as cytokine production that correlate with severity. Targeting hILCs during early innate response to DENV might help shape subsequent immune responses and potentially lessen the disease severity in the future.

Published
2020

114. Dengue viremia kinetics in asymptomatic and symptomatic infection

Author

Kajohnpong Manopwisedjaroen, Veasna Duong, Anavaj Sakuntabhai, Tawatchai Yingtaweesak, Swangjit Suraamornkul, Nada Pitabut, Pratap Singhasivanon, Richard Paul, Ponpan Matangkasombut, Sasikanya Thaloengsok, Mahidol University [Bangkok], Vajira Hospital [Bangkok], Thasongyang Hospital [Tak, Thaïland], Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), This study was supported by the European Union Seventh Framework Program (FP7/2007–2013) [under Grant Agreement #282,378 (DENFREE)] (to AS, RP, PS, PM) and a National Research University grant (Mahidol, to AS, PM)., and European Project: 282378,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,DENFREE(2012)

Subjects
0301 basic medicine, Male, viruses, MESH: Dengue, Dengue virus, medicine.disease_cause, MESH: Dengue Virus, Dengue fever, Dengue, 0302 clinical medicine, MESH: Child, 030212 general & internal medicine, Child, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Denv serotypes, MESH: Kinetics, Virus kinetics, Transmission (medicine), virus diseases, General Medicine, Inapparent, 3. Good health, Asymptomatic, Infectious Diseases, MESH: Young Adult, Female, medicine.symptom, Clearance, Microbiology (medical), Adult, medicine.medical_specialty, Adolescent, 030106 microbiology, Viremia, Serogroup, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Young Adult, Internal medicine, medicine, Humans, lcsh:RC109-216, MESH: Viremia, MESH: Adolescent, MESH: Humans, business.industry, MESH: Adult, MESH: Serogroup, Dengue Virus, medicine.disease, MESH: Male, Kinetics, Viral decay, business, MESH: Female, Viremia duration
Abstract

International audience; Background: Dengue infection is a global health threat. While symptomatic cases contribute to morbidity and mortality, the majority of infected people are asymptomatic but serve as an important reservoir. However, the kinetics of viremia in asymptomatic infections remains unknown. Methods: We enrolled 279 hospital-based symptomatic index cases and quantified dengue virus (DENV) RNA at enrollment and at the day of defervescence. To identify asymptomatic cases, 175 household members of index cases were monitored for clinical symptoms during follow-up, and blood was taken twice weekly to test for and quantify DENV RNA until cleared. Results: We detected DENV in thirteen asymptomatic household members (7.43%). Their DENV serotypes were primarily the same as those of their family index cases. The median peak DENV viremia in asymptomatic subjects was lower than that of symptomatic individuals during the febrile phase, and the viral decay rate was slower in asymptomatic infections. Conclusions: DENV level and kinetics in asymptomatic individuals differed significantly from those of symptomatic cases. Despite the lower viremia, the slower decay rate in asymptomatic infections could lead to their prolonging the infectious reservoir. The improvement of transmission control to prevent such long-lived asymptomatic infections from transmitting the DENV is needed.

Published
2020
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115. Experimental adaptation of dengue virus 1 to Aedes albopictus mosquitoes by in vivo selection

Author

Louis Lambrechts, Anavaj Sakuntabhai, Xavier de Lamballerie, Henri Jupille, Laurence Mousson, Rachel Bellone, Marie Vazeille, Gaelle Gabiane, Gorben P. Pijlman, Giel P. Göertz, Pei-Shi Yen, Sebastian Lequime, Fabien Aubry, Géraldine Piorkowski, and Anna-Bella Failloux

Subjects
Infectivity, 0303 health sciences, Aedes albopictus, biology, viruses, 030231 tropical medicine, virus diseases, Aedes aegypti, Dengue virus, biology.organism_classification, medicine.disease_cause, Virology, Reverse genetics, Virus, 3. Good health, 03 medical and health sciences, 0302 clinical medicine, Vector (epidemiology), medicine, 030304 developmental biology, Subgenomic mRNA
Abstract

In most of the world, Dengue virus (DENV) is mainly transmitted by the mosquito Aedes aegypti while in Europe, Aedes albopictus is responsible for human DENV cases since 2010. Identifying mutations that make DENV more competent for transmission by Ae. albopictus will help to predict emergence of epidemic strains. Ten serial passages in vivo in Ae. albopictus led to select DENV-1 strains with greater infectivity for this vector in vivo and in cultured mosquito cells. These changes were mediated by multiple adaptive mutations in the virus genome, including a mutation at position 10,418 in the DENV 3’UTR within an RNA stem-loop structure involved in subgenomic flavivirus RNA (sfRNA) production. Using reverse genetics, we showed that the 10,418 mutation alone does not confer a detectable increase in transmission efficiency in vivo. These results reveal the complex adaptive landscape of DENV transmission by mosquitoes and emphasize the role of epistasis in shaping evolutionary trajectories of DENV variants.

Published
2020
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116. Variants in non-coding regions of the TLR2 gene associated with severe bacterial infection in pediatric sickle cell anemia

Author

David, Susana, Aguiar, Pedro, Antunes, Liliana, Dias, Alexandra, Morais, Anabela, Sakuntabhai, Anavaj, and Lavinha, João

Subjects
Infeção Bacteriana, Doenças Infecciosas, Anemia Falciforme Pediátrica, Gene TLR2, Anemia Falciforme, Doenças Genéticas
Abstract

Este artigo constitui, no essencial, uma tradução abreviada da publicação: David S, Aguiar P, Antunes L, Dias A, Morais A, Sakuntabhai A, Lavinha J. Variants in the non-coding region of the TLR2 gene associated with infectious subphenotypes in pediatric sickle cell anemia. Immunogenetics. 2018 Jan;70(1):37-51. Epub 2017 Jun 30. https://doi.org/10.1007/s00251-017-1013-7 A anemia falciforme é caracterizada por hemólise crónica, crises vaso- -oclusivas (CVO) e infeções recorrentes frequentemente graves. Uma coorte de 95 doentes pediátricos com anemia falciforme foi estudada quanto à associação genótipo-fenótipo para o subfenótipo “infeção bacteriana grave pelo menos uma vez durante o período de acompanhamento do doente” e três regiões polimórficas não codificantes do gene TLR2, a saber, a indel -196 a -174, o SNP rs4696480 e uma repetição em tandem (GT) n. A ausência do haplótipo [Del] -T- [n≥17] (Hap7) em homozigotia parece proteger contra a infeção bacteriana grave, numa associação estatisticamente significativa, resistindo à correção para testes múltiplos. Além disso, uma redução na taxa de incidência da infeção bacteriana grave foi associada a um aumento do componente hemolítico, aos níveis de hemoglobina fetal (antes do tratamento pela hidroxiureia) e à prevalência da alfa-talassemia de 3,7 kb. Estes resultados poderão vir a ter implicações práticas nas estratégias de cuidados de saúde para reduzir a morbilidade e mortalidade dos doentes com anemia falciforme. Sickle cell anemia (SCA) is characterized by chronic hemolysis, severe vasoocclusive crises (VOC) and recurrent often-severe infections. A cohort of 95 SCA pediatric patients was the background for genotype- -to-phenotype association of the patient’s infectious disease phenotype “severe bacterial infection at least once during the patient’s follow-up” and three noncoding polymorphic regions of the TLR2 gene, the -196 to -174 indel, SNP rs4696480 and a (GT)n short tandem repeat. The absence of the haplotype [Del]-T-[n≥17] (Hap7) in homozygocity protected against severe bacterial infection, in a statistically significant association, resisting correction for multiple testing. Moreover, a reduction in the incidence rate of severe bacterial infection was associated to a rise in the hemolytic score, fetal hemoglobin levels (prior to hydroxyureia treatment) and 3.7-kb alpha-thalassemia. These results could have practical implications in health care strategies to lower the morbidity and mortality of SCA patients. Este estudo foi realizado com o apoio da FCT/MEC através de fundos nacionais e cofinanciado pelo FEDER, no âmbito do Acordo de parceria PT2020 (UIDMULTI/00211/2013). Foi ainda parcialmente financiado por subvenções da FCT (PIC/IC/83084/2007) e do Centro de Investigação em Genética Molecular Humana info:eu-repo/semantics/publishedVersion

Published
2020

117. Identification and molecular characterization of the first complete genome sequence of Human Parechovirus type 15

Author

Etienne Simon-Loriere, Kader Ndiaye, Anavaj Sakuntabhai, Maria Dolores Fernandez-Garcia, Ousmane Kebe, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Institut Pasteur [Paris], Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], The authors gratefully acknowledge Institut Pasteur of Dakar and Institut Pasteur Paris for their technical and financial support. ESL acknowledges funding from the INCEPTION program (Investissements d’Avenir grant ANR-16-CONV-0005), ANR-16-CONV-0005,INCEPTION,Institut Convergences pour l'étude de l'Emergence des Pathologies au Travers des Individus et des populatiONs(2016), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, lcsh:Medicine, Parechovirus, Genome, Viral, [SDV.BID]Life Sciences [q-bio]/Biodiversity, Biology, Genome, Article, 03 medical and health sciences, Open Reading Frames, 0302 clinical medicine, Virology, Coding region, Humans, Paralysis, 030212 general & internal medicine, lcsh:Science, Whole genome sequencing, Genetics, Multidisciplinary, Phylogenetic tree, Molecular epidemiology, Whole Genome Sequencing, Human parechovirus, lcsh:R, Molecular Sequence Annotation, Genomics, Sequence Analysis, DNA, Phylogenetics, 030104 developmental biology, Metagenomics, GenBank, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Next-generation sequencing, lcsh:Q, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie
Abstract

Using a metagenomics approach, we have determined the first full-length genome sequence of a human parechovirus type 15 (HPeV15) strain, isolated from a child with acute flaccid paralysis and co-infected with EV-A71. HPeV15 is a rarely reported type. To date, no full-length genome sequence of HPeV15 is available in the GenBank database, where only limited VP1 sequences of this virus are available. Pairwise comparisons of the complete VP1 nucleotide and deduced amino acid sequences revealed that the study strain belongs to type 15 as it displayed 79.6% nucleotide and 93.4% amino acid identity with the HPeV15 prototype strain. Comparative analysis of available genomic regions and phylogenetic analysis using the P2 and P3 coding regions revealed low nucleotide identity to HPeV reference genomes. Phylogenetic and similarity plot analyses showed that genomic recombination events might have occurred in the UTRs and nonstructural region during HPeV15 evolution. The study strain has high similarity features with different variants of HPeV3 suggesting intertypic recombination. Our data contributes to the scarce data available on HPeVs in Africa and provides valuable information for future studies that aim to understand the evolutionary history, molecular epidemiology or biological and pathogenic properties of HPeV15.

Published
2020
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118. Long-term persistence of monotypic dengue transmission in small size isolated populations, French Polynesia, 1978-2014

Author

Bernard Cazelles, Anavaj Sakuntabhai, Carlos J. Dommar, Henrik Salje, Xavier Rodó, Richard Paul, Maite Aubry, Van-Mai Cao-Lormeau, Yoann Teissier, Institut Louis Malardé [Papeete] (ILM), Institut de Recherche pour le Développement (IRD), UFR Sciences Fondamentales et Biomédicales [Sciences] - Université Paris Cité, Université Paris Cité (UPCité), Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), ICREA Infection Biology Laboratory (Department of Experimental and Health Sciences), Universitat Pompeu Fabra [Barcelona] (UPF), Instituto de Salud Global - Institute For Global Health [Barcelona] (ISGlobal), Modélisation mathématique des maladies infectieuses - Mathematical modelling of Infectious Diseases, Unité de modélisation mathématique et informatique des systèmes complexes [Bondy] (UMMISCO), Université de Yaoundé I-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Sorbonne Université (SU)-Institut de Recherche pour le Développement (IRD [France-Nord]), Interdisciplinary and Global Environmental Studies (iGLOBES), University of Arizona-Centre National de la Recherche Scientifique (CNRS), Institut de biologie de l'ENS Paris (IBENS), Département de Biologie - ENS Paris, École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS-PSL), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), The research leading to these results has received funding from the European Commission Seventh Framework Program [FP7/2007-2013] for the DENFREE project under Grant Agreement n ̊ 282378.Délégation à la Recherche de la Polynésie française, European Project: 282378,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,DENFREE(2012), Université de Paris - UFR Sciences Fondamentales et Biomédicales [Sciences], Université de Paris (UP), Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut de Recherche pour le Développement (IRD [France-Nord])-Institut de la francophonie pour l'informatique-Université Cheikh Anta Diop [Dakar, Sénégal] (UCAD)-Université Gaston Bergé (Saint-Louis, Sénégal)-Université Cadi Ayyad [Marrakech] (UCA)-Université de Yaoundé I-Sorbonne Université (SU), Institut de biologie de l'ENS Paris (UMR 8197/1024) (IBENS), École normale supérieure - Paris (ENS Paris), Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure - Paris (ENS Paris), Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Département de Biologie - ENS Paris, Université Paris sciences et lettres (PSL)-Université Paris sciences et lettres (PSL)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Paul, Richard [0000-0002-0665-5089], and Apollo - University of Cambridge Repository

Subjects
Male, Serotype, Topography, Epidemiology, RC955-962, French Polynesia, Social Sciences, Dengue virus, Pathology and Laboratory Medicine, MESH: Dengue Virus, Geographical locations, 0302 clinical medicine, Arctic medicine. Tropical medicine, MESH: Child, MESH: Incidence, Child, Islands, Aged, 80 and over, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, MESH: Middle Aged, Geography, Incidence, Eukaryota, Spatial epidemiology, MESH: Polynesia, Island hopping, MESH: Infant, Viral Persistence and Latency, 3. Good health, Medical Microbiology, MESH: Young Adult, Viral Pathogens, Child, Preschool, Public aspects of medicine, Zoology, MESH: Disease Transmission, Infectious, Human Geography, Serogroup, Microbiology, 03 medical and health sciences, Disease Transmission, Infectious, Humans, Epidemics, Microbial Pathogens, Aged, MESH: Adolescent, MESH: Humans, Flaviviruses, MESH: Child, Preschool, Organisms, Public Health, Environmental and Occupational Health, Infant, MESH: Adult, Dengue Virus, medicine.disease, Invertebrates, Insect Vectors, Species Interactions, 030104 developmental biology, Period (geology), Human Mobility, People and places, MESH: Female, RNA viruses, 0301 basic medicine, Spatial Epidemiology, MESH: Dengue, Disease Vectors, medicine.disease_cause, Mosquitoes, Dengue fever, Dengue, MESH: Aged, 80 and over, Medicine and Health Sciences, MESH: Aged, Population size, Incidence (epidemiology), MESH: Infant, Newborn, Middle Aged, Insects, Air Travel, Infectious Diseases, Viruses, Female, Pathogens, RA1-1270, Research Article, Adult, Arthropoda, Adolescent, Oceania, 030231 tropical medicine, Polynesia, Young Adult, Virology, medicine, Animals, MESH: Epidemics, Landforms, Biology and life sciences, Infant, Newborn, Geomorphology, MESH: Serogroup, MESH: Male, Earth Sciences, Viral Transmission and Infection
Abstract

Understanding the transition of epidemic to endemic dengue transmission remains a challenge in regions where serotypes co-circulate and there is extensive human mobility. French Polynesia, an isolated group of 117 islands of which 72 are inhabited, distributed among five geographically separated subdivisions, has recorded mono-serotype epidemics since 1944, with long inter-epidemic periods of circulation. Laboratory confirmed cases have been recorded since 1978, enabling exploration of dengue epidemiology under monotypic conditions in an isolated, spatially structured geographical location. A database was constructed of confirmed dengue cases, geolocated to island for a 35-year period. Statistical analyses of viral establishment, persistence and fade-out as well as synchrony among subdivisions were performed. Seven monotypic and one heterotypic dengue epidemic occurred, followed by low-level viral circulation with a recrudescent epidemic occurring on one occasion. Incidence was asynchronous among the subdivisions. Complete viral die-out occurred on several occasions with invasion of a new serotype. Competitive serotype replacement has been observed previously and seems to be characteristic of the South Pacific. Island population size had a strong impact on the establishment, persistence and fade-out of dengue cases and endemicity was estimated achievable only at a population size in excess of 175 000. Despite island remoteness and low population size, dengue cases were observed somewhere in French Polynesia almost constantly, in part due to the spatial structuration generating asynchrony among subdivisions. Long-term persistence of dengue virus in this group of island populations may be enabled by island hopping, although could equally be explained by a reservoir of sub-clinical infections on the most populated island, Tahiti., Author summary Dengue virus is the most significant arthropod-borne virus infecting man. Understanding how long dengue virus can persist in populations of varying size is key to understanding its epidemiology. This is, however, impossible to achieve in settings where dengue is endemic, because of continued human movement and is further complexified by the occurrence of several co-circulating serotypes. By contrast, French Polynesia, an isolated group of 72 inhabited islands in the South Pacific, has had intermittent majoritarily monotypic dengue epidemics since the 1940s and offers a unique opportunity to address questions of viral persistence, turnover and the importance of spatial sub-structure in determining dengue epidemiology. Collating and analyzing a database of laboratory-confirmed dengue cases from across French Polynesia over a 35 year period we were able to show that dengue virus die-out can occur with or without replacement by a new serotype, monotypic transmission of dengue viruses fails to be maintained within small island populations but can persist for years among isolated islands connected via air and sea links. This remarkable long-term persistence of dengue virus in French Polynesia could be maintained by asynchronous viral transmission among connected islands and/or by repeated seeding from a reservoir of sub-clinical infections in the most populated island, Tahiti.

Published
2020
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119. Single-cell temporal analysis of natural dengue infection reveals skin-homing lymphocyte expansion one day before defervescence

Author

Jantarika Kumar Arora, Anunya Opasawatchai, Tiraput Poonpanichakul, Natnicha Jiravejchakul, Waradon Sungnak, Oranart Matangkasombut, Sarah A. Teichmann, Ponpan Matangkasombut, Varodom Charoensawan, Anavaj Sakuntabhai, Pratap Singhasivanon, Swangjit Suraamornkul, Tawatchai Yingtaweesak, Khajohnpong Manopwisedjaroen, and Nada Pitabut

Subjects
Multidisciplinary
Abstract

Effective clinical management of acute dengue virus (DENV) infection relies on the timing of suitable treatments during the disease progression. We analyzed single-cell transcriptomic profiles of the peripheral blood mononuclear cell samples from two DENV patients, collected daily during acute phase and also at convalescence. Key immune cell types demonstrated different dynamic responses over the course of the infection. On the day before defervescence (Day -1), we observed the peak expression of several prominent genes in the adaptive immunological pathways. We also characterized unique effector T cell clusters that expressed skin-homing signature genes at Day -1, whereas upregulation of skin and gut homing genes was also observed in plasma cells and plasmablasts during the febrile period. This work provides an overview of unique molecular dynamics that signify the entry of the critical phase, and the findings could improve the patient management of DENV infection.

Published
2022
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120. Clinical and virological study of dengue cases and the members of their households: the multinational DENFRAME Project.

Author

Philippe Dussart, Laurence Baril, Laure Petit, Lydie Beniguel, Luong Chan Quang, Sowath Ly, Raimunda do Socorro Silva Azevedo, Jean-Baptiste Meynard, Sirenda Vong, Loïc Chartier, Aba Diop, Ong Sivuth, Veasna Duong, Cao Minh Thang, Michael Jacobs, Anavaj Sakuntabhai, Marcio Roberto Teixeira Nunes, Vu Ti Que Huong, Philippe Buchy, and Pedro Fernando da Costa Vasconcelos

Subjects
Arctic medicine. Tropical medicine, RC955-962, Public aspects of medicine, RA1-1270
Abstract

BACKGROUND: Dengue has emerged as the most important vector-borne viral disease in tropical areas. Evaluations of the burden and severity of dengue disease have been hindered by the frequent lack of laboratory confirmation and strong selection bias toward more severe cases. METHODOLOGY: A multinational, prospective clinical study was carried out in South-East Asia (SEA) and Latin America (LA), to ascertain the proportion of inapparent dengue infections in households of febrile dengue cases, and to compare clinical data and biological markers from subjects with various dengue disease patterns. Dengue infection was laboratory-confirmed during the acute phase, by virus isolation and detection of the genome. The four participating reference laboratories used standardized methods. PRINCIPAL FINDINGS: Among 215 febrile dengue subjects-114 in SEA and 101 in LA-28 (13.0%) were diagnosed with severe dengue (from SEA only) using the WHO definition. Household investigations were carried out for 177 febrile subjects. Among household members at the time of the first home visit, 39 acute dengue infections were detected of which 29 were inapparent. A further 62 dengue cases were classified at early convalescent phase. Therefore, 101 dengue infections were found among the 408 household members. Adding these together with the 177 Dengue Index Cases, the overall proportion of dengue infections among the study participants was estimated at 47.5% (278/585; 95% CI 43.5-51.6). Lymphocyte counts and detection of the NS1 antigen differed significantly between inapparent and symptomatic dengue subjects; among inapparent cases lymphocyte counts were normal and only 20% were positive for NS1 antigen. Primary dengue infection and a specific dengue virus serotype were not associated with symptomatic dengue infection. CONCLUSION: Household investigation demonstrated a high proportion of household members positive for dengue infection, including a number of inapparent cases, the frequency of which was higher in SEA than in LA.

Published
2012
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121. Host ancestry and dengue fever: from mapping of candidate genes to prediction of worldwide genetic risk

Author

Luísa Pereira, Verónica Fernandes, Marisa Oliveira, Anavaj Sakuntabhai, and Joana Ferreira

Subjects
0301 basic medicine, Genetics, 03 medical and health sciences, Candidate gene, 030104 developmental biology, Host (biology), Virology, medicine, 030105 genetics & heredity, Biology, Genetic risk, medicine.disease, Dengue fever
Abstract

Prevalence of many complex diseases, including dengue disease, is not even across the world. Dengue is endemic in several overpopulated urban centers in poor Asian and American countries, representing a risk to two-thirds of the human population. High-throughput genomic screenings and new algorithms of admixture mapping are allowing confirming that ancestry plays a major role in dengue disease. Allele and haplotype candidate frequencies display high heterogeneity between population groups, especially in comparison with Africans. Genetic risk evaluation testifies African ancestry protection against the more severe forms of the disease, most probably due to natural selection of protective variants. European genetic predisposition is identical to the Asian for severer forms, but lower for mild dengue fever.

Published
2018
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122. Genetic Characterization of Enterovirus A71 Circulating in Africa

Author

Ousmane Kebe, Michael R. Wiley, Javier Martin, Maël Bessaud, Francis Delpeyroux, Maria Dolores Fernandez-Garcia, Serge Alain Sadeuh-Mba, Manasi Majumdar, Gustavo Palacios, Romain Volle, Ionela Gouandjika-Vasilache, Anavaj Sakuntabhai, Etienne Simon-Loriere, Marie-Line Joffret, Kader Ndiaye, Institut Pasteur de Dakar, Réseau International des Instituts Pasteur (RIIP), Institut Pasteur [Paris], Institut National de la Santé et de la Recherche Médicale (INSERM), Centre Pasteur du Cameroun, Institut Pasteur de Bangui, University of Nebraska Medical Center, University of Nebraska System, U.S. Army Medical Research Institute of Infectious Diseases, National Institute for Biological Standards and Control (NIBSC), Medicines and Healthcare Products Regulatory Agency (MHRA), The next-generation sequencing equipment at Institut Pasteur of Dakar was provided by the Defense Biological Product Assurance Office under the Targeted Acquisition of Reference Materials Augmenting Capabilities Initiative. This work was supported by the IPD, the Pasteur Institute’s Transverse Research Program PTR484, Actions Concertées Inter-Pasteuriennes A22-16, Fondation Total Grant S-CM15010-05B, Roux Howard Cantarini postdoctoral fellowship, and Grant Calmette and Yersin from the International Directorate of the Institut Pasteur., We thank Karla Prieto and Catherine Pratt, who assisted in obtaining nearly complete genomes of West Africa strains, and Joseph Chitty for analysis of the next-generation sequencing data., Institut Pasteur [Paris] (IP), and U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID)

Subjects
0301 basic medicine, Microbiology (medical), Acute flaccid paralysis, Genotype, Epidemiology, viruses, lcsh:Medicine, Genome, Viral, Biology, medicine.disease_cause, West africa, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Genetic Characterization of Enterovirus A71 Circulating in Africa, medicine, Enterovirus Infections, Humans, lcsh:RC109-216, Phylogeny, Recombination, Genetic, [SDV.GEN]Life Sciences [q-bio]/Genetics, whole-genome analysis, enterovirus, phylogenetic analysis, lcsh:R, Dispatch, Genetic Variation, virus diseases, Enterovirus a71, Virology, recombination, Enterovirus A, Human, 030104 developmental biology, Infectious Diseases, enterovirus A71, Africa, Enterovirus, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, acute flaccid paralysis
Abstract

International audience; We analyzed whole-genome sequences of 8 enterovirus A71 isolates (EV-A71). We confirm the circulation of geno-group C and the new genogroup E in West Africa. Our analysis demonstrates wide geographic circulation and describes genetic exchanges between EV-A71 and autochtho-nous EV-A that might contribute to the emergence of patho-genic lineages.

Published
2018
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123. Impact of changing drug treatment and malaria endemicity on the heritability of malaria phenotypes in a longitudinal family-based cohort study.

Author

Cheikh Loucoubar, Bronner Goncalves, Adama Tall, Cheikh Sokhna, Jean-François Trape, Fatoumata Diène Sarr, Joseph Faye, Abdoulaye Badiane, Alioune Badara Ly, Aliou Diop, Avner Bar-Hen, Jean-François Bureau, Anavaj Sakuntabhai, and Richard Paul

Subjects
Medicine, Science
Abstract

Despite considerable success of genome wide association (GWA) studies in identifying causal variants for many human diseases, their success in unraveling the genetic basis to complex diseases has been more mitigated. Pathogen population structure may impact upon the infectious phenotype, especially with the intense short-term selective pressure that drug treatment exerts on pathogens. Rigorous analysis that accounts for repeated measures and disentangles the influence of genetic and environmental factors must be performed. Attempts should be made to consider whether pathogen diversity will impact upon host genetic responses to infection.We analyzed the heritability of two Plasmodium falciparum phenotypes, the number of clinical malaria episodes (PFA) and the proportion of these episodes positive for gametocytes (Pfgam), in a family-based cohort followed for 19 years, during which time there were four successive drug treatment regimes, with documented appearance of drug resistance. Repeated measures and variance components analyses were performed with fixed environmental, additive genetic, intra-individual and maternal effects for each drug period. Whilst there was a significant additive genetic effect underlying PFA during the first drug period of study, this was lost in subsequent periods. There was no additive genetic effect for Pfgam. The intra-individual effect increased significantly in the chloroquine period.The loss of an additive genetic effect following novel drug treatment may result in significant loss of power to detect genes in a GWA study. Prior genetic analysis must be a pre-requisite for more detailed GWA studies. The temporal changes in the individual genetic and the intra-individual estimates are consistent with those expected if there were specific host-parasite interactions. The complex basis to the human response to malaria parasite infection likely includes dominance/epistatic genetic effects encompassed within the intra-individual variance component. Evaluating their role in influencing the outcome of infection through host genotype by parasite genotype interactions warrants research effort.

Published
2011
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124. A variant in the CD209 promoter is associated with severity of dengue disease

Author

Sakuntabhai, Anavaj, Turbpaiboon, Chairat, Casadémont, Isabelle, Chuansumrit, Ampaiwan, Lowhnoo, Tassanee, Kajaste-Rudnitski, Anna, Kalayanarooj, Sita Mint, Tangnararatchakit, Kanchana, Tangthawornchaikul, Nattaya, Vasanawathana, Sirijit, Chaiyaratana, Wathanee, Yenchitsomanus, Pa-thai, Suriyaphol, Prapat, Avirutnan, Panisadee, Chokephaibulkit, Kulkanya, Matsuda, Fumihiko, Yoksan, Sutee, Jacob, Yves, Lathrop, G Mark, Malasit, Prida, Desprès, Philippe, and Julier, Cécile

Published
2005
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125. Deciphering the ancient and complex evolutionary history of human arylamine N-acetyltransferase genes

Author

Patin, Etienne, Barreiro, Luis B., Sabeti, Pardis C., Austerlitz, Frederic, Luca, Francesca, Sajantila, Antti, Behar, Doron M., Semino, Ornella, Sakuntabhai, Anavaj, Guiso, Nicole, Gicquel, Brigitte, McElreavey, Ken, Harding, Rosalind M., Heyer, Evelyne, and Quintana-Murci, Lluis

Subjects
Transferases -- Research, Gene mutations -- Research, Genetic research, Biological sciences
Published
2006

126. Heritability of the human infectious reservoir of malaria parasites.

Author

Yaye Ramatoulaye Lawaly, Anavaj Sakuntabhai, Laurence Marrama, Lassana Konate, Waraphon Phimpraphi, Cheikh Sokhna, Adama Tall, Fatoumata Diène Sarr, Chayanon Peerapittayamongkol, Chalisa Louicharoen, Bradley S Schneider, Anaïs Levescot, Arthur Talman, Isabelle Casademont, Didier Menard, Jean-François Trape, Christophe Rogier, Jaranit Kaewkunwal, Thanyachai Sura, Issarang Nuchprayoon, Frederic Ariey, Laurence Baril, Pratap Singhasivanon, Odile Mercereau-Puijalon, and Rick Paul

Subjects
Medicine, Science
Abstract

BackgroundStudies on human genetic factors associated with malaria have hitherto concentrated on their role in susceptibility to and protection from disease. In contrast, virtually no attention has been paid to the role of human genetics in eliciting the production of parasite transmission stages, the gametocytes, and thus enhancing the spread of disease.Methods and findingsWe analysed four longitudinal family-based cohort studies from Senegal and Thailand followed for 2-8 years and evaluated the relative impact of the human genetic and non-genetic factors on gametocyte production in infections of Plasmodium falciparum or P. vivax. Prevalence and density of gametocyte carriage were evaluated in asymptomatic and symptomatic infections by examination of Giemsa-stained blood smears and/or RT-PCR (for falciparum in one site). A significant human genetic contribution was found to be associated with gametocyte prevalence in asymptomatic P. falciparum infections. By contrast, there was no heritability associated with the production of gametocytes for P. falciparum or P. vivax symptomatic infections. Sickle cell mutation, HbS, was associated with increased gametocyte prevalence but its contribution was small.ConclusionsThe existence of a significant human genetic contribution to gametocyte prevalence in asymptomatic infections suggests that candidate gene and genome wide association approaches may be usefully applied to explore the underlying human genetics. Prospective epidemiological studies will provide an opportunity to generate novel and perhaps more epidemiologically pertinent gametocyte data with which similar analyses can be performed and the role of human genetics in parasite transmission ascertained.

Published
2010
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127. COVID-19 critique et anticorps anti-Interféron : série de 11 cas

Author

A. Bourgarit, Y. Tandjaoui-Lambiotte, C. Chauvin, Laurent Gilardin, C. Dubost, M. Vasse, P. Bastard, Anavaj Sakuntabhai, H. Nielly, A. Bousquet, M. Roumier, Jagadeesh Bayry, and C. Roth

Subjects
Gynecology, 2019-20 coronavirus outbreak, medicine.medical_specialty, Coronavirus disease 2019 (COVID-19), Co071, business.industry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Gastroenterology, Internal Medicine, medicine, business
Abstract

Introduction La survenue de formes severes ou critiques de COVID-19, avec necessite d’une hospitalisation en reanimation, est associee a la presence d’anticorps anti-Interferon de classe I dans environ 10 % des cas [1] . Ces anticorps identifies dans le contexte de la COVID-19 bloquent les molecules d’interferon (IFN) et expliqueraient chez ces patients, la survenue d’une atteinte grave de COVID-19, avec une absence d’elimination precoce du virus SARS-CoV-2. Ainsi, il s’agirait d’une forme de deficit immunitaire, acquis, dirige contre le virus SARS-CoV-2 mais aussi potentiellement contre d’autres virus. Les caracteristiques cliniques, biologiques et morphologiques des patients presentant ces anticorps n’ont pas ete decrites precisement, l’evolution des patients n’est pas connue. Patients et methodes Une recherche d’anticorps anti-Interferon a ete realisee chez des patients ayant ete pris en charge en reanimation a l’hopital Begin, a l’hopital Avicenne et a l’hopital Foch pour une COVID-19. La presence d’anticorps anti-IFNalpha2 et anti-IFNomega etaient recherchee par test ELISA puis confirmee par un test fonctionnel d’inhibition de la phosphorylation de STAT1. Les caracteristiques cliniques des patients ont ete relevees a partir des dossiers medicaux. Un suivi medical a ete organise afin de suivre leur evolution sur le plan clinique, biologique et morphologique. Resultats Onze patients ont ete identifies. Il s’agissait de 11 hommes. L’âge median au diagnostic etait de 60 ans (min 36 - max 80). Parmi les autres facteurs de risques de COVID-19 grave classiquement identifies, on retrouvait chez eux, du diabete pour 1 patient, de l’hypertension arterielle pour 6 patients et de l’obesite (IMC > 30 kg/m2) pour 5 patients. L’IMC median etait de 29,8 kg/m2 (min 24 - max 32,8). Il n’etait pas note d’antecedent remarquable, notamment pas d’argument pour un deficit immunitaire, pas d’endocrinopathie auto-immune. On retrouvait 1 BPCO, 2 asthmes, 1 coronaropathie et 1 valve aortique mecanique. Au diagnostic de COVID-19, les signes cliniques initiaux habituels de l’infection etaient retrouves : asthenie (n = 11), fievre (n= 10), toux (n = 5). Deux patients presentaient des diarrhees et 2 de l’insuffisance renale aigue, moderee. Chez 2 patients, on notait une embolie pulmonaire sur le scanner initial. L’evolution etait marquee par une aggravation justifiant une admission en reanimation apres une mediane de 7 jours (min 3 - max 12), pour une forme severe chez 2 patients avec au maximum une oxygenotherapie au masque a haute concentration jusqu’a 15L/min pour 1 patient et 4L/min pour 1 autre. Une forme critique survenait chez 9 patients, avec recours a une intubation oro-tracheale pour ventilation mecanique pour 7 cas, une oxygenotherapie nasale a haut debit (OPTIFLOW) etait suffisante dans 2 cas. Des pneumopathies bacteriennes documentees necessitaient une antibiotherapie specifique dans 6 cas. Dans 10 cas, des traitements a visee specifique du COVID-19 etaient entrepris : corticotherapie (n = 4), hydroxychloroquine (n = 4), lopinavir/ritonavir (n = 3) et tocilizumab (n = 2). En raison du developpement d’un SDRA severe, des seances d’optimisation de l’oxygenotherapie par decubitus ventral etaient entreprises chez 5 patients, avec necessite d’un recours a une ECMO veno-veineuse pour le jeune patient de 36 ans. Afin d’eliminer les Ac antiIFN, ce dernier a egalement beneficie avec succes de 3 seances d’echanges plasmatiques. Au total, 9 patients ont survecu, la duree mediane d’hospitalisaiton en reanimation etait de 16 jours (min 2 - max 31). Les 2 deces sont intervenus apres limitation therapeutique pour SDRA refractaire. Avec un suivi median de 4,2 mois (min 1 - max 11,2), on note une bonne evolution chez l’ensemble des patients survivants, aucune reinfection n’a ete observee et une regression quasi complete des lesions pulmonaires scanographiques (n = 4/5) etait retrouvee a 3 mois. Lors du dernier bilan realise, il n’etait pas constate d’anomalie de la NFS (n = 7/8), ni syndrome inflammatoire (n = 6/7) et le taux d’immunoglobulines etait normal (4/4). Conclusion Cette serie de cas donne une premiere description des patients ayant presente une forme critique de COVID-19 avec Ac anti-IFN de classe I. En dehors de la faible prevalence de comorbidites, il ne semble pas y avoir de phenotype clinique particulier chez cette population en dehors de la predominance masculine.

Published
2021
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129. Genetic determination and linkage mapping of Plasmodium falciparum malaria related traits in Senegal.

Author

Anavaj Sakuntabhai, Rokhaya Ndiaye, Isabelle Casadémont, Chayanon Peerapittayamongkol, Christophe Rogier, Patricia Tortevoye, Adama Tall, Richard Paul, Chairat Turbpaiboon, Waraphon Phimpraphi, Jean-Francois Trape, André Spiegel, Simon Heath, Odile Mercereau-Puijalon, Alioune Dieye, and Cécile Julier

Subjects
Medicine, Science
Abstract

Plasmodium falciparum malaria episodes may vary considerably in their severity and clinical manifestations. There is good evidence that host genetic factors contribute to this variability. To date, most genetic studies aiming at the identification of these genes have used a case/control study design for severe malaria, exploring specific candidate genes. Here, we performed a family-based genetic study of falciparum malaria related phenotypes in two independent longitudinal survey cohorts, as a first step towards the identification of genes and mechanisms involved in the outcome of infection. We studied two Senegalese villages, Dielmo and Ndiop that differ in ethnicity, malaria transmission and endemicity. We performed genome-scan linkage analysis of several malaria-related phenotypes both during clinical attacks and asymptomatic infection. We show evidence for a strong genetic contribution to both the number of clinical falciparum malaria attacks and the asymptomatic parasite density. The asymptomatic parasite density showed linkage to chromosome 5q31 (LOD = 2.26, empirical p = 0.0014, Dielmo), confirming previous findings in other studies. Suggestive linkage values were also obtained at three additional chromosome regions: the number of clinical malaria attacks on chromosome 5p15 (LOD = 2.57, empirical p = 0.001, Dielmo) and 13q13 (LOD = 2.37, empirical p = 0.0014 Dielmo), and the maximum parasite density during asymptomatic infection on chromosome 12q21 (LOD = 3.1, empirical p

Published
2008
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130. Heritability of P. falciparum and P. vivax malaria in a Karen population in Thailand.

Author

Waraphon Phimpraphi, Richard Paul, Bhee Witoonpanich, Chairat Turbpaiboon, Chayanon Peerapittayamongkol, Chalisa Louicharoen, Isabelle Casademont, Sumalee Tungpradabkul, Srivicha Krudsood, Jaranit Kaewkunwal, Thanyachai Sura, Sornchai Looareesuwan, Pratap Singhasivanon, and Anavaj Sakuntabhai

Subjects
Medicine, Science
Abstract

The majority of studies concerning malaria host genetics have focused on individual genes that confer protection against rather than susceptibility to malaria. Establishing the relative impact of genetic versus non-genetic factors on malaria infection and disease is essential to focus effort on key determinant factors. This relative contribution has rarely been evaluated for Plasmodium falciparum and almost never for Plasmodium vivax. We conducted a longitudinal cohort study in a Karen population of 3,484 individuals in a region of mesoendemic malaria, Thailand from 1998 to 2005. The number of P. falciparum and P. vivax clinical cases and the parasite density per person were determined. Statistical analyses were performed to account for the influence of environmental factors and the genetic heritability of the phenotypes was calculated using the pedigree-based variance components model. The genetic contribution to the number of clinical episodes resulting from P. falciparum and P. vivax were 10% and 19% respectively. There was also moderate genetic contribution to the maximum and overall parasite trophozoite density phenotypes for both P. falciparum (16%&16%) and P. vivax (15%&13%). These values, for P. falciparum, were similar to those previously observed in a region of much higher transmission intensity in Senegal, West Africa. Although environmental factors play an important role in acquiring an infection, genetics plays a determinant role in the outcome of an infection with either malaria parasite species prior to the development of immunity.

Published
2008
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132. Standardized Whole-Blood Transcriptional Profiling Enables the Deconvolution of Complex Induced Immune Responses

Author

Alejandra Urrutia, Darragh Duffy, Vincent Rouilly, Céline Posseme, Raouf Djebali, Gabriel Illanes, Valentina Libri, Benoit Albaud, David Gentien, Barbara Piasecka, Milena Hasan, Magnus Fontes, Lluis Quintana-Murci, Matthew L. Albert, Laurent Abel, Andres Alcover, Kalla Astrom, Philippe Bousso, Pierre Bruhns, Ana Cumano, Caroline Demangel, Ludovic Deriano, James Di Santo, Françoise Dromer, Gérard Eberl, Jost Enninga, Jacques Fellay, Antonio Freitas, Odile Gelpi, Ivo Gomperts-Boneca, Serge Hercberg, Olivier Lantz, Claude Leclerc, Hugo Mouquet, Sandra Pellegrini, Stanislas Pol, Lars Rogge, Anavaj Sakuntabhai, Olivier Schwartz, Benno Schwikowski, Spencer Shorte, Vassili Soumelis, Frédéric Tangy, Eric Tartour, Antoine Toubert, Marie-Noëlle Ungeheuer, Illanes Gabriel, Universidad de la República (Uruguay). Facultad de Ciencias. Centro de Matemática., Urrutia Alejandra, Rouilly Vincent, Posseme Céline, Djebali Raouf, Libri Valentina, Albaud Benoit, Gentien David, Piasecka Barbara, Hasan Milena, Fontes Magnus, Quintana-Murci Lluis, Albert Matthew L., Genentech, Inc. [San Francisco], Immunobiologie des Cellules dendritiques, Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de Recherche Translationnelle - Center for Translational Science (CRT), Institut Pasteur [Paris], Centro de Matemática [Montevideo] (CMAT), Universidad de la República [Montevideo] (UCUR), International Group for Data Analysis (IGDA), Plateforme de génomique [Institut Curie], Institut Curie [Paris], Centre for Mathematical Sciences, Mathematical Statistics, Lund University [Lund], Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work benefited from support of the French government’s Invest in theFuture program managed by the Agence Nationale de la Recherche (ANR, reference 10-LABX-69-01), Milieu Intérérieur Consortium (34 collaborateurs) : Abel L, Alcover A, Astrom K, Bousso P, Bruhns P, Cumano A, Demangel C, Deriano L, Di Santo J, Dromer F, Eberl G, Enninga J, Fellay J, Freitas A, Gelpi O, Gomperts-Boneca I, Hercberg S, Lantz O, Leclerc C, Mouquet H, Pellegrini S, Pol S, Rogge L, Sakuntabhai A, Schwartz O, Schwikowski B, Shorte S, Soumelis V, Tangy F, Tartour E, Toubert A, Ungeheuer MN, Quintana-Murci L, Albert ML., ANR-10-LABX-0069,MILIEU INTERIEUR,GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE(2010), Vougny, Marie-Christine, Laboratoires d'excellence - GENETIC & ENVIRONMENTAL CONTROL OF IMMUNE PHENOTYPE VARIANCE: ESTABLISHING A PATH TOWARDS PERSONALIZED MEDICINE - - MILIEU INTERIEUR2010 - ANR-10-LABX-0069 - LABX - VALID, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Institut Pasteur [Paris] (IP), Universidad de la República [Montevideo] (UDELAR), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Adult, Male, Cell type, [SDV.IMM] Life Sciences [q-bio]/Immunology, Transcription, Genetic, medicine.medical_treatment, Stimulation, Computational biology, Biology, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Immune system, Complex induced immune responses, Gene expression, medicine, Humans, Lymphocytes, Receptor, Gene, lcsh:QH301-705.5, Innate immune system, Bacteria, Gene Expression Profiling, Toll-Like Receptors, Immunity, 030104 developmental biology, Cytokine, Blood, Gene Expression Regulation, lcsh:Biology (General), Immunology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cytokines, Female, Whole-blood
Abstract

Figura como autor también el Milieu Intérieur Consortium Systems approaches for the study of immune signaling pathways have been traditionally based on purified cells or cultured lines. However, in vivo responses involve the coordinated action of multiple cell types, which interact to establish an inflammatory microenvironment. We employed standardized whole-blood stimulation systems to test the hypothesis that responses to Toll-like receptor ligands or whole microbes can be defined by the transcriptional signatures of key cytokines. We found 44 genes, identified using Support Vector Machine learning, that captured the diversity of complex innate immune responses with improved segregation between distinct stimuli. Furthermore, we used donor variability to identify shared inter-cellular pathways and trace cytokine loops involved in gene expression. This provides strategies for dimension reduction of large datasets and deconvolution of innate immune responses applicable for characterizing immunomodulatory molecules. Moreover, we provide an interactive R-Shiny application with healthy donor reference values for induced inflammatory genes.

Published
2016
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133. Viral evolution sustains a dengue outbreak of enhanced severity

Author

Inizan, Catherine, primary, Minier, Marine, additional, Prot, Matthieu, additional, O’Connor, Olivia, additional, Forfait, Carole, additional, Laumond, Sylvie, additional, Marois, Ingrid, additional, Biron, Antoine, additional, Gourinat, Ann-Claire, additional, Goujart, Marie-Amélie, additional, Descloux, Elodie, additional, Sakuntabhai, Anavaj, additional, Tarantola, Arnaud, additional, Simon-Lorière, Etienne, additional, and Dupont-Rouzeyrol, Myrielle, additional

Published
2021
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134. Comparison of dengue case classification schemes and evaluation of biological changes in different dengue clinical patterns in a longitudinal follow-up of hospitalized children in Cambodia

Author

Dussart, Philippe, primary, Duong, Veasna, additional, Bleakley, Kevin, additional, Fortas, Camille, additional, Lorn Try, Patrich, additional, Kim, Kim Srorn, additional, Choeung, Rithy, additional, In, Saraden, additional, Andries, Anne-Claire, additional, Cantaert, Tineke, additional, Flamand, Marie, additional, Buchy, Philippe, additional, and Sakuntabhai, Anavaj, additional

Published
2020
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135. Experimental adaptation of dengue virus 1 to Aedes albopictus mosquitoes by in vivo selection

Author

Bellone, Rachel, primary, Lequime, Sebastian, additional, Jupille, Henri, additional, Göertz, Giel P., additional, Aubry, Fabien, additional, Mousson, Laurence, additional, Piorkowski, Géraldine, additional, Yen, Pei-Shi, additional, Gabiane, Gaelle, additional, Vazeille, Marie, additional, Sakuntabhai, Anavaj, additional, Pijlman, Gorben P., additional, de Lamballerie, Xavier, additional, Lambrechts, Louis, additional, and Failloux, Anna-Bella, additional

Published
2020
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138. Human candidate gene polymorphisms and risk of severe malaria in children in Kilifi, Kenya: a case-control association study

Author

Ndila, Carolyne M, Uyoga, Sophie, Macharia, Alexander W, Nyutu, Gideon, Peshu, Norbert, Ojal, John, Shebe, Mohammed, Awuondo, Kennedy O, Mturi, Neema, Tsofa, Benjamin, Sepúlveda, Nuno, Clark, Taane G, Band, Gavin, Clarke, Geraldine, Rowlands, Kate, Hubbart, Christina, Jeffreys, Anna, Kariuki, Silvia, Marsh, Kevin, Mackinnon, Margaret, Maitland, Kathryn, Kwiatkowski, Dominic P, Rockett, Kirk A, Williams, Thomas N, Abathina, Amadou, Abubakar, Ismaela, Achidi, Eric, Agbenyega, Tsiri, Aiyegbo, Mohammed, Akoto, Alex, Allen, Angela, Allen, Stephen, Amenga-Etego, Lucas, Amodu, Folakemi, Amodu, Olukemi, Anchang-Kimbi, Judith, Ansah, Nana, Ansah, Patrick, Ansong, Daniel, Antwi, Sampson, Anyorigiya, Thomas, Apinjoh, Tobias, Asafo-Agyei, Emmanuel, Asoala, Victor, Atuguba, Frank, Auburn, Sarah, Bah, Abdou, Bamba, Kariatou, Bancone, Germana, Barnwell, David, Barry, Abdoulaye, Bauni, Evasius, Besingi, Richard, Bojang, Kalifa, Bougouma, Edith, Bull, Susan, Busby, George, Camara, Abdoulie, Camara, Landing, Campino, Susana, Carter, Richard, Carucci, Dan, Casals-Pascual, Climent, Ceesay, Ndey, Ceesay, Pa, Chau, Tran, Chuong, Ly, Clark, Taane, Cole-Ceesay, Ramou, Conway, David, Cook, Katharine, Cook, Olivia, Cornelius, Victoria, Corran, Patrick, Correa, Simon, Cox, Sharon, Craik, Rachel, Danso, Bakary, Davis, Timothy, Day, Nicholas, Deloukas, Panos, Dembele, Awa, Devries, Jantina, Dewasurendra, Rajika, Diakite, Mahamadou, Diarra, Elizabeth, Dibba, Yaya, Diss, Andrea, Djimdé, Abdoulaye, Dolo, Amagana, Doumbo, Ogobara, Doyle, Alan, Drakeley, Chris, Drury, Eleanor, Duffy, Patrick, Dunstan, Sarah, Ebonyi, Augustine, Elhassan, Ahmed, Elhassan, Ibrahim, Elzein, Abier, Enimil, Anthony, Esangbedo, Pamela, Evans, Jennifer, Evans, Julie, Farrar, Jeremy, Fernando, Deepika, Fitzpatrick, Kathryn, Fullah, Janet, Garcia, Jacob, Ghansah, Anita, Gottleib, Michael, Green, Angie, Hart, Lee, Hennsman, Meike, Hien, Tran, Hieu, Nguyen, Hilton, Eliza, Hodgson, Abraham, Horstmann, Rolf, Hughes, Catherine, Hussein, Ayman, Hutton, Robert, Ibrahim, Muntaser, Ishengoma, Deus, Jaiteh, Jula, Jallow, Mariatou, Jallow, Muminatou, Jammeh, Kebba, Jasseh, Momodou, Jobarteh, Amie, Johnson, Kimberly, Joseph, Sarah, Jyothi, Dushyanth, Kachala, David, Kamuya, Dorcas, Kanyi, Haddy, Karunajeewa, Harin, Karunaweera, Nadira, Keita, Momodou, Kerasidou, Angeliki, Khan, Aja, Kivinen, Katja, Kokwaro, Gilbert, Konate, Amadou, Konate, Salimata, Koram, Kwadwo, Kwiatkowski, Dominic, Laman, Moses, Si, Le, Leffler, Ellen, Lemnge, Martha, Lin, Enmoore, Alioune, Ly, Macharia, Alexander, Macinnis, Bronwyn, Mai, Nguyen, Makani, Julie, Malangone, Cinzia, Mangano, Valentina, Manjurano, Alphaxard, Manneh, Lamin, Manning, Laurens, Manske, Magnus, Marsh, Vicki, Maslen, Gareth, Maxwell, Caroline, Mbunwe, Eric, Mccreight, Marilyn, Mead, Daniel, Mendy, Alieu, Mendy, Anthony, Mensah, Nathan, Michon, Pascal, Miles, Alistair, Miotto, Olivo, Modiano, David, Mohamed, Hiba, Molloy, Sile, Molyneux, Malcolm, Molyneux, Sassy, Moore, Mike, Moyes, Catherine, Mtei, Frank, Mtove, George, Mueller, Ivo, Mugri, Regina, Munthali, Annie, Mutabingwa, Theonest, Nadjm, Behzad, Ndi, Andre, Ndila, Carolyne, Newton, Charles, Niangaly, Amadou, Njie, Haddy, Njie, Jalimory, Njie, Madi, Njie, Malick, Njie, Sophie, Njiragoma, Labes, Nkrumah, Francis, Ntunthama, Neema, Nyika, Aceme, Nyirongo, Vysaul, O'Brien, John, Obu, Herbert, Oduro, Abraham, Ofori, Alex, Olaniyan, Subulade, Olaosebikan, Rasaq, Oluoch, Tom, Omotade, Olayemi, Oni, Olajumoke, Onykwelu, Emmanuel, Opi, Daniel, Orimadegun, Adebola, O'Riordan, Sean, Ouedraogo, Issa, Oyola, Samuel, Parker, Michael, Pearson, Richard, Pensulo, Paul, Phiri, Ajib, Phu, Nguyen, Pinder, Margaret, Pirinen, Matti, Plowe, Chris, Potter, Claire, Poudiougou, Belco, Puijalon, Odile, Quyen, Nguyen, Ragoussis, Ioannis, Ragoussis, Jiannis, Rasheed, Oba, Reeder, John, Reyburn, Hugh, Riley, Eleanor, Risley, Paul, Rockett, Kirk, Rodford, Joanne, Rogers, Jane, Rogers, William, Ruano-Rubio, Valentín, Sabally-Ceesay, Kumba, Sadiq, Abubacar, Saidy-Khan, Momodou, Saine, Horeja, Sakuntabhai, Anavaj, Sall, Abdourahmane, Sambian, David, Sambou, Idrissa, Sanjoaquin, Miguel, Shah, Shivang, Shelton, Jennifer, Siba, Peter, Silva, Nilupa, Simmons, Cameron, Simpore, Jaques, Singhasivanon, Pratap, Sinh, Dinh, Sirima, Sodiomon, Sirugo, Giorgio, Sisay-Joof, Fatoumatta, Sissoko, Sibiry, Small, Kerrin, Somaskantharajah, Elilan, Spencer, Chris, Stalker, Jim, Stevens, Marryat, Suriyaphol, Prapat, Sylverken, Justice, Taal, Bintou, Tall, Adama, Taylor, Terrie, Teo, Yik, Thai, Cao, Thera, Mahamadou, Titanji, Vincent, Toure, Ousmane, Troye-Blomberg, Marita, Usen, Stanley, Vanderwal, Aaron, Wangai, Hannah, Watson, Renee, Williams, Thomas, Wilson, Michael, Wrigley, Rebecca, Yafi, Clarisse, Yamoah, Lawrence, The Wellcome Trust Centre for Human Genetics [Oxford], University of Oxford, London School of Hygiene and Tropical Medicine (LSHTM), The Wellcome Trust Sanger Institute [Cambridge], St Mary's Hospital, Imperial College, TNW and MM are funded through awards from the Wellcome Trust (grants 091758 and 202800 [to TNW] and grant 088634 [to MM]) and DPK and TGC receive support from the Medical Research Council (grant G19/9 [to DPK] and grants MR/K000551/1, MR/M01360X/1, MR/N010469/1, and MC_PC_15103 [to TGC]). The research leading to these results received funding from the European Community's Seventh Framework Programme (FP7/2007-2013, under grant agreement 242095) and from the Medical Research Council (grant G0600718). MalariaGEN is supported by the Wellcome Trust (WT077383/Z/05/Z) and by the Foundation for the National Institutes of Health (grant 566) as part of the Bill & Melinda Gates' Grand Challenges in Global Health Initiative. The Resource Centre for Genomic Epidemiology of Malaria is supported by the Wellcome Trust (grant 090770/Z/09/Z). Support was also provided by the Medical Research Council (grant G0600718). The Wellcome Trust also provides core awards to the Wellcome Trust Centre for Human Genetics (grant 090532/Z/09/Z) and to the Wellcome Trust Sanger Institute (grant 098051). This work forms part of a larger collaboration with the MalariaGEN Consortium, whose members are listed at http://www.malariagen.net/projects/host/consortium-members. This paper is published with permission from the Director of the Kenya Medical Research Institute (KEMRI)., MalariaGEN Consortium (Anavaj Sakuntabhai), and European Project: 242095,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,EVIMALAR(2009)

Subjects
Case-Control Studies, Child, Child, Preschool, Female, Gene Frequency, Genetic Predisposition to Disease, Humans, Kenya, Malaria, Male, Polymorphism, Genetic, Hematology, macromolecular substances, [SDV.BIBS]Life Sciences [q-bio]/Quantitative Methods [q-bio.QM], Article, Genetic, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, parasitic diseases, [SDV.MP.PAR]Life Sciences [q-bio]/Microbiology and Parasitology/Parasitology, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Polymorphism, Preschool
Abstract

Summary Background Human genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress. Methods We did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria. Findings Between June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell trait (odds ratio [OR] 0·15, 95% CI 0·11–0·20; p=2·61 × 10−58), blood group O (0·74, 0·66–0·82; p=6·26 × 10−8), and –α3·7-thalassaemia (0·83, 0·76–0·90; p=2·06 × 10−6). We also found strong associations between overall risk of severe malaria and polymorphisms in both ATP2B4 (OR 0·76, 95% CI 0·63–0·92; p=0·001) and FREM3 (0·64, 0·53–0·79; p=3·18 × 10−14). The association with FREM3 could be accounted for by linkage disequilibrium with a complex structural mutation within the glycophorin gene region (comprising GYPA, GYPB, and GYPE) that encodes for the rare Dantu blood group antigen. Heterozygosity for Dantu was associated with risk for severe malaria (OR 0·57, 95% CI 0·49–0·68; p=3·22 × 10−11), as was homozygosity (0·26, 0·11–0·62; p=0·002). Interpretation Both ATP2B4 and the Dantu blood group antigen are associated with the structure and function of red blood cells. ATP2B4 codes for plasma membrane calcium-transporting ATPase 4 (the major calcium pump on red blood cells) and the glycophorins are ligands for parasites to invade red blood cells. Future work should aim at uncovering the mechanisms by which these polymorphisms can result in severe malaria protection and investigate the implications of these associations for wider health. Funding Wellcome Trust, UK Medical Research Council, European Union, and Foundation for the National Institutes of Health as part of the Bill & Melinda Gates Grand Challenges in Global Health Initiative.

Published
2018
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139. Genetic Diversity of Collaborative Cross Mice Controls Viral Replication, Clinical Severity, and Brain Pathology Induced by Zika Virus Infection, Independently of Oas1b

Author

Jean-Jacques Panthier, Caroline Manet, Laurine Conquet, Anavaj Sakuntabhai, Etienne Simon-Loriere, Xavier Montagutelli, David Hardy, Matthieu Prot, Marie Flamand, Grégory Jouvion, Génétique de la souris - Mouse Genetics, Institut Pasteur [Paris], Génomique évolutive des virus à ARN - Evolutionary genomics of RNA viruses, Neuropathologie expérimentale - Experimental neuropathology, Institut Pasteur [Paris]-Université Paris Descartes - Paris 5 (UPD5), Virologie Structurale - Structural Virology, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], This work was supported by a grant from the French government’s Investissement d’Avenir program, Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases (grant no. ANR-10-LABX-62-IBEID). C.M. was supported by a fellowship from grant no. ANR-10-LABX-62-IBEID., We are grateful to the Virology Laboratory of the Institut Pasteur of French Guiana (National Reference Center for Arboviruses) for providing the FG15 ZIKV strain and Valérie Choumet for providing the IS-98-ST1 WNV strain. We thank Thérèse Couderc and Claude Ruffié for providing B6-Ifnar1 and 129-Ifnar1 mice, Laetitia Joullié and Marion Doladilhe for technical help, Magali Tichit for performance of the histopathology techniques, Isabelle Lanctin, Tommy Penel, and Jerôme Le Boydre for careful breeding of the CC mice, and the animal facility staff for animal care in biocontainment units (DTPS-C2RA-Central Animal Facility platform). We are grateful to Jean Jaubert, Michel Cohen-Tannoudji, and Aurore Vidy-Roche for useful discussions throughout the project and to Rachel Meade for editorial suggestions., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), Virologie Structurale, ANR-10-LABX-62-IBEID,IBEID,Laboratoire d'Excellence 'Integrative Biology of Emerging Infectious Diseases'(2010), Institut Pasteur [Paris] (IP), Institut Pasteur [Paris] (IP)-Université Paris Descartes - Paris 5 (UPD5), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Pathology, medicine.medical_specialty, mouse model, Immunology, Population, Disease, Microbiology, Collaborative Cross, Zika virus, Dengue fever, 03 medical and health sciences, Zika, 0302 clinical medicine, flavivirus, Virology, medicine, education, Gene, 030304 developmental biology, 0303 health sciences, education.field_of_study, biology, genetic diversity, medicine.disease, biology.organism_classification, 3. Good health, [SDV.GEN.GA]Life Sciences [q-bio]/Genetics/Animal genetics, Flavivirus, host genetics, Viral replication, Insect Science, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, Viral load, 030217 neurology & neurosurgery
Abstract

International audience; The explosive spread of Zika virus (ZIKV) has been associated with major variations in severe disease and congenital afflictions among infected populations, suggesting an influence of host genes. We investigated how genome-wide variants could impact susceptibility to ZIKV infection in mice. We first describe that the susceptibility of Ifnar1-knockout mice is largely influenced by their genetic background. We then show that Collaborative Cross (CC) mice, which exhibit a broad genetic diversity, in which the type I interferon receptor (IFNAR) was blocked by an anti-IFNAR antibody expressed phenotypes ranging from complete resistance to severe symptoms and death, with large variations in the peak and the rate of decrease in the plasma viral load, in the brain viral load, in brain histopathology, and in the viral replication rate in infected cells. The differences in susceptibility to ZIKV between CC strains correlated with the differences in susceptibility to dengue and West Nile viruses between the strains. We identified highly susceptible and resistant mouse strains as new models to investigate the mechanisms of human ZIKV disease and other flavivirus infections. Genetic analyses revealed that phenotypic variations are driven by multiple genes with small effects, reflecting the complexity of ZIKV disease susceptibility in the human population. Notably, our results rule out the possibility of a role of the Oas1b gene in the susceptibility to ZIKV. Altogether, the findings of this study emphasize the role of host genes in the pathogeny of ZIKV infection and lay the foundation for further genetic and mechanistic studies.IMPORTANCE In recent outbreaks, ZIKV has infected millions of people and induced rare but potentially severe complications, including Guillain-Barré syndrome and encephalitis in adults. While several viral sequence variants were proposed to enhance the pathogenicity of ZIKV, the influence of host genetic variants in mediating the clinical heterogeneity remains mostly unexplored. We addressed this question using a mouse panel which models the genetic diversity of the human population and a ZIKV strain from a recent clinical isolate. Through a combination of in vitro and in vivo approaches, we demonstrate that multiple host genetic variants determine viral replication in infected cells and the clinical severity, the kinetics of blood viral load, and brain pathology in mice. We describe new mouse models expressing high degrees of susceptibility or resistance to ZIKV and to other flaviviruses. These models will facilitate the identification and mechanistic characterization of host genes that influence ZIKV pathogenesis.

Published
2020
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140. A global network for investigating the genomic epidemiology of malaria

Author

Achidi, Eric Akum, Agbenyega, Tsiri, Allen, Stephen, Amodu, Olukemi, Bojang, Kalifa, Conway, David, Corran, Patrick, Deloukas, Panos, Djimde, Abdoulaye, Dolo, Amagana, Doumbo, Ogobara, Drakeley, Chris, Duffy, Patrick, Dunstan, Sarah, Evans, Jennifer, Farrar, Jeremy, Fernando, Deepika, Hien, Tran Tinh, Horstmann, Rolf, Ibrahim, Muntaser, Karunaweera, Nadira, Kokwaro, Gilbert, Koram, Kojo, Kwiatkowski, Dominic, Lemnge, Martha, Makani, Julie, Marsh, Kevin, Michon, Pascal, Modiano, David, Molyneux, Malcolm E., Mueller, Ivo, Mutabingwa, Theonest, Peshu, Norbert, Plowe, Chris, Puijalon, Odile, Ragoussis, Jiannis, Reeder, John, Reyburn, Hugh, Riley, Eleanor, Rogers, Jane, Sakuntabhai, Anavaj, Singhasivanon, Pratap, Sirima, Sodiomon, Sirugo, Giorgio, Tall, Adama, Taylor, Terrie, Thera, Mahamadou, Troye-Blomberg, Marita, Williams, Tom, Wilson, Michael, Amenga-Etego, Lucas, Apinjoh, Tobias O., Bougouma, Edith, Dewasurendra, Rajika, Diakite, Mahamadou, Enimil, Anthony, Hussein, Ayman, Ishengoma, Deus, Jallow, Muminatou, Lin, Enmoore, Ly, Alioune, Mangano, Valentina D., Manjurano, Alphaxard, Manning, Laurens, Ndila, Carolyne M., Nyirongo, Vysaul, Oluoch, Tom, Quyen, Nguyen T. N., Suriyaphol, Prapat, Toure, Ousman, Kwiatkowski, Dominic, Alcock, Daniel, Auburn, Sarah, Barnwell, David, Bull, Susan, Campino, Susana, deVries, Jantina, Elzein, Abier, Evans, Julie, Fitzpatrick, Kathryn, Ghansah, Anita, Green, Angie, Hart, Lee, Hilton, Eliza, Hubbart, Christina, Hughes, Catherine, Jeffreys, Anna E., Kivinen, Katja, MacInnis, Bronwyn, Manske, Magnus, Maslen, Gareth, McCreight, Marilyn, Mendy, Alieu, Moyes, Catherine, Nyika, Aceme, Potter, Claire, Risley, Paul, Rowlands, Kate, SanJoaquin, Miguel, Small, Kerrin, Somaskantharajah, Elilan, Stevens, Marryat, Teo, YikYing, Watson, Renee, Carucci, Dan, Cook, Katharine, Doyle, Alan, Duombo, Ogobara, Gottlieb, Michael, Kwiatkowski, Dominic, Rockett, Kirk A., Vanderwal, Aaron, Clark, Taane, Parker, Michael, and Wrigley, Rebecca

Published
2008
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141. Erratum: Structural basis of potent Zikadengue virus antibody cross-neutralization

Author

Barba-Spaeth, Giovanna, Dejnirattisai, Wanwisa, Rouvinski, Alexander, Vaney, Marie-Christine, Medits, Iris, Sharma, Arvind, Simon-Lorire, Etienne, Sakuntabhai, Anavaj, Cao-Lormeau, Van-Mai, Haouz, Ahmed, England, Patrick, Stiasny, Karin, Mongkolsapaya, Juthathip, Heinz, Franz X., Screaton, Gavin R., and Rey, Flix A.

Abstract

Author(s): Giovanna Barba-Spaeth; Wanwisa Dejnirattisai; Alexander Rouvinski; Marie-Christine Vaney; Iris Medits; Arvind Sharma; Etienne Simon-Lorire; Anavaj Sakuntabhai; Van-Mai Cao-Lormeau; Ahmed Haouz; Patrick England; Karin Stiasny; Juthathip Mongkolsapaya; Franz X. Heinz; [...]

Published
2016
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142. Comparison of dengue case classification schemes and evaluation of biological changes in different dengue clinical patterns in a longitudinal follow-up of hospitalized children in Cambodia

Author

Anne-Claire Andries, Philippe Dussart, Anavaj Sakuntabhai, Saraden In, Kim Sroin Kim, Veasna Duong, Marie Flamand, Kevin Bleakley, Philippe Buchy, Tineke Cantaert, Patrich Lorn Try, Camille Fortas, Rithy Choeung, Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP), Statistique mathématique et apprentissage (CELESTE), Inria Saclay - Ile de France, Institut National de Recherche en Informatique et en Automatique (Inria)-Institut National de Recherche en Informatique et en Automatique (Inria)-Laboratoire de Mathématiques d'Orsay (LMO), Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS)-Université Paris-Saclay-Centre National de la Recherche Scientifique (CNRS), Kampong Cham Provincial hospital [Cambodia], Virologie Structurale - Structural Virology, Centre National de la Recherche Scientifique (CNRS)-Institut Pasteur [Paris], GlaxoSmithKline, Glaxo Smith Kline, Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, Dengue hemorrhagic fever, RC955-962, NS1 antigen, Disease, Pathology and Laboratory Medicine, Severity of Illness Index, Biochemistry, Vascular Medicine, 0302 clinical medicine, Medical Conditions, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, MESH: Child, Arctic medicine. Tropical medicine, Prospective Studies, Child, dengue classification, Lipids, 3. Good health, Cholesterol, Blood, Arboviral Infections, Medical Microbiology, Child, Preschool, Viral Pathogens, Disease Progression, MESH: Disease Progression, Public aspects of medicine, MESH: Triglycerides, medicine.medical_specialty, Classification scheme, MESH: Severe Dengue, Hemorrhage, MESH: Child, Hospitalized, Dengue shock syndrome, World Health Organization, Microbiology, Severe dengue, 03 medical and health sciences, MESH: Cross-Sectional Studies, Signs and Symptoms, MESH: Severity of Illness Index, Humans, Microbial Pathogens, MESH: Adolescent, MESH: Humans, Flaviviruses, MESH: Child, Preschool, Public Health, Environmental and Occupational Health, Organisms, lipid markers, Biology and Life Sciences, Chikungunya Infection, Dengue Virus, medicine.disease, Tropical Diseases, 030104 developmental biology, Cross-Sectional Studies, MESH: Viral Nonstructural Proteins, Clinical Medicine, MESH: Female, Child, Hospitalized, 0301 basic medicine, RNA viruses, Pediatrics, Viral Diseases, Physiology, Viral Nonstructural Proteins, MESH: World Health Organization, Dengue fever, Dengue Fever, MESH: Cholesterol, Medicine and Health Sciences, Hematology, Body Fluids, Infectious Diseases, Hematocrit, Viruses, Female, RA1-1270, Pathogens, Anatomy, Cambodia, Research Article, Neglected Tropical Diseases, Adolescent, 030231 tropical medicine, macromolecular substances, World health, Blood Plasma, medicine, In patient, Severe Dengue, Triglycerides, business.industry, MESH: Cambodia, MESH: Prospective Studies, MESH: Male, Blood Counts, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business
Abstract

Background The World Health Organization (WHO) proposed guidelines on dengue clinical classification in 1997 and more recently in 2009 for the clinical management of patients. The WHO 1997 classification defines three categories of dengue infection according to severity: dengue fever (DF), dengue hemorrhagic fever (DHF), and dengue shock syndrome (DSS). Alternative WHO 2009 guidelines provide a cross-sectional classification aiming to discriminate dengue fever from dengue with warning signs (DWWS) and severe dengue (SD). The primary objective of this study was to perform a comparison of two dengue classifications. The secondary objective was to describe the changes of hematological and biochemical parameters occurring in patients presenting with different degrees of severity during the course of the disease, since progression to more severe clinical forms is unpredictable. Methodology/Principal findings We performed a prospective, monocentric, cross-sectional study of hospitalized children in Cambodia, aged from 2 to 15 years old with severe and non-severe dengue. We enrolled 243 patients with acute dengue-like illness: 71.2% were dengue infections confirmed using quantitative reverse transcription PCR or NS1 antigen capture ELISA, of which 87.2% and 9.0% of DF cases were respectively classified DWWS and SD, and 35.9% of DHF were designated SD using an adapted WHO 2009 classification for SD case definition. Systematic use of ultrasound at patient admission was crucial for detecting plasma leakage. No difference was observed in the concentration of secreted NS1 protein between different dengue severity groups. Lipid profiles were different between DWWS and SD at admission, characterized by a decrease in total cholesterol, HDL cholesterol, and LDL cholesterol, in SD. Conclusions/Significance Our results show discrepancies between the two classifications, including misclassification of severe dengue cases as mild cases by the WHO 1997 classification. Using an adapted WHO 2009 classification, SD more precisely defines the group of patients requiring careful clinical care at a given time during hospitalization., Author summary Dengue is a viral disease that results in various health conditions, ranging from strictly asymptomatic infections to life-threatening severe dengue. Here we have compared the two World Health Organization (WHO) dengue classification schemes from 1997 and 2009, which define different categories of dengue fever and have been at the root of much debate in the dengue research community. We enrolled a Cambodian pediatric cohort of hospitalized dengue-confirmed patients, with clinical and biological follow-up. Our findings demonstrate that (i) the WHO 1997 classification is a longitudinal dengue-case classification which uses strict prerequisite clinical and/or biological signs to move from one level of severity to another, and (ii) the WHO 2009 classification, being a transversal dengue-case classifier, is more flexible and when adapted with systematic use of ultrasound is more accurate in identifying severe dengue case for timely and appropriate clinical management of hospitalized patients. Our laboratory results found that lipid profiles exhibited changes and differences between different dengue severity groups at hospital.

Published
2019
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143. Asymptomatic Dengue Virus Infections, Cambodia, 2012–2013

Author

Tarik Benmarhnia, Anavaj Sakuntabhai, Veasna Duong, Sopheak Sorn, Sowath Ly, Arnaud Tarantola, Kunthy Nguon, Kim Srorn Kim, Richard Paul, Philippe Dussart, Sowathy Buoy, Camille Fortas, Sivuth Ong, Lim Voeung, Rekol Huy, Souv Kimsan, Philippe Buchy, Siam Chan, Unité d'Épidémiologie et de Santé Publique [Phnom Penh], Institut Pasteur du Cambodge, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Réseau International des Instituts Pasteur (RIIP), Unité de Virologie, Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Génétique fonctionnelle des Maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), National Center of Parasitology (CNM), National Malaria Center [Phnom Penh], Kampong Cham Provincial hospital [Cambodia], Tboung Khmum District Referral Hospital, GlaxoSmithKline Vaccines [Singapore], Génétique fonctionnelle des maladies infectieuses - Functional Genetics of Infectious Diseases, Institut Pasteur [Paris], University of California [San Diego] (UC San Diego), University of California, National Center for Parasitology, Entomology and Malaria Control [Phnom Penh, Cambodia] (CNM), Dengue Framework for Resisting Epidemics in Europe studies were funded by a grant (no. 282378) from the European Union 7th FP.P.B. is a former head of virology at Institut Pasteur du Cambodge and is an employee of GSK Vaccines, Singapore., The authors gratefully acknowledge participating hospitals, villages, and study participants, as well as Tineke Cantaert for her editorial comments and suggestion, European Project: 282378,EC:FP7:HEALTH,FP7-HEALTH-2011-single-stage,DENFREE(2012), University of California (UC), Institut Pasteur [Paris] (IP), Tarantola, Arnaud, and Dengue research Framework for Resisting Epidemics in Europe - DENFREE - - EC:FP7:HEALTH2012-01-01 - 2016-12-31 - 282378 - VALID

Subjects
Male, History, viruses, vector-borne infections, lcsh:Medicine, Asymptomatic Dengue Virus Infections, Cambodia, 2012–2013, Dengue virus, medicine.disease_cause, Disease Outbreaks, Dengue, 0302 clinical medicine, Aedes aegypti, [SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Mass Screening, risk factors, Public Health Surveillance, 030212 general & internal medicine, Child, ComputingMilieux_MISCELLANEOUS, [SDV.MHEP.ME]Life Sciences [q-bio]/Human health and pathology/Emerging diseases, Age Factors, virus diseases, Aedes albopictus, 21st Century, 3. Good health, Infectious Diseases, Medical Microbiology, Child, Preschool, Public Health and Health Services, [SDV.MHEP.MI] Life Sciences [q-bio]/Human health and pathology/Infectious diseases, Female, epidemiology, medicine.symptom, Cambodia, Microbiology (medical), Adult, Asia, Adolescent, Clinical Sciences, 030231 tropical medicine, Microbiology, Asymptomatic, History, 21st Century, lcsh:Infectious and parasitic diseases, 03 medical and health sciences, Young Adult, medicine, Humans, asymptomatic, lcsh:RC109-216, Preschool, mosquitoes, Mekong, dengue virus, business.industry, Research, lcsh:R, biochemical phenomena, metabolism, and nutrition, Virology, Asymptomatic Diseases, incidence, business, Sentinel Surveillance
Abstract

International audience; We investigated dengue virus (DENV) and asymptomatic DENV infections in rural villages of Kampong Cham Province, Cambodia, during 2012 and 2013. We conducted perifocal investigations in and around households for 149 DENV index cases identified through hospital and village surveillance. We tested participants 0.5–30 years of age by using nonstructural 1 rapid tests and confirmed DENV infections using quantitative reverse transcription PCR or nonstructural 1–capture ELISA. We used multivariable Poisson regressions to explore links between participants’ DENV infection status and household characteristics. Of 7,960 study participants, 346 (4.4%) were infected with DENV, among whom 302 (87.3%) were

Published
2019
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144. Genetic diversity of Collaborative Cross mice controls viral replication, clinical severity and brain pathology induced by Zika virus infection, independently of Oas1b

Author

Jean-Jacques Panthier, Grégory Jouvion, Etienne Simon-Loriere, David Hardy, Caroline Manet, Xavier Montagutelli, Marie Flamand, Anavaj Sakuntabhai, and Matthieu Prot

Subjects
0303 health sciences, education.field_of_study, Pathology, medicine.medical_specialty, biology, Population, Disease, biology.organism_classification, medicine.disease, Phenotype, 3. Good health, Zika virus, Dengue fever, 03 medical and health sciences, 0302 clinical medicine, Viral replication, medicine, education, Gene, Viral load, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract

The explosive spread of Zika virus (ZIKV) has been associated with major variations in severe disease and congenital afflictions among infected populations, suggesting an influence of host genes. We investigated how genome-wide variants could impact susceptibility to ZIKV infection in mice. We first describe that the susceptibility of Ifnar1 knockout mice is largely influenced by their genetic background. We then show that the broad genetic diversity of Collaborative Cross mice, which receptor to type I interferon (IFNAR) was blocked by anti-IFNAR antibody, expressed phenotypes ranging from complete resistance to severe symptoms and death with large variations in the peak and rate of decrease of plasma viral load, in brain viral load, in brain histopathology and in viral replication rate in infected cells. Differences of susceptibility between CC strains were correlated between Zika, Dengue and West Nile viruses. We identified highly susceptible and resistant mouse strains as new models to investigate the mechanisms of human ZIKV disease and other flavivirus infections. Genetic analyses revealed that phenotypic variations are driven by multiple genes with small effects, reflecting the complexity of ZIKV disease susceptibility in human population. Notably, our results rule out a role of the Oas1b gene in the susceptibility to ZIKV. Altogether, this study emphasizes the role of host genes in the pathogeny of ZIKV infection and lays the foundation for further genetic and mechanistic studies.IMPORTANCEIn recent outbreaks, ZIKV has infected millions of people and induced rare but potentially severe complications, including Guillain-Barré syndrome and encephalitis in adults. While several viral sequence variants were proposed to enhance the pathogenicity of ZIKV, the influence of host genetic variants in the clinical heterogeneity remains mostly unexplored. We have addressed this question using a mouse panel which models the genetic diversity of human population and a ZIKV strain from a recent clinical isolate. Through a combination of in vitro and in vivo approaches, we demonstrate that multiple host genetic variants determine viral replication in infected cells, and clinical severity, kinetics of blood viral load and brain pathology in mice. We describe new mouse models expressing high susceptibility or resistance to ZIKV and to other flaviviruses. These models will facilitate the identification and mechanistic characterization of host genes that influence ZIKV pathogenesis.

Published
2019
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145. Genetic Diversity of Collaborative Cross Mice Controls Viral Replication, Clinical Severity, and Brain Pathology Induced by Zika Virus Infection, Independently of

Author

Caroline, Manet, Etienne, Simon-Lorière, Grégory, Jouvion, David, Hardy, Matthieu, Prot, Laurine, Conquet, Marie, Flamand, Jean-Jacques, Panthier, Anavaj, Sakuntabhai, and Xavier, Montagutelli

Subjects
Collaborative Cross Mice, Male, Mice, Knockout, Zika Virus Infection, Brain, Genetic Variation, Receptor, Interferon alpha-beta, Zika Virus, Viral Load, Virus Replication, Disease Models, Animal, Mice, Chlorocebus aethiops, 2',5'-Oligoadenylate Synthetase, Animals, Humans, Pathogenesis and Immunity, Female, Vero Cells, West Nile virus
Abstract

The explosive spread of Zika virus (ZIKV) has been associated with major variations in severe disease and congenital afflictions among infected populations, suggesting an influence of host genes. We investigated how genome-wide variants could impact susceptibility to ZIKV infection in mice. We first describe that the susceptibility of Ifnar1-knockout mice is largely influenced by their genetic background. We then show that Collaborative Cross (CC) mice, which exhibit a broad genetic diversity, in which the type I interferon receptor (IFNAR) was blocked by an anti-IFNAR antibody expressed phenotypes ranging from complete resistance to severe symptoms and death, with large variations in the peak and the rate of decrease in the plasma viral load, in the brain viral load, in brain histopathology, and in the viral replication rate in infected cells. The differences in susceptibility to ZIKV between CC strains correlated with the differences in susceptibility to dengue and West Nile viruses between the strains. We identified highly susceptible and resistant mouse strains as new models to investigate the mechanisms of human ZIKV disease and other flavivirus infections. Genetic analyses revealed that phenotypic variations are driven by multiple genes with small effects, reflecting the complexity of ZIKV disease susceptibility in the human population. Notably, our results rule out the possibility of a role of the Oas1b gene in the susceptibility to ZIKV. Altogether, the findings of this study emphasize the role of host genes in the pathogeny of ZIKV infection and lay the foundation for further genetic and mechanistic studies. IMPORTANCE In recent outbreaks, ZIKV has infected millions of people and induced rare but potentially severe complications, including Guillain-Barré syndrome and encephalitis in adults. While several viral sequence variants were proposed to enhance the pathogenicity of ZIKV, the influence of host genetic variants in mediating the clinical heterogeneity remains mostly unexplored. We addressed this question using a mouse panel which models the genetic diversity of the human population and a ZIKV strain from a recent clinical isolate. Through a combination of in vitro and in vivo approaches, we demonstrate that multiple host genetic variants determine viral replication in infected cells and the clinical severity, the kinetics of blood viral load, and brain pathology in mice. We describe new mouse models expressing high degrees of susceptibility or resistance to ZIKV and to other flaviviruses. These models will facilitate the identification and mechanistic characterization of host genes that influence ZIKV pathogenesis.

Published
2019

146. Deletions within COL7A1 exons distant from consensus splice sites alter splicing and produce shortened polypeptides in dominant dystrophic epidermolysis bullosa

Author

Sakuntabhai, Anavaj, Hammami-Hauasli, Nadja, Bodemer, Christine, Rochat, Ariane, Prost, Catherine, Barrandon, Yann, Prost, Yves de, Lathrop, Mark, Wojnarowska, Fenella, Bruckner-Tuderman, Leena, and Hovnanian, Alain

Subjects
Epidermolysis bullosa -- Genetic aspects, Chromosome deletion -- Research, Collagen diseases -- Genetic aspects, Biological sciences
Abstract

Genetic deletions in COL7A1 have been found to be associated with dominant dystrophic epidermolysis bullosa (DDEB) in a study of two familial cases. COL7A1 is the gene associated with type VII collagen. The study indicates that shortened type VII collagen polypeptides affect formation of anchoring fibrils in DDEB. A 28-bp deletion in exon 73 was found in one patient, and a 27-bp deletion in exon 87 was found in the other patient. These exonic sequences may govern splicing of COL7A1 pre-mRNA.

Published
1998

147. Refined genetic mapping of the Darier locus to a <1-cM region of chromosome 12q24.1, and construction of a complete, high-resolution P1 artificial chromosome/bacterial artificial chromosome contig of the critical region

Author

Monk, Sarah, Sakuntabhai, Anavaj, Carter, Simon A., Bryce, Steven D., Cox, Roger, Harrington, Louise, Levy, Elaine, Ruiz-Perez, Victor L., Katsantoni, Eleni, Kodvawala, Ahmer, Munro, Colin S., Burge, Susan, Larregue, Marc, Nagy, Gyula, Rees, Jonathan L., Lathrop, Mark, Monaco, Anthony P., Strachan, Tom, and Hovnanian, Alain

Subjects
Genetic disorders -- Research, Chromosome mapping -- Usage, Skin -- Abnormalities, Keratinization -- Genetic aspects, Cell adhesion -- Genetic aspects, Biological sciences
Abstract

Darier disease (DD), an autosomal dominant skin disorder involving loss of adhesion between epidermal cells and abnormal keratinization, has been studied in four families. Linkage analysis has shown key recombination events to refine the DD locus to a

Published
1998

148. Autoantibodies against type I IFNs in patients with life-threatening COVID-19

Author

Bastard, P., Zhang, Q., Michailidis, E., Hoffmann, H.H., Zhang, Y., Dorgham, Karim, Philippot, Q., Rosain, J., Béziat, V., Manry, J., Shaw, E., Haljasmägi, L., Peterson, P., Lorenzo, L., Bizien, L., Trouillet-Assant, S., Dobbs, K., de Jesus, A.A., Belot, A., Kallaste, A., Catherinot, E., Tandjaoui-Lambiotte, Y., Le Pen, J., Kerner, G., Bigio, B., Seeleuthner, Y., Yang, R., Bolze, A., Spaan, A.N., Delmonte, O.M., Abers, M.S., Aiuti, A., Casari, G., Lampasona, V., Piemonti, L., Ciceri, F., Bilguvar, K., Lifton, R.P., Vasse, M., Smadja, D.M., Migaud, M., Hadjadj, J., Terrier, B., Duffy, D., Quintana-Murci, L., van de Beek, D., Roussel, L., Vinh, D.C., Tangye, S., Haerynck, F., Dalmau, D., Martinez-Picado, J., Brodin, P., Nussenzweig, M.C., Boisson-Dupuis, S., Rodríguez-Gallego, C., Vogt, G., Mogensen, T.H., Oler, A.J., Gu, J., Burbelo, P.D., Cohen, J.I., Biondi, A., Bettini, L.R., DÁngio, M., Bonfanti, P., Rossignol, P., Mayaux, J., Rieux-Laucat, F., Husebye, E.S., Fusco, F., Ursini, M.V., Imberti, L., Sottini, A., Paghera, S., Quiros-Roldan, E., Rossi, C., Castagnoli, R., Montagna, D., Licari, A., Marseglia, G.L., Duval, X., Ghosn, J., Tsang, J.S., Goldbach-Mansky, R., Kisand, K., Lionakis, M.S., Puel, A., Zhang, S.Y., Holland, S.M., Gorochov, G., Jouanguy, E., Rice, C.M., Cobat, A., Notarangelo, L.D., Abel, L., Su, H.C., Casanova, J.L., Arias, A.A., Boisson, B., Boucherit, S., Bustamante, J., Chbihi, M., Chen, J., Chrabieh, M., Kochetkov, T., Le Voyer, T., Liu, D., Nemirovskaya, Y., Ogishi, M., Papandrea, D., Patissier, C., Rapaport, F., Roynard, M., Vladikine, N., Woollett, M., Zhang, P., Kashyap, A., Ding, L., Bosticardo, M., Wang, Q., Ochoa, S., Liu, H., Chauvin, S.D., Stack, M., Koroleva, G., Bansal, N., Dalgard, C.L., Snow, A.L., Abad Capa, Jorge, Aguilera-Albesa, S., Akcan, O.M., Darazam, I.A., Aldave, J.C., Ramos, M.A., Nadji, S.A., Alkan, G., Allardet-Servent, J., Allende, L.M., Alsina, L., Alyanakian, M.A., Amador-Borrero, B., Amoura, Z., Antolí, A., Arslan, S., Assant, S., Auguet, T., Azot, A., Bajolle, F., Baldolli, A., Ballester, M., Feldman, H.B., Barrou, B., Beurton, A., Bilbao, A., Blanchard-Rohner, G., Blanco, I., Blandinières, A., Blazquez-Gamero, D., Bloomfield, M., Bolivar-Prados, Mireia, Borie, R., Bousfiha, A.A., Bouvattier, C., Boyarchuk, O., Bueno, M.R.P., Agra, J.J.C., Calimli, S., Capra, R., Carrabba, M., Casasnovas, Carlos, Caseris, M., Castelle, M., Castelli, F., de Vera, M.C., Castro, M.V., Chalumeau, M., Charbit, B., Cheng, M.P., Clavé, P., Clotet, B., Codina, A., Colkesen, F., Colobrán Oriol, Roger, Comarmond, C., Corsico, A.G., Darley, D.R., Dauby, N., Dauger, S., de Pontual, L., Dehban, A., Delplancq, G., Demoule, A., Di Sabatino, A., Diehl, J.L., Dobbelaere, S., Durand, S., Eldars, W., Elgamal, M., Elnagdy, M.H., Emiroglu, M., Erdeniz, E.H., Aytekin, S.E., Euvrard, R., Evcen, R., Fabio, G., Faivre, L., Falck, A., Fartoukh, M., Faure, M., Arquero, M.F., Flores, Carlos, Francois, B., Fumadó, V., Solis, B.G., Gaussem, P., Gil-Herrera, J., Gilardin, L., Alarcon, M.G., Girona-Alarcón, M., Goffard, J.C., Gok, F., González-Montelongo, R., Guerder, A., Gul, Y., Guner, S.N., Gut, M., Halwani, R., Hammarström, L., Hatipoglu, N., Hernandez-Brito, E., Holanda-Peña, M.S., Horcajada, J.P., Hraiech, S., Humbert, L., Iglesias, A.D., Íñigo-Campos, A., Jamme, M., Arranz, M.J., Jordan, I., Kanat, F., Kapakli, H., Kara, I., Karbuz, A., Yasar, K.K., Keles, S., Demirkol, Y.K., Klocperk, A., Król, Z.J., Kuentz, P., Kwan, Y.W.M., Lagier, J.C., Lau, Y.L., Le Bourgeois, F., Leo, Y.S., Lopez, R.L., Leung, D., Levin, M., Levy, M., Lévy, R., Li, Z., Linglart, A., Lorenzo-Salazar, J.M., Louapre, C., Lubetzki, C., Luyt, C.E., Lye, D.C., Mansouri, D., Marjani, M., Pereira, J.M., Martin, A., Pueyo, D.M., Marzana, I., Mathian, A., Matos, L.R.B., Matthews, G.V., Mège, J.L., Melki, I., Meritet, J.F., Metin, O., Meyts, I., Mezidi, M., Migeotte, I., Millereux, M., Mirault, T., Mircher, C., Mirsaeidi, M., Melián, A.M., Martinez, A.M., Morange, P., Mordacq, C., Morelle, G., Mouly, S., Muñoz-Barrera, A., Nafati, C., Neves, J.F., Ng, L.F.P., Medina, Y.N., Cuadros, E.N., Gonzalo Ocejo-Vinyals, J., Orbak, Z., Oualha, M., Ozcelik, T., Hammarström, Q.P., Parizot, C., Pascreau, T., Paz-Artal, E., de Diego, R.P., Philippe, A., Philippota, Q., Planas-Serra, L., Ploin, D., Poissy, J., Poncelet, G., Pouletty, M., Quentric, P., Raoult, D., Rebillat, A.S., Reisli, I., Ricart, P., Richard, J.C., Rivet, N., Rivière, J.G., Blanch, G.R., Rodrigo, C., Rodriguez-Gallego, C., Rodríguez-Palmero, A., Romero, C.S., Rothenbuhler, A., Rozenberg, F., del Prado, M.Y.R., Riera, J.S., Sanchez, O., Sánchez-Ramón, S., Schluter, A., Schmidt, M., Schweitzer, C.E., Scolari, F., Sediva, A., Seijo, L.M., Sene, D., Senoglu, S., Seppänen, M.R.J., Ilovich, A.S., Shahrooei, M., Smadja, D., Sobh, A., Moreno, X.S., Solé-Violán, J., Soler, C., Soler-Palacín, P., Stepanovskiy, Y., Stoclin, A., Taccone, F., Tandjaoui-Lambiottea, Y., Taupin, J.L., Tavernier, S.J., Thumerelle, C., Tomasoni, G., Toubiana, J., Alvarez, J.T., Trouillet-Assanta, S., Troya, J., Tucci, A., Uzunhan, Y., Vabres, P., Valencia-Ramos, J., van Den Rym, A.M., Vandernoot, I., Vatansev, H., Vélez-Santamaria, V., Viel, S., Vilain, C., Vilaire, M.E., Vincent, A., Voiriot, G., Vuotto, F., Yosunkaya, A., Young, B.E., Yucel, F., Zannad, F., Zatz, M., Belota, A., Foti, Giuseppe, Bellani, G., Citerio, G., Contro, E., Pesci, A., Valsecchi, M.G., Cazzaniga, M., Bole-Feysot, C., Lyonnet, S., Masson, C., Nitschke, P., Pouliet, A., Schmitt, Y., Tores, F., Zarhrate, M., Abela, L., Andrejak, C., Angoulvant, F., Bachelet, D., Basmaci, R., Behillil, S., Beluze, M., Benkerrou, D., Bhavsar, K., Bompart, F., Bouadma, L., Bouscambert, M., Caralp, M., Cervantes-Gonzalez, M., Chair, A., Coelho, A., Couffignal, C., Couffin-Cadiergues, S., D'ortenzio, E., da Silveira, C., Debray, M.P., Deplanque, D., Descamps, D., Desvallées, M., Diallo, A., Diouf, A., Dorival, C., Dubos, F., Eloy, P., Enouf, V.V.E., Espérou, H., Esposito-Farese, M., Etienne, M., Ettalhaoui, N., Gault, N., Gaymard, A., Gigante, T., Gorenne, I., Guedj, J., Hoctin, A., Hoffmann, I., Jaafoura, S., Kafif, O., Kaguelidou, F., Kali, S., Khalil, A., Khan, C., Laouénan, C., Laribi, S., Le, M., Le Hingrat, Q., Le Mestre, S., Le Nagard, H., Lescure, F.X., Lévy, Y., Levy-Marchal, C., Lina, B., Lingas, G., Lucet, J.C., Malvy, D., Mambert, M., Mentré, F., Mercier, N., Meziane, A., Mouquet, H., Mullaert, J., Neant, N., Noret, M., Pages, J., Papadopoulos, A., Paul, C., Peiffer-Smadja, N., Petrov-Sanchez, V., Peytavin, G., Picone, O., Puéchal, O., Rosa-Calatrava, M., Rossignol, B., Roy, C., Schneider, M., Semaille, C., Mohammed, N.S., Tagherset, L., Tardivon, C., Tellier, M.C., Téoulé, F., Terrier, O., Timsit, J.F., Treoux, T., Tual, C., Tubiana, S., van der Werf, S., Vanel, N., Veislinger, A., Visseaux, B., Wiedemann, A., Yazdanpanah, Y., Abelc, L., Alcover, A., Aschard, H., Astrom, K., Bousso, P., Bruhns, P., Cumano, A., Demangel, C., Deriano, L., Santo, J.D., Dromer, F., Eberl, G., Enninga, J., Fellay, Jacques, Gomperts-Boneca, I., Hasan, M., Hercberg, S., Lantz, O., Patin, E., Pellegrini, S., Pol, S., Rausell, A., Rogge, L., Sakuntabhai, A., Schwartz, O., Schwikowski, B., Shorte, S., Tangy, F., Toubert, A., Touvier, M., Ungeheuer, M.N., Albert, M.L., Alavoine, L., Amat, K.K.A., Bielicki, J., Bruijning, P., Burdet, C., Caumes, E., Charpentier, C., Coignard, B., Costa, Y., Damond, F., Dechanet, A., Delmas, C., Ecobichon, J.L., Enouf, V., Frezouls, W., Houhou, N., Ilic-Habensus, E., Kikoine, J., Lebeaux, D., Leclercq, A., Lehacaut, J., Letrou, S., Manchon, P., Mandic, M., Meghadecha, M., Motiejunaite, J., Nouroudine, M., Piquard, V., Postolache, A., Quintin, C., Rexach, J., Roufai, L., Terzian, Z., Thy, M., Vignali, V., van Agtmael, M., Algera, A.G., van Baarle, F., Bax, D., Beudel, M., Bogaard, H.J., Bomers, M., Bos, Lieuwe D, Botta, M., de Brabander, J., Bree, G., Brouwer, M.C., de Bruin, S., Bugiani, M., Bulle, E., Chouchane, O., Cloherty, A., Elbers, P., Fleuren, L., Geerlings, S., Geerts, B., Geijtenbeek, T., Girbes, A., Goorhuis, B., Grobusch, M.P., Hafkamp, F., Hagens, L., Hamann, J., Harris, V., Hemke, R., Hermans, S.M., Heunks, L., Hollmann, M.W., Horn, J., Hovius, J.W., de Jong, M.D., Koning, R., van Mourik, N., Nellen, J., Paulus, F., Peters, E., van der Poll, T., Preckel, B., Prins, J.M., Raasveld, J., Reijnders, T., Schinkel, M., Schultz, M.J., Schuurman, A., Sigaloff, K., Smit, M., Stijnis, C.S., Stilma, Willemke, Teunissen, C., Thoral, P., Tsonas, A., van der Valk, M., Veelo, D., Vlaar, A.P.J., de Vries, H., van Vugt, M., Joost Wiersinga, W., Wouters, D., Zwinderman, A.H., Abelb, L., Iuti, F., Muhsen, S.A., Al-Mulla, F., Anderson, M.S., Bogunovic, D., Bondarenko, A., Bryceson, Y., Bustamante, C.D., Butte, M., Chakravorty, S., Christodoulou, J., Cirulli, E., Condino-Neto, A., Cooper, M.A., DeRisi, J.L., Desai, M., Drolet, B.A., Espinosa, S., Franco, J.L., Gregersen, P.K., Hagin, D., Heath, J., Henrickson, S.E., Hsieh, E., Imai, K., Itan, Y., Karamitros, T., Kisanda, K., Ku, C.L., Ling, Y., Lucas, C.L., Maniatis, T., Marodi, L., Milner, J.D., Mironska, K., Morio, T., Notarangeloa, L.D., Novelli, G., Novelli, A., O'Farrelly, C., Okada, S., Planas, A.M., Prando, C., Pujol, A., Renia, L., Renieri, A., Sancho-Shimizu, V., Sankaran, V., Barrett, K.S., Snow, A., Turvey, S., Uddin, F., Uddin, M.J., Vazquez, S.E., von Bernuth, H., Washington, N., Zawadzki, P., Sua, H.C., Casanovaa, J.L., Rosen, L.B., Universitat Autònoma de Barcelona, Bastard, P., Zhang, Q., Michailidis, E., Hoffmann, H.H., Zhang, Y., Dorgham, Karim, Philippot, Q., Rosain, J., Béziat, V., Manry, J., Shaw, E., Haljasmägi, L., Peterson, P., Lorenzo, L., Bizien, L., Trouillet-Assant, S., Dobbs, K., de Jesus, A.A., Belot, A., Kallaste, A., Catherinot, E., Tandjaoui-Lambiotte, Y., Le Pen, J., Kerner, G., Bigio, B., Seeleuthner, Y., Yang, R., Bolze, A., Spaan, A.N., Delmonte, O.M., Abers, M.S., Aiuti, A., Casari, G., Lampasona, V., Piemonti, L., Ciceri, F., Bilguvar, K., Lifton, R.P., Vasse, M., Smadja, D.M., Migaud, M., Hadjadj, J., Terrier, B., Duffy, D., Quintana-Murci, L., van de Beek, D., Roussel, L., Vinh, D.C., Tangye, S., Haerynck, F., Dalmau, D., Martinez-Picado, J., Brodin, P., Nussenzweig, M.C., Boisson-Dupuis, S., Rodríguez-Gallego, C., Vogt, G., Mogensen, T.H., Oler, A.J., Gu, J., Burbelo, P.D., Cohen, J.I., Biondi, A., Bettini, L.R., DÁngio, M., Bonfanti, P., Rossignol, P., Mayaux, J., Rieux-Laucat, F., Husebye, E.S., Fusco, F., Ursini, M.V., Imberti, L., Sottini, A., Paghera, S., Quiros-Roldan, E., Rossi, C., Castagnoli, R., Montagna, D., Licari, A., Marseglia, G.L., Duval, X., Ghosn, J., Tsang, J.S., Goldbach-Mansky, R., Kisand, K., Lionakis, M.S., Puel, A., Zhang, S.Y., Holland, S.M., Gorochov, G., Jouanguy, E., Rice, C.M., Cobat, A., Notarangelo, L.D., Abel, L., Su, H.C., Casanova, J.L., Arias, A.A., Boisson, B., Boucherit, S., Bustamante, J., Chbihi, M., Chen, J., Chrabieh, M., Kochetkov, T., Le Voyer, T., Liu, D., Nemirovskaya, Y., Ogishi, M., Papandrea, D., Patissier, C., Rapaport, F., Roynard, M., Vladikine, N., Woollett, M., Zhang, P., Kashyap, A., Ding, L., Bosticardo, M., Wang, Q., Ochoa, S., Liu, H., Chauvin, S.D., Stack, M., Koroleva, G., Bansal, N., Dalgard, C.L., Snow, A.L., Abad Capa, Jorge, Aguilera-Albesa, S., Akcan, O.M., Darazam, I.A., Aldave, J.C., Ramos, M.A., Nadji, S.A., Alkan, G., Allardet-Servent, J., Allende, L.M., Alsina, L., Alyanakian, M.A., Amador-Borrero, B., Amoura, Z., Antolí, A., Arslan, S., Assant, S., Auguet, T., Azot, A., Bajolle, F., Baldolli, A., Ballester, M., Feldman, H.B., Barrou, B., Beurton, A., Bilbao, A., Blanchard-Rohner, G., Blanco, I., Blandinières, A., Blazquez-Gamero, D., Bloomfield, M., Bolivar-Prados, Mireia, Borie, R., Bousfiha, A.A., Bouvattier, C., Boyarchuk, O., Bueno, M.R.P., Agra, J.J.C., Calimli, S., Capra, R., Carrabba, M., Casasnovas, Carlos, Caseris, M., Castelle, M., Castelli, F., de Vera, M.C., Castro, M.V., Chalumeau, M., Charbit, B., Cheng, M.P., Clavé, P., Clotet, B., Codina, A., Colkesen, F., Colobrán Oriol, Roger, Comarmond, C., Corsico, A.G., Darley, D.R., Dauby, N., Dauger, S., de Pontual, L., Dehban, A., Delplancq, G., Demoule, A., Di Sabatino, A., Diehl, J.L., Dobbelaere, S., Durand, S., Eldars, W., Elgamal, M., Elnagdy, M.H., Emiroglu, M., Erdeniz, E.H., Aytekin, S.E., Euvrard, R., Evcen, R., Fabio, G., Faivre, L., Falck, A., Fartoukh, M., Faure, M., Arquero, M.F., Flores, Carlos, Francois, B., Fumadó, V., Solis, B.G., Gaussem, P., Gil-Herrera, J., Gilardin, L., Alarcon, M.G., Girona-Alarcón, M., Goffard, J.C., Gok, F., González-Montelongo, R., Guerder, A., Gul, Y., Guner, S.N., Gut, M., Halwani, R., Hammarström, L., Hatipoglu, N., Hernandez-Brito, E., Holanda-Peña, M.S., Horcajada, J.P., Hraiech, S., Humbert, L., Iglesias, A.D., Íñigo-Campos, A., Jamme, M., Arranz, M.J., Jordan, I., Kanat, F., Kapakli, H., Kara, I., Karbuz, A., Yasar, K.K., Keles, S., Demirkol, Y.K., Klocperk, A., Król, Z.J., Kuentz, P., Kwan, Y.W.M., Lagier, J.C., Lau, Y.L., Le Bourgeois, F., Leo, Y.S., Lopez, R.L., Leung, D., Levin, M., Levy, M., Lévy, R., Li, Z., Linglart, A., Lorenzo-Salazar, J.M., Louapre, C., Lubetzki, C., Luyt, C.E., Lye, D.C., Mansouri, D., Marjani, M., Pereira, J.M., Martin, A., Pueyo, D.M., Marzana, I., Mathian, A., Matos, L.R.B., Matthews, G.V., Mège, J.L., Melki, I., Meritet, J.F., Metin, O., Meyts, I., Mezidi, M., Migeotte, I., Millereux, M., Mirault, T., Mircher, C., Mirsaeidi, M., Melián, A.M., Martinez, A.M., Morange, P., Mordacq, C., Morelle, G., Mouly, S., Muñoz-Barrera, A., Nafati, C., Neves, J.F., Ng, L.F.P., Medina, Y.N., Cuadros, E.N., Gonzalo Ocejo-Vinyals, J., Orbak, Z., Oualha, M., Ozcelik, T., Hammarström, Q.P., Parizot, C., Pascreau, T., Paz-Artal, E., de Diego, R.P., Philippe, A., Philippota, Q., Planas-Serra, L., Ploin, D., Poissy, J., Poncelet, G., Pouletty, M., Quentric, P., Raoult, D., Rebillat, A.S., Reisli, I., Ricart, P., Richard, J.C., Rivet, N., Rivière, J.G., Blanch, G.R., Rodrigo, C., Rodriguez-Gallego, C., Rodríguez-Palmero, A., Romero, C.S., Rothenbuhler, A., Rozenberg, F., del Prado, M.Y.R., Riera, J.S., Sanchez, O., Sánchez-Ramón, S., Schluter, A., Schmidt, M., Schweitzer, C.E., Scolari, F., Sediva, A., Seijo, L.M., Sene, D., Senoglu, S., Seppänen, M.R.J., Ilovich, A.S., Shahrooei, M., Smadja, D., Sobh, A., Moreno, X.S., Solé-Violán, J., Soler, C., Soler-Palacín, P., Stepanovskiy, Y., Stoclin, A., Taccone, F., Tandjaoui-Lambiottea, Y., Taupin, J.L., Tavernier, S.J., Thumerelle, C., Tomasoni, G., Toubiana, J., Alvarez, J.T., Trouillet-Assanta, S., Troya, J., Tucci, A., Uzunhan, Y., Vabres, P., Valencia-Ramos, J., van Den Rym, A.M., Vandernoot, I., Vatansev, H., Vélez-Santamaria, V., Viel, S., Vilain, C., Vilaire, M.E., Vincent, A., Voiriot, G., Vuotto, F., Yosunkaya, A., Young, B.E., Yucel, F., Zannad, F., Zatz, M., Belota, A., Foti, Giuseppe, Bellani, G., Citerio, G., Contro, E., Pesci, A., Valsecchi, M.G., Cazzaniga, M., Bole-Feysot, C., Lyonnet, S., Masson, C., Nitschke, P., Pouliet, A., Schmitt, Y., Tores, F., Zarhrate, M., Abela, L., Andrejak, C., Angoulvant, F., Bachelet, D., Basmaci, R., Behillil, S., Beluze, M., Benkerrou, D., Bhavsar, K., Bompart, F., Bouadma, L., Bouscambert, M., Caralp, M., Cervantes-Gonzalez, M., Chair, A., Coelho, A., Couffignal, C., Couffin-Cadiergues, S., D'ortenzio, E., da Silveira, C., Debray, M.P., Deplanque, D., Descamps, D., Desvallées, M., Diallo, A., Diouf, A., Dorival, C., Dubos, F., Eloy, P., Enouf, V.V.E., Espérou, H., Esposito-Farese, M., Etienne, M., Ettalhaoui, N., Gault, N., Gaymard, A., Gigante, T., Gorenne, I., Guedj, J., Hoctin, A., Hoffmann, I., Jaafoura, S., Kafif, O., Kaguelidou, F., Kali, S., Khalil, A., Khan, C., Laouénan, C., Laribi, S., Le, M., Le Hingrat, Q., Le Mestre, S., Le Nagard, H., Lescure, F.X., Lévy, Y., Levy-Marchal, C., Lina, B., Lingas, G., Lucet, J.C., Malvy, D., Mambert, M., Mentré, F., Mercier, N., Meziane, A., Mouquet, H., Mullaert, J., Neant, N., Noret, M., Pages, J., Papadopoulos, A., Paul, C., Peiffer-Smadja, N., Petrov-Sanchez, V., Peytavin, G., Picone, O., Puéchal, O., Rosa-Calatrava, M., Rossignol, B., Roy, C., Schneider, M., Semaille, C., Mohammed, N.S., Tagherset, L., Tardivon, C., Tellier, M.C., Téoulé, F., Terrier, O., Timsit, J.F., Treoux, T., Tual, C., Tubiana, S., van der Werf, S., Vanel, N., Veislinger, A., Visseaux, B., Wiedemann, A., Yazdanpanah, Y., Abelc, L., Alcover, A., Aschard, H., Astrom, K., Bousso, P., Bruhns, P., Cumano, A., Demangel, C., Deriano, L., Santo, J.D., Dromer, F., Eberl, G., Enninga, J., Fellay, Jacques, Gomperts-Boneca, I., Hasan, M., Hercberg, S., Lantz, O., Patin, E., Pellegrini, S., Pol, S., Rausell, A., Rogge, L., Sakuntabhai, A., Schwartz, O., Schwikowski, B., Shorte, S., Tangy, F., Toubert, A., Touvier, M., Ungeheuer, M.N., Albert, M.L., Alavoine, L., Amat, K.K.A., Bielicki, J., Bruijning, P., Burdet, C., Caumes, E., Charpentier, C., Coignard, B., Costa, Y., Damond, F., Dechanet, A., Delmas, C., Ecobichon, J.L., Enouf, V., Frezouls, W., Houhou, N., Ilic-Habensus, E., Kikoine, J., Lebeaux, D., Leclercq, A., Lehacaut, J., Letrou, S., Manchon, P., Mandic, M., Meghadecha, M., Motiejunaite, J., Nouroudine, M., Piquard, V., Postolache, A., Quintin, C., Rexach, J., Roufai, L., Terzian, Z., Thy, M., Vignali, V., van Agtmael, M., Algera, A.G., van Baarle, F., Bax, D., Beudel, M., Bogaard, H.J., Bomers, M., Bos, Lieuwe D, Botta, M., de Brabander, J., Bree, G., Brouwer, M.C., de Bruin, S., Bugiani, M., Bulle, E., Chouchane, O., Cloherty, A., Elbers, P., Fleuren, L., Geerlings, S., Geerts, B., Geijtenbeek, T., Girbes, A., Goorhuis, B., Grobusch, M.P., Hafkamp, F., Hagens, L., Hamann, J., Harris, V., Hemke, R., Hermans, S.M., Heunks, L., Hollmann, M.W., Horn, J., Hovius, J.W., de Jong, M.D., Koning, R., van Mourik, N., Nellen, J., Paulus, F., Peters, E., van der Poll, T., Preckel, B., Prins, J.M., Raasveld, J., Reijnders, T., Schinkel, M., Schultz, M.J., Schuurman, A., Sigaloff, K., Smit, M., Stijnis, C.S., Stilma, Willemke, Teunissen, C., Thoral, P., Tsonas, A., van der Valk, M., Veelo, D., Vlaar, A.P.J., de Vries, H., van Vugt, M., Joost Wiersinga, W., Wouters, D., Zwinderman, A.H., Abelb, L., Iuti, F., Muhsen, S.A., Al-Mulla, F., Anderson, M.S., Bogunovic, D., Bondarenko, A., Bryceson, Y., Bustamante, C.D., Butte, M., Chakravorty, S., Christodoulou, J., Cirulli, E., Condino-Neto, A., Cooper, M.A., DeRisi, J.L., Desai, M., Drolet, B.A., Espinosa, S., Franco, J.L., Gregersen, P.K., Hagin, D., Heath, J., Henrickson, S.E., Hsieh, E., Imai, K., Itan, Y., Karamitros, T., Kisanda, K., Ku, C.L., Ling, Y., Lucas, C.L., Maniatis, T., Marodi, L., Milner, J.D., Mironska, K., Morio, T., Notarangeloa, L.D., Novelli, G., Novelli, A., O'Farrelly, C., Okada, S., Planas, A.M., Prando, C., Pujol, A., Renia, L., Renieri, A., Sancho-Shimizu, V., Sankaran, V., Barrett, K.S., Snow, A., Turvey, S., Uddin, F., Uddin, M.J., Vazquez, S.E., von Bernuth, H., Washington, N., Zawadzki, P., Sua, H.C., Casanovaa, J.L., Rosen, L.B., and Universitat Autònoma de Barcelona

Abstract

Interindividual clinical variability in the course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is vast. We report that at least 101 of 987 patients with life-threatening coronavirus disease 2019 (COVID-19) pneumonia had neutralizing immunoglobulin G (IgG) autoantibodies (auto-Abs) against interferon-w (IFN-w) (13 patients), against the 13 types of IFN-a (36), or against both (52) at the onset of critical disease; a few also had auto-Abs against the other three type I IFNs. The auto-Abs neutralize the ability of the corresponding type I IFNs to block SARS-CoV-2 infection in vitro. These auto-Abs were not found in 663 individuals with asymptomatic or mild SARS-CoV-2 infection and were present in only 4 of 1227 healthy individuals. Patients with auto-Abs were aged 25 to 87 years and 95 of the 101 were men. A B cell autoimmune phenocopy of inborn errors of type I IFN immunity accounts for life-threatening COVID-19 pneumonia in at least 2.6% of women and 12.5% of men.

Published
2020

149. Association of a single nucleotide polymorphism in the ubxn6 gene with long-term non-progression phenotype in HIV-positive individuals

Author

Instituto de Salud Carlos III, European Commission, LabexMER, Díez-Fuertes, Francisco, Torre-Tarazona, H.E.De La, Calonge, E., Pernas, María, Bermejo, M., García-Pérez, A., Álvarez, A., Capa, L., García-García, Francisco, Saumoy, M., Riera, Melchor, Boland-Auge, A., López-Galíndez, Cecilio, Lathrop, M., Dopazo, Joaquín, Sakuntabhai, A., Alcamí, José, Instituto de Salud Carlos III, European Commission, LabexMER, Díez-Fuertes, Francisco, Torre-Tarazona, H.E.De La, Calonge, E., Pernas, María, Bermejo, M., García-Pérez, A., Álvarez, A., Capa, L., García-García, Francisco, Saumoy, M., Riera, Melchor, Boland-Auge, A., López-Galíndez, Cecilio, Lathrop, M., Dopazo, Joaquín, Sakuntabhai, A., and Alcamí, José

Abstract

[Objectives]: The long-term non-progressors (LTNPs) are a heterogeneous group of HIV-positive individuals characterized by their ability to maintain high CD4+ T-cell counts and partially control viral replication for years in the absence of antiretroviral therapy. The present study aims to identify host single nucleotide polymorphisms (SNPs) associated with non-progression in a cohort of 352 individuals., [Methods]: DNA microarrays and exome sequencing were used for genotyping about 240 000 functional polymorphisms throughout more than 20 000 human genes. The allele frequencies of 85 LTNPs were compared with a control population. SNPs associated with LTNPs were confirmed in a population of typical progressors. Functional analyses in the affected gene were carried out through knockdown experiments in HeLa–P4, macrophages and dendritic cells., [Results]: Several SNPs located within the major histocompatibility complex region previously related to LTNPs were confirmed in this new cohort. The SNP rs1127888 (UBXN6) surpassed the statistical significance of these markers after Bonferroni correction (q = 2.11 × 10−6). An uncommon allelic frequency of rs1127888 among LTNPs was confirmed by comparison with typical progressors and other publicly available populations. UBXN6 knockdown experiments caused an increase in CAV1 expression and its accumulation in the plasma membrane. In vitro infection of different cell types with HIV-1 replication-competent recombinant viruses caused a reduction of the viral replication capacity compared with their corresponding wild-type cells expressing UBXN6., [Conclusions]: A higher prevalence of Ala31Thr in UBXN6 was found among LTNPs within its N-terminal region, which is crucial for UBXN6/VCP protein complex formation. UBXN6 knockdown affected CAV1 turnover and HIV-1 replication capacity.

Published
2020

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