Status: Funded - Open
BACKGROUND: Outbreaks of chilblains, a hallmark sign of type I interferonopathies, have been extensively reported in children during the COVID-19 pandemic. Despite exposure to the virus, children with SARS-CoV-2-related chilblains (also known as “COVID-toes”) did not develop COVID-19 symptoms or adaptive immunity against the virus. GAP: Lack of infection markers in chilblain cases limits the ability to conclude an association and understand the underlying pathomechanisms. HYPOTHESIS: 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. METHODS: We will recruit chilblain cases suggestive of resistance; search for candidate causing variants by analyzing whole-exome sequencing (WES) using both candidate gene approach and unbiased genome-wide strategies; and perform extensive functional studies to characterize candidate variants biochemically and immunologically. RESULTS: Pending. IMPACT: The project should unravel the “COVID-toe” enigma and identify correlates of protective innate immunity against SARS-CoV-2. It also 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.