Multi-omic analysis of anti-viral immunity: From relevant biological pathways to inborn errors of immunity in patients with severe viral diseases

Viral infections remain a major threat for humankind with a number of alarming signs including 1) the limited effect or the absence of vaccines and/or efficient anti-viral drugs against a large number of viral infections, and 2) the recurrent emergence of new viral infections as attested by the recent pandemics of influenza viruses, Ebola virus, and coronaviruses with the current dramatic example of SARS-CoV-2 infection. In all these viral infections, there is a huge inter-individual variability in the response ranging from asymptomatic infection to lethal disease. In most cases, only a small proportion of otherwise healthy, young people develop the most severe forms of the disease, strongly suggesting the role of human genetic factors. We and others have already identified a number of monogenic inborn errors of immunity (IEIs) underlying life-threatening acute viral diseases, such as herpes simplex virus encephalitis (HSE), fulminant viral hepatitis, severe cytomegalovirus primary infection, and severe influenza virus or rhinovirus pneumonitis. However, most patients with severe viral infections have no identified genetic defects yet. In the present project, we hypothesize that severe viral infections such as HSE, and life-threatening pneumonitis due to influenza virus, rhinoviruses, respiratory syncytial virus, or SARS-CoV-2 infection in otherwise healthy individuals can be the consequence of a diverse collection of IEI to viruses, at least in a substantial proportion of patients. We further hypothesize that these IEI may affect specific pathways, and that the expression patterns of response to viral stimuli observed in a healthy population may inform on the involved pathways. To test these hypotheses, our project will tackle two specific aims: 1) to identify relevant pathways involved in the response to viral antigens using transcriptomic studies in an extensively studied cohort of 1000 healthy subjects; 2) to discover novel IEI underlying severe viral infections using next generation sequencing of the patients' exomes, bioinformatic analysis and in-depth functional studies of biochemical and immunological nature, by means of cutting-edge strategies we already developed in our previous identifications of IEIs that will be optimized by the findings obtained in specific aim 1. This highly innovative project is feasible based on the complementary and synergic expertise of the two participating laboratories, unique cohorts of patients, and strong preliminary results. The immunological implications of our project are considerable with the discovery of the critical pathways involved in the development of these severe viral infections, and the dissection of mechanisms of immunity to viruses in pulmonary and central nervous system infections. Our project will also have major medical implications by providing new tools for diagnosis and genetic counselling that may lead to specific preventive measures in the predisposed subjects, and by paving the way toward novel preventive and therapeutic strategies including anti-viral drugs (e.g. aimed at restoring a deficient immunity) and vaccines (e.g. aimed at boosting certain immunological pathways). Overall, our human genetic approach to discover IEI underlying severe viral infections, and consequently to understand the pathogenesis of these diseases, is critical to provide new ways to combat the current global threat of viral infections.