Primary immunodeficiencies associated with susceptibility to Epstein Barr virus infection : studies from natural mutants to gene functions – IMMUNEBV

Epstein-Barr Virus (EBV) infection is one of the most powerful trigger of the immune system in humans causing severe pathologies including lymphoproliferative disorders. There are several known pediatric inherited immunodeficiencies leading to a susceptibility to EBV infection. These natural mutants represent unique models to study the immune response to EBV. Mutations in several factors involved in the development and the functions of T lymphocytes have been identified to be responsible of these disorders. However, in more than 50% of pediatric patients with susceptibility to EBV, the genetic basis of their disease is not known but defects in T cell responses can be observed in most of the cases. The objectives of this project are: 1) to identify novel gene defects causing inherited susceptibility to EBV by investigating patients for whom the molecular origin of their disease is not known 2) to study and decipher in depth the functions of the newly identified genes by in vitro and in vivo approaches including the development of cell and mice models. For this part of the project, we will first focus on the study of CTPS1 (CTP synthetase 1) gene. We recently show that CTPS1 deficiency in humans caused a severe combined immunodeficiency characterized by a susceptibility to EBV infection and we provide the evidence that CTPS1 is required for sustained proliferation of activated T lymphocytes.
All these investigations will allow a better understanding the pathophysiology of these primary immunodeficiencies and will bring novel fundamental insights the function of the immune system. Also, they will provide new diagnosis tools for genetic counseling and could help to define novel therapeutic strategies for EBV-associated lymphoproliferative disorders. Our preliminary data identified several novel gene defects (not yet reported) including CTPS1 deficiency. These data fully supports the feasibility and the approach of the project. Importantly, they reveal potential unexpected and new pathways controlling the immune response, in particular in the context of EBV infection.