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.