Project

Back to overview

Immunogenetics of Viral Infections - Focus on human herpes simplex virus I

English title Immunogenetics of Viral Infections - Focus on human herpes simplex virus I
Applicant Bochud Pierre-Yves
Number 192616
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 01.04.2020 - 31.03.2024
Approved amount 800'000.00
Show all

All Disciplines (3)

Discipline
Clinical Immunology and Immunopathology
Infectious Diseases
Immunology, Immunopathology

Keywords (9)

Large nested project; STCS; Genetics/genomics; TLR3; Interferon; Innate Immunity; Herpetic encephalitits; Large nested project; STCS

Lay Summary (French)

Lead
Les virus de la famille de l’herpès peuvent causer plusieurs types d’infections, la plupart du temps banales, se résolvant spontanément mais aussi des maladies beaucoup plus sévères et mortelles comme l’encéphalite herpétique (HSE). L’HSE est associée à un taux de mortalité d’environ 70% en l’absence de traitement antiviral et affecte un individu apparemment « immunocompétent » sur 250’000-500'000 individus par an, avec une répartition par âge bimodale, comprenant les enfants et les adultes de plus de 50 ans.Le but de ce projet est d’identifier les variants génétiques rares qui pourraient expliquer la survenue de l’encéphalite herpétique chez les enfants et les adultes, et de les caractériser fonctionnellement. Ce projet vise également à détecter des variants génétiques communs associés à la réactivation des infections causées par le virus de l’herpès chez des patients immunodéprimés; cette réactivation étant plus fréquente et sévère que chez des individus immunocompétents.
Lay summary

Dans la première partie de ce projet, nous continuerons à collecter des échantillons biologiques chez des patients développant une encéphalite herpétique et des membres de leur famille. Le séquençage des exomes permettra d’identifier les variants génétiques associées à la prédisposition à l’encéphalite herpétique. L’impact fonctionnel de ces variants sera estimé en utilisant des approches expérimentales in vitro, ex vivo et chaque fois que cela sera possible en utilisant un modèle animal de HSE.

La pertinence physiologique de ces variants sera évaluée en utilisant des technologies de différentiation cellulaire spécifiques au cerveau, à partir de cellules souches pluripotentes issues des patients et des membres de leur famille. Cette étude permettra de mieux comprendre la physio-pathologie de l’HSE.

Dans la deuxième partie du projet, nous déterminerons si des variants génétiques communs influent la sensibilité aux infections causées par le virus de l’herpès chez des receveurs d’organe(s) solide(s) en utilisant successivement une approche « gène candidat » et une approche à l’échelle du génome (GWAS). Cette étude pourrait améliorer la prévention et le traitement des infections causées par le virus de l’herpès chez les patients immunodéprimés.

Dans sa globalité, ce projet aidera à comprendre s’il existe un continuum reliant, pour des mêmes gènes ou voies de signalisation, des variants génétiques rares à des variants génétiques communs, dans le contexte des infections causées par le virus de l’herpès.

Direct link to Lay Summary Last update: 27.03.2020

Lay Summary (English)

Lead
Human herpes viruses can cause a vast array of infections in humans, ranging from banal, spontaneously resolutive to severe, life-threatening diseases. Herpes simplex encephalitis (HSE) is the most common cause of sporadic fatal viral encephalitis in Western countries with a mortality rate of ~70% in the absence of antiviral treatment. It occurs in 1 out of 250’000-500’000 apparently “immunocompetent” patients per year, with a bimodal age distribution including children and adults over the age of 50 years.The aim of this project is to identify rare genetic variants which could explain the development of HSE in both children and adults and to functionally characterize them. In addition, this project also aims to detect common genetic variants associated with reactivation of HSV infections among solid organ transplant recipients, which is more frequent and severe than among immunocompetent individuals.
Lay summary

In the first part of the project, we will continue collecting samples from HSE patients and family members and perform whole exome sequencing in order to identify genetic variants associated with HSE predisposition. Functional impact of variants will be estimated by both in vitro and ex vivo approaches and whenever feasible by using an animal model of HSE.

Their physiological relevance will be assessed by using brain-specific cell differentiation technologies from patients’ induced pluripotent stem cells. Altogether, this study will provide new insights in the immuno-pathogenesis of HSE.

In the second part of the project, we will examine whether common genetic variants influence susceptibility to HSV infections among SOT recipients from the Swiss transplant cohort study by successively using a candidate gene and a genomewide approach. This study may improve the prevention and treatment of HSV infections among immunosuppressed patients.

    Altogether, this study will help understand whether a continuum exists in some genes/immune pathways linking rare and common genetic variants towards susceptibility to HSV-1 infection.

 

Direct link to Lay Summary Last update: 27.03.2020

Responsible applicant and co-applicants

Employees

Associated projects

Number Title Start Funding scheme
177522 Swiss Transplant Cohort Study 01.02.2018 Cohort Studies Large
165954 Immunogenetics of Viral Infections - Focus on human herpesviruses (HHVs) 01.06.2016 Project funding (special)
179636 Using Genetic Risk Factors to Stratify Antifungal Prophylaxis in Patients with Acute Myeloid Leukemia 01.06.2018 Investigator Initiated Clinical Trials (IICT)

Abstract

Herpes simplex encephalitis (HSE) is a rare, sporadic form of encephalitis caused by HSV-1 (occasionnally HSV-2) which occurs in 2-4 individuals per million per year and has a mortality rate of >70% if untreated. It mainly occurs in children (e.g. as a result of primo-infection) and adults >50 years old (e.g. as a result of reactivation). The reasons why HSV-1 causes such a devastating disease in a very limited number of individuals have long been unknown. In fact, susceptibility to HSE in children results from mutations in genes belonging to the “Toll-like receptor 3 (TLR3) /interferon (IFN) axis”, an immune pathway involved in viral detection, production of type-1 and type-3 interferons, and subsequent interferon-stimulated genes (ISGs) activation. However, such variants explain only a subset of HSE among children and limited data support the role of such variants in adults HSE.The goal of this proposal is to extend our knowledge on genetic variants associated with HSE and to determine to which extent the same genetic variants (or variants in the same immune pathways) can explain the disease in both children and adults. Furthermore, it will explore whether common variants in genes involved in the same pathways are associated with milder manifestations of HSV-1 infection (e.g. muco-cutaneous reactivation).AIM 1. To detect rare genetic variants associated with Herpes simplex encephalitis (HSE) in children and/or adults. We will perform whole exome sequencing (WES) in previously (N=32) and prospectively collected DNA samples from children and adult patients with HSE. Disease-associated variants within or outside the TLR3/IFN signalling pathway will be detected both at the individual level (using tools such as the DOMINO or the pLI scores to avoid background noise due to benign heterozygous variants) and at the gene-level (using a gene burden test), after excluding previously described variants (or genes containing such variants).AIM 2. To functionally characterize rare variants associated with HSE.Functional consequences of variants identified in Aim 1 will be analysed by using a combination of in vitro and ex-vivo experiments, as well as an animal model of HSE. Briefly, these experiments will be designed to detect the impact of genetic variants on the output of immune pathways involved in HSV-1 detection and/or HSV-1 replication itself. We will use peripheral blood mononuclear cells (PBMCs) as well as induced pluripotent stem cells (iPSCs) to derive neural stem cells (NSCs), astrocytes and neurons from HSE patients, family members and healthy controls. Preliminary data (Aim 1&2). We identified a novel rare non-synonymous variant (p.R841H) at the heterozygous state in WWP2, encoding an E3 ubiquitin ligase, in a 2-years old girl who developed HSE concomitantly with varicella. This enzyme negatively regulates the TLR3 pathway by targeting TRIF for ubiquitination and degradation. Our preliminary data suggest that both PBMCs and iPSCs-derived NSCs from WWP2 p.R841H carriers have a reduced capability to control HSV-1 infection compared to PBMCs and NCSs from WT individuals, which is due to impaired IFN and ISGs production. Thus, gain-of-function variants leading to excessive TRIF ubiquitination and/or degradation may cause HSE.AIM3. To detect common genetic variants associated with HSV infection in solid organ transplant (SOT) recipients. We will determine whether single nucleotide polymorphisms (SNPs) are associated with HSV-1 or HSV-2 reactivation, by successively using a candidate gene and a genomewide approach. We will use a cohort of ~3000 SOT recipients from the Swiss Transplant Cohort Study (STCS), as HSV reactivation is more frequent, more severe and more difficult to treat among SOT recipients than among immunocompetent individuals.Preliminary data (Aim 3). We found that a SNP in Interferon regulatory factor 1 (IRF-1) influences HSV-1 reactivation in SOT from the STCS.Relevance. This study will provide new highlights on the pathogenesis of HSE with novel genetic variants and mechanisms associated with the disease. Furthermore, it will help understand whether a continuum exists in some genes/immune pathways linking rare and common genetic variants towards susceptibility to HSV-1 infection.
-