Project

Discipline

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

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

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

Active participation

Number	Title	Start	Funding scheme

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.