Project

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Immunogenetics of Viral Infections - Focus on human herpesviruses (HHVs)

English title Immunogenetics of Viral Infections - Focus on human herpesviruses (HHVs)
Applicant Bochud Pierre-Yves
Number 165954
Funding scheme Project funding (special)
Research institution Service des Maladies Infectieuses Département de Médecine Interne CHUV
Institution of higher education University of Lausanne - LA
Main discipline Clinical Immunology and Immunopathology
Start/End 01.06.2016 - 31.05.2019
Approved amount 430'500.00
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All Disciplines (3)

Discipline
Clinical Immunology and Immunopathology
Immunology, Immunopathology
Infectious Diseases

Keywords (6)

Genetics/genomics; large nested project (HIV, STCS); IFNL3/4; Herpesviruses; Herpetic encephalitits; Innate Immunity

Lay Summary (French)

Lead
Les virus humains de la famille de l’herpès (HHVs) peuvent causer plusieurs types d’infections, qui se limitent le plus souvent à des maladie banales, spontanément résolutives, chez les individus immunocompétents, mais peuvent se manifester par des maladies beaucoup plus sévères, parfois mortelles, chez les patients immunocompromis, comme les receveurs de greffes d’organes ou les personnes qui sont infectés par le virus du SIDA. L’encéphalite herpétique (HSE) représent une forme très rare et particulièrement sévère d’infection au virus herpes simplex (HSV) qui touche 1 individu apparemment « immunocompétent » sur 250'000 à 500'000 personnes par an. Les raisons pour lesquelles certains individus sont touchés par ces infections, alors que d’autres n’en développent pas, sont en grande partie inconnues. Le but de ce projet est de déterminer si des polymorphismes génétiques peuvent expliquer les différences individuelles de susceptibilité aux infections.
Lay summary

Dans la première partie de ce projet, nous allons examiner si des polymorphismes présents dans des gènes du système immunitaire influencent la susceptibiltié aux infections dues au cytomegalovirus (CMV), au virus herpes simplex (HSV) et au virus de la varicelle-zona (VZV) chez des patients de la cohorte suisse de transplantation (STCS) et des patients de la cohorte suisse VIH. Les polymorphismes seront détectés à partir d’échantillons des patients et corrélés à la survenue des infections en tenant compte de la durée et de la sévérité de l’immunosuppression. Dans un premier temps, nous examinerons des gènes connus pour leur rôle dans l’immunité antiviriale (étude gène candidat). Dans un deuxième temps, nous effectuerons un screening systématique de l’ensemble du génome (genomewide association study). Ces études pourraient contribuer à une meilleure compréhension des mécanismes de réponse antivirale et à améliorer la prévention et le traitement des infections virales chez les patients immunocompromis.

Dasn la seconde partie du projet, nous allons examiner si des mutations rares dans certains gènes sont associées au développement de l’encéphalite herpétiques. Certaines mutations ont déjà été associées à cette maladies chez les enfants, mais peu d’études ont examiné si de telles mutations peuvent expliquer la susceptibilité à la la maladie chez l’adulte. Des échantillons biologiques seront collectés chez des patients adultes ayant développé une HSE et des membres de leur famille. Différents tests seront pratiqués à la recherche d’un déficit immunitaire. Si un tel déficit est retrouvé, il sera corrélé à une mutation au niveau du génome du patient. Cette étude permettra de mieux comprendre la physio-pathologie de l’HSE chez l’adulte et mettre en évidence des mécanismes soit similaire, soit différents de la maladie telle qu’elle se présente chez les enfants.

Direct link to Lay Summary Last update: 17.05.2016

Lay Summary (English)

Lead
Human herpes viruses (HHVs) can cause a vast array of infections in humans, ranging from banal, spontane-ously resolutive diseases in immunocompetent individuals, to severe, life-threatening conditions in immuno-compromised patients, such as organ transplant recipients or patients with AIDS. Herpes simplex en-cephalitis (HSE) is a particular, potentially life-threatening form of infection due to herpes simplex virus (HSV) that affects 1 out of 250’000-500’000 apparently “immunocompetent” patients per year. The reasons why some individuals develop severe HHVs infections, while other do not, are unknown. The aim of this project is to determine whether polymorphisms in immune genes explain difference in susceptibility to such infections.
Lay summary

In the first part of the project, we will examine whether common polymorphisms in host immune genes influence susceptiblitly to infections due to cytomegalovirus (CMV), HSV and varicella-zoster virus (VZV) among patients from the Swiss Transplant Cohort study. Genetic polymorphisms will be detected from patients samples and correlated with the occurrence of infections according to the duration and severity of immunosuppression. First, we will focus on selected genes, which are known to be involved in immune responses against viral infections (candidate gene approach). Second, we will perform an analyses of polymorphisms throughout the whole genome (genomewide association study). These studies may contribute to a better understanding of antiviral immune mechanisms and improve the prevention and treatment of severe viral infections, especially among immunosuppressed patients.

In the second part of the project, we will examine whether mutations in specific genes are responsible for the development of herpetic encephalitits. While certain mutations have been associated with HSE among children, there are only limited data on the genetic predisposition to HSE among adult patients. We will collect samples from adult patients with HSE and family members. We will perform different tests to determine whether these patients have immune deficiencies and correlate these deficiencies with the presence of genetic mutations. This study will provide new highlights on the pathogenesis of HSE in adult patients, which may be similar to or very distinct from those of pediatric HSE. 

Direct link to Lay Summary Last update: 17.05.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Mapping the human genetic architecture of COVID-19
Niemi Mari E. K., Karjalainen Juha, Liao Rachel G., Neale Benjamin M., Daly Mark, Ganna Andrea, Pathak Gita A., Andrews Shea J., Kanai Masahiro, Veerapen Kumar, Fernandez-Cadenas Israel, Schulte Eva C., Striano Pasquale, Marttila Minttu, Minica Camelia, Marouli Eirini, Karim Mohd Anisul, Wendt Frank R., Savage Jeanne, Sloofman Laura, Butler-Laporte Guillaume, Kim Han-Na, Kanoni Stavroula, Okada Yukinori, et al. (2021), Mapping the human genetic architecture of COVID-19, in Nature, 600(7889), 472-477.
Cohort profile: The Swiss Transplant Cohort Study (STCS): A nationwide longitudinal cohort study of all solid organ recipients in Switzerland
Stampf Susanne, Mueller Nicolas J, van Delden Christian, Pascual Manuel, Manuel Oriol, Banz Vanessa, Binet Isabelle, De Geest Sabina, Bochud Pierre-Yves, Leichtle Alexander, Schaub Stefan, Steiger Jürg, Koller Michael (2021), Cohort profile: The Swiss Transplant Cohort Study (STCS): A nationwide longitudinal cohort study of all solid organ recipients in Switzerland, in BMJ Open, 11(12), e051176-e051176.
Postmortem Cardiopulmonary Pathology in Patients with COVID-19 Infection: Single-Center Report of 12 Autopsies from Lausanne, Switzerland
Berezowska Sabina, Lefort Karine, Ioannidou Kalliopi, Ndiaye Daba-Rokhya, Maison Damien, Petrovas Constantinos, Rotman Samuel, Piazzon Nathalie, Milowich Dina, Sala Nathalie, Tsai Chun-Yi, Multone Eleonore, Bochud Pierre-Yves, Oddo Mauro, Bisig Bettina, de Leval Laurence (2021), Postmortem Cardiopulmonary Pathology in Patients with COVID-19 Infection: Single-Center Report of 12 Autopsies from Lausanne, Switzerland, in Diagnostics, 11(8), 1357-1357.
Postmortem Cardiopulmonary Pathology in Patients with COVID-19 Infection: Single-Center Report of 12 Autopsies from Lausanne, Switzerland
Berezowska Sabina, Lefort Karine, Ioannidou Kalliopi, Ndiaye Daba-Rokhya, Maison Damien, Petrovas Constantinos, Rotman Samuel, Piazzon Nathalie, Milowich Dina, Sala Nathalie, Tsai Chun-Yi, Multone Eleonore, Bochud Pierre-Yves, Oddo Mauro, Bisig Bettina, de Leval Laurence (2021), Postmortem Cardiopulmonary Pathology in Patients with COVID-19 Infection: Single-Center Report of 12 Autopsies from Lausanne, Switzerland, in Diagnostics, 11(8), 1357-1357.
Transcriptomic Signature Differences Between SARS-CoV-2 and Influenza Virus Infected Patients
Bibert Stéphanie, Guex Nicolas, Lourenco Joao, Brahier Thomas, Papadimitriou-Olivgeris Matthaios, Damonti Lauro, Manuel Oriol, Liechti Robin, Götz Lou, Tschopp Jonathan, Quinodoz Mathieu, Vollenweider Peter, Pagani Jean-Luc, Oddo Mauro, Hügli Olivier, Lamoth Frédéric, Erard Véronique, Voide Cathy, Delorenzi Mauro, Rufer Nathalie, Candotti Fabio, Rivolta Carlo, Boillat-Blanco Noémie, Bochud Pierre-Yves (2021), Transcriptomic Signature Differences Between SARS-CoV-2 and Influenza Virus Infected Patients, in Frontiers in Immunology, 12, 1-25.
Herpes simplex encephalitis in adult patients with MASP-2 deficiency
Bibert Stéphanie, Piret Jocelyne, Quinodoz Mathieu, Collinet Emilie, Zoete Vincent, Michielin Olivier, Menasria Rafik, Meylan Pascal, Bihl Titus, Erard Véronique, Fellmann Florence, Rivolta Carlo, Boivin Guy, Bochud Pierre-Yves (2019), Herpes simplex encephalitis in adult patients with MASP-2 deficiency, in PLOS Pathogens, 15(12), e1008168-e1008168.
IL-4 polymorphism influences susceptibility to Pneumocystis jirovecii pneumonia in HIV-positive patients
Wójtowicz Agnieszka, Bibert Stéphanie, Taffé Patrick, Bernasconi Enos, Furrer Hansjakob, Günthard Huldrych F., Hoffmann Matthias, Osthoff Michael, Cavassini Matthias, Bochud Pierre-Yves (2019), IL-4 polymorphism influences susceptibility to Pneumocystis jirovecii pneumonia in HIV-positive patients, in AIDS, 33(11), 1719-1727.
Genetic and clinic predictors of new onset diabetes mellitus after transplantation
Saigi-Morgui Núria, Quteineh Lina, Bochud Pierre-Yves, Crettol Severine, Kutalik Zoltán, Mueller Nicolas J., Binet Isabelle, Van Delden Christian, Steiger Jürg, Mohacsi Paul, Dufour Jean-francois, Soccal Paola M., Pascual Manuel, Eap Chin B. (2019), Genetic and clinic predictors of new onset diabetes mellitus after transplantation, in The Pharmacogenomics Journal, 19(1), 53-64.
Interferon lambda 3/4 polymorphisms are associated with AIDS-related Kaposis sarcoma
Bibert Stéphanie, Wójtowicz Agnieszka, Taffé Patrick, Tarr Philip E., Bernasconi Enos, Furrer Hansjakob, Günthard Huldrych F., Hoffmann Matthias, Kaiser Laurent, Osthoff Michael, Fellay Jacques, Cavassini Matthias, Bochud Pierre-Yves (2018), Interferon lambda 3/4 polymorphisms are associated with AIDS-related Kaposis sarcoma, in AIDS, 32(18), 2759-2765.
Pentraxin-3 polymorphisms and invasive mold infections in acute leukemia patients receiving intensive chemotherapy
Brunel Anne-Sophie, Wójtowicz Agnieszka, Lamoth Frédéric, Spertini Olivier, Neofytos Dionysios, Calandra Thierry, Marchetti Oscar, Bochud Pierre-Yves (2018), Pentraxin-3 polymorphisms and invasive mold infections in acute leukemia patients receiving intensive chemotherapy, in Haematologica, 103(11), e527-e530.
Genetic immune and inflammatory markers associated with diabetes in solid organ transplant recipients
Quteineh Lina, Wójtowicz Agnieszka, Bochud Pierre‐Yves, Crettol Severine, Vandenberghe Frederik, Venetz Jean‐Pierre, Manuel Oriol, Golshayan Dela, Lehmann Roger, Mueller Nicolas J., Binet Isabelle, Delden Christian, Steiger Jürg, Mohacsi Paul, Dufour Jean‐Francois, Soccal Paola M., Kutalik Zoltan, Marques‐Vidal Pedro, Vollenweider Peter, Recher Mike, Hess Christoph, Pascual Manuel, Eap Chin B. (2018), Genetic immune and inflammatory markers associated with diabetes in solid organ transplant recipients, in American Journal of Transplantation, 19(1), 238-246.
LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions
Yu Kang, Davidson Chelsea L., Wójtowicz Agnieszka, Lisboa Luiz, Wang Ting, Airo Adriana M., Villard Jean, Buratto Jeremie, Sandalova Tatyana, Achour Adnane, Humar Atul, Boggian Katia, Cusini Alexia, van Delden Christian, Egli Adrian, Manuel Oriol, Mueller Nicolas, Bochud Pierre-Yves, Burshtyn Deborah N. (2018), LILRB1 polymorphisms influence posttransplant HCMV susceptibility and ligand interactions, in Journal of Clinical Investigation, 128(4), 1523-1537.
A systematic review and meta-analysis of HCV clearance
Gauthiez Emeline, Habfast-Robertson Ines, Rüeger Sina, Kutalik Zoltan, Aubert Vincent, Berg Thomas, Cerny Andreas, Gorgievski Meri, George Jacob, Heim Markus H., Malinverni Raffaele, Moradpour Darius, Müllhaupt Beat, Negro Francesco, Semela David, Semmo Nasser, Villard Jean, Bibert Stéphanie, Bochud Pierre-Yves (2017), A systematic review and meta-analysis of HCV clearance, in Liver International, 37(10), 1431-1445.
Susceptibility to Mycobacterium ulcerans Disease (Buruli ulcer) Is Associated with IFNG and iNOS Gene Polymorphisms
Bibert Stéphanie, Bratschi Martin W., Aboagye Samuel Y., Collinet Emilie, Scherr Nicole, Yeboah-Manu Dorothy, Beuret Christian, Pluschke Gerd, Bochud Pierre-Yves (2017), Susceptibility to Mycobacterium ulcerans Disease (Buruli ulcer) Is Associated with IFNG and iNOS Gene Polymorphisms, in Frontiers in Microbiology, 8, 1-10.
BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease
Oussalah Abderrahim, Avogbe Patrice Hodonou, Avogbe Patrice Hodonou, Guyot Erwan, Chery Céline, Guéant-Rodriguez Rosa-Maria, Ganne-Carrié Nathalie, Cobat Aurélie, Moradpour Darius, Nalpas Bertrand, Negro Francesco, Poynard Thierry, Pol Stanislas, Bochud Pierre-Yves, Abel Laurent, Jeulin Hélène, Schvoerer Evelyne, Chabi Nicodème, Amouzou Emile, Sanni Ambaliou, Barraud Hélène, Rouyer Pierre, Josse Thomas, Goffinet Laetitia, et al. (2017), BRIP1 coding variants are associated with a high risk of hepatocellular carcinoma occurrence in patients with HCV- or HBV-related liver disease, in Oncotarget, 8(38), 62842-62857.
Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection
Fischer Janett, Weber Alexander N R, Böhm Stephan, Dickhöfer Sabine, El Maadidi Souhayla, Deichsel Danilo, Knop Viola, Klinker Hartwig, Möller Bernd, Rasenack Jens, Wang Lisa, Sharma Manu, Hinrichsen Holger, Spengler Ulrich, Buggisch Peter, Sarrazin Christoph, Pawlita Michael, Waterboer Tim, Wiese Manfred, Probst-Müller Elsbeth, Malinverni Raffaele, Bochud Pierre-Yves, Gardiner Clair, O'Farrelly Cliona, et al. (2017), Sex-specific effects of TLR9 promoter variants on spontaneous clearance of HCV infection, in Gut, 66(10), 1829-1837.
Catheter retention as a consequence rather than a cause of unfavorable outcome in candidemia
Damonti Lauro, Erard Véronique, Garbino Jorge, Schrenzel Jacques, Zimmerli Stefan, Mühlethaler Konrad, Imhof Alexander, Zbinden Reinhard, Fehr Jan, Boggian Katia, Bruderer Thomas, Flückiger Ursula, Frei Reno, Orasch Christina, Conen Anna, Khanna Nina, Bregenzer Thomas, Bille Jacques, Lamoth Frédéric, Marchetti Oscar, Bochud Pierre-Yves (2017), Catheter retention as a consequence rather than a cause of unfavorable outcome in candidemia, in Intensive Care Medicine, 43(6), 935-939.
Human microRNA responses predict cytomegalovirus replication following solid organ transplantation
Han Sang Hoon, Kumar D., Ferreira V. H., Egli A., Hirsch H. H., Weisser M., Garzoni C., van Delden C., Bochud P.Y, Manuel O., Meylan P., Boggian K., Husain S., Mueller N. J., Humar A. (2016), Human microRNA responses predict cytomegalovirus replication following solid organ transplantation, in Journal of Infectious Diseases, jiw596-jiw596.
Weighted Genetic Risk Scores and Prediction of Weight Gain in Solid Organ Transplant Populations
Saigi-Morgui Núria, Quteineh Lina, Bochud Pierre-Yves, Crettol Severine, Kutalik Zoltán, Wojtowicz Agnieszka, Bibert Stéphanie, Beckmann Sonja, Mueller Nicolas J, Binet Isabelle, van Delden Christian, Steiger Jürg, Mohacsi Paul, Stirnimann Guido, Soccal Paola M., Pascual Manuel, Eap Chin B (2016), Weighted Genetic Risk Scores and Prediction of Weight Gain in Solid Organ Transplant Populations, in PLOS ONE, 11(10), e0164443-e0164443.
Host – hepatitis C viral interactions: The role of genetics
Heim Markus H., Bochud Pierre-Yves, George Jacob (2016), Host – hepatitis C viral interactions: The role of genetics, in Journal of Hepatology, 65(1), S22-S32.
Risk stratification and immunogenetic risk for infections following stem cell transplantation
Wójtowicz Agnieszka, Bochud Pierre-Yves (2016), Risk stratification and immunogenetic risk for infections following stem cell transplantation, in Virulence, 7(8), 917-929.

Collaboration

Group / person Country
Types of collaboration
Swiss HIV Cohort Study (SHCS) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Zoltan Kutalik Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
- Exchange of personnel
Guy Boivin Université Laval Québec Canada (North America)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Swiss Institute of Bioinformatics Mauro Delorenzi Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Swiss Transplant Cohort Study (STCS) Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Exchange of personnel
Groupe Abel/Casanova (France/USA) France (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Antimicrobial Therapy in Immunocompromised and Critically Ill Patients (ATCIP) 2018 Talk given at a conference Personalized medicine in the diagnostic workout of viral and fungal infections 04.10.2018 Lugano, Switzerland Bochud Pierre-Yves;
Swiss Society of Infectiology meeting 2018 Talk given at a conference Pentraxin-3 Polymorphisms and Invasive Mold Infections in Acute Leukemia Patients with Intensive Chemotherapy 12.09.2018 Interlaken, Switzerland Bochud Pierre-Yves;
Myk 2018 Talk given at a conference Host genetics of invasive aspergillosis 07.09.2018 Innsbruck, Austria Bochud Pierre-Yves;
International Immunocompromised Host Society (ICSH) meeting 2018 Talk given at a conference Host genetics of invasive fungal infections 17.06.2018 Athens, Greece Bochud Pierre-Yves;
International Immunocompromised Host Society (ICSH) meeting 2018 Talk given at a conference Whole genome sequencing and infectious diseases: the host 17.06.2018 Athens, Greece Bochud Pierre-Yves;
Swiss Transplant Cohort Study 10 year meeting Talk given at a conference Host Genomics: A transversal tool for the STCS 04.05.2018 Berne, Switzerland Bochud Pierre-Yves;
European Congress of Microbology and Infectious Diseases 2018 Talk given at a conference Pentraxin-3 polymorphisms and invasive mold infections in patients undergoing myeloablative chemotherapy for acute leukemia 19.04.2018 Madrid, Spain Bochud Pierre-Yves;
European Congress of Microbology and Infectious Diseases 2018 Talk given at a conference Immunogenetics of viral infections 17.04.2018 Madrid, Spain Bochud Pierre-Yves;
Congrès de la Société françasie de mycologie médicale Talk given at a conference Host genetics of fungal infections 29.03.2017 Toulouse, France Bochud Pierre-Yves;
Challenges in virology 2017 Talk given at a conference Human genetics of infections 27.01.2017 Grindelwald, Switzerland Bochud Pierre-Yves;
Meeting of the Swiss Tranplant Society Talk given at a conference Genetic studies (Swiss Tranplant Cohort Study) 25.01.2017 Thun, Switzerland Bochud Pierre-Yves;
International Roche Infectious Diseases Symposium Talk given at a conference The power of the host signature in understanding and predicting disease 2016 19.09.2016 Madrid, Spain Bochud Pierre-Yves;
Swiss Society of Infectiology Talk given at a conference Infectious Risk and Host Genetics 01.09.2016 Montreux, Switzerland Bochud Pierre-Yves;
ASM Microbe 2016 Talk given at a conference CMV Donor Seropositivity and the Immunogenetics of Aspergillosis 16.06.2016 Boston, United States of America Bochud Pierre-Yves;
Journées nationales d'infectiologie Talk given at a conference Host susceptibility (invisave fungal infection session) 07.06.2016 Lille, France Bochud Pierre-Yves;
European Society of Microbiology and Infectious disease (ESCMID) course on precision medicine Talk given at a conference Immunogenetics, from genome-wide association studies to gene function 02.06.2016 Tübingen, Germany Bochud Pierre-Yves;


Associated projects

Number Title Start Funding scheme
144054 Immunogenetics of Viral Infections - Extending the Scope beyond IL28B SNPs and Hepatitis C 01.10.2012 Project funding (special)
192616 Immunogenetics of Viral Infections - Focus on human herpes simplex virus I 01.04.2020 Project funding (special)
127613 Innate Immunogenetic Study of Invasive Aspergillosis in Hematopoietic Cells Transplant Recipients 01.11.2009 Project funding
196036 Host factors in severe COVID-19: learning from extreme cases 01.06.2020 Special Call on Coronaviruses

Abstract

Background. Human herpes viruses (HHVs) can cause a vast array of infections in humans, ranging from banal, spontaneously resolutive diseases in immunocompetent individuals, to severe, life-threatening conditions in immunocompromised patients, such as organ transplant (SOT) recipients or patients with AIDS. The reasons why some individuals develop severe HHVs infections, while other, under similar exposure and immunosuppressive conditions, do not, are unknown. These differences may result, at least in part, from genetic factors influencing host immune responses. Characterization of these factors may contribute to a better understanding of antiviral immune mechanisms and improve the prevention and treatment of severe viral infections.Herpes simplex encephalitis (HSE) is a particular, potentially life-threatening form of HSV infection that affects 1 out of 250’000-500’000 apparently “immunocompetent” patients per year. The immunopathogenesis of the disease remains largely unknown. Recent studies demonstrated that HSE in children can specifically result from monogenic mutations in genes controlling the Toll-like receptor 3 (TLR3) immune pathway which mediates antiviral immunity in the central nervous system, mainly through the production of type-1 and type-3 interferons (IFN). However, these inborn errors of immunity explain only a small fraction of HSE among children, and children account for <10% of HSE cases. Thus, there is a clear need to discover alternative mutations and to understand the cause of this disease in adult patients.Aim 1.To detect and functionaly characterize polymorphisms in immune genes that influence the course of infections due to HSV, CMV and VZV and Kaposi sarcoma (HHV8).Specifically, we will focus on viral phenotypes that are well characterized in two cohorts of immunocompromised patients, including CMV infection and disease (SOT recipient from the Swiss Tranplant Cohort Study [STCS]), CMV retinitis in AIDS patients (Swiss HIV cohort study [SHCS]), Kaposi sarcoma (SHCS), severe ulcerative HSV lesions as well as multidermatoma/severe VZV infections (STCS and SHCS).DNA from patients developing these infections and controls will be first analysed by a candidate gene approach, including IFNLs (as started in the 2012-15 part of this grant) as well as other systematically selected genes, followed by a genome-wide association study (GWAS, STCS).Preliminary data. By using a candidate gene approach, we detected a trend toward an association between IFNLs polymorphisms in multidermatoma VZV infection in the STCS. By using a GWAS approach, we have detected two genome-wide significant loci associated with CMV or VZV infection among 1056 SOT recipients. These promising observations will request replication within larger cohorts.Relevance. These studies can contribute to a better understanding of antiviral immune mechanisms and improve the prevention and treatment of severe viral infections, especially among immunosuppressed patients.Aim 2. To detect and functionaly characterize rare genetic mutations contributing to HSE in adults.We will collect samples (blood, DNA, skin biopsies) from patients with HSE and family members. Functional testing will be used to determine whether adult patients with HSE have a deficient TLR3-IFNs pathway. In parallel, we will perform whole exome sequencing (WES) to determine whether specific mutations in TLR3-related genes correlate with immune defect(s).In addition, WES will allow identify novel genes unrelated to the TLR3 pathway, which will be also assessed functionally. The identification of novel HSE-related mutations will be facilitated by the combined analysis of whole exome data from both adult and pediatric patients (through our collaboration with French investigators) and function of relevant immunological pathways.Preliminary data.By performing WES in 10 patients with HSE, we identified a novel non synonymous mutation in MASP2, encoding a protease involved in the activation of the lectin pathway of the complement which is important for viral elimination. Our in vitro protein characterization suggests an impaired activity of the lectin pathway in individuals carrying the mutation.Relevance. This study will provide new highlights on the pathogenesis of HSE leading to the discovery of novel mechanisms associated with adult HSE, which may be similar to or very distinct from those of pediatric HSE.
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