Human genetic basis of natural resistance to SARS-CoV-2 infection

Outbreaks of chilblains, a hallmark sign of type I interferonopathies, have been reported during the COVID-19 pandemic. They mostly occur in otherwise asymptomatic patients in which PCR and serology failed to demonstrate SARS-CoV-2 infection. Our hypothesis is that genetic factors predispose these individuals to mount a robust innate immunity against the virus, making them resistant to the infection. The innate immune response is linked to a strong type I interferon (I-IFN) response, which clinically manifests as chilblains, promotes early viral clearance, avoiding the development of both disease and adaptive immunity. This hypothesis is based on 3 observations: (1) Chilblain patients had close contact with SARS-CoV-2 infected individuals before disease onset; (2) Despite exposure to the virus, they did not develop COVID-19 symptoms or adaptive immunity against the virus, suggesting resistance to infection; and (3) Chilblains are linked to a strong I-IFN activity, as demonstrated by the dominant lesional I-IFN expression signature. We will test our hypothesis by first measuring I-IFN responses in a cohort of SARS-CoV-2-associated chilblain patients. To assess the intrinsic functionality of their innate anti-viral immune system, we will stimulate peripheral blood mononuclear cells (PBMCs) with surrogates of viral nucleic acids. Because intrinsic functionality of the innate immune system is strongly controlled by genetic variation, we will search for monogenic inborn variations of I-IFN-mediated resistance by analyzing whole-exome sequencing (WES) data in large cohort of chilblain cases. We will recruit chilblain patients including family clusters at the international level through the global COVID Human Genetic Effort; search for candidate mediators of innate resistance using innovative strategies developed in the laboratory to analyze WES data; and perform extensive functional studies to understand the mechanisms through which they influence innate defenses against SARS-CoV-2.This project should unravel the "COVID-toe" enigma and identify correlates of protective innate immunity against SARS-CoV-2. It has the potential to identify previously unrecognized genes and pathways involved in innate immunity and drive the discovery of new targets to boost anti-viral responses.