Host factors contributing to susceptibility to COVID-19 disease

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These studies have been organized as part of a broader effort among multiple principal investigators in the Intramural Research Programs of NIAID, NIDCR, NCI, and NIAMS, as well as a research collaborative agreement with investigators at the American Genome Center/Uniformed Services University of the Health Sciences. We have assembled an international collaboration to study patients enrolled at centers in Italy, which was later expanded to include centers in East Asia, the Middle East, and the Americas. An IRB-approved COVID protocol involving send-in samples was written to facilitate studies at other centers lacking their own COVID protocols. We have partnered with the COVID-Human Genetic Effort, and multiple papers have come out of this international collaboration. In FY 2022, we extended our previous discovery of genetic and acquired defects in type I IFN responses as a cause of severe or critical COVID-19. We characterized the kinetics of neutralizing autoantibodies against type I IFN and found that these were dynamically produced during acute infection but decreased during convalescence, suggesting that disease pathogenesis might involve a memory response with implications for detecting individuals with such autoantibodies before infection. In various collaborations with the NIAID COVID-19 Consortium and the COVID Human Genetic Effort, we have also assisted with the characterization of potential role of neurological biomarkers and clonal hematopoiesis in respiratory COVID-19, as well as potential genetic contribution to other forms of SARS-CoV-2 infection (MIS-C, pernio). Finally, ongoing work led by our research group is investigating the potential role of genetic variants of dsRNA sensors in COVID-19 outcome.