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 2023, we extended our previous discovery of genetic and acquired defects in type I IFN responses as a cause of severe or critical COVID-19. In various collaborations with the NIAID COVID-19 Consortium and the COVID Human Genetic Effort, we have also contributed to the identification of new monogenic forms of multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection. Through these large international collaborative efforts, children were discovered with rare biallelic loss-of-function mutations in the OAS1, OAS2, or RNASEL genes. These mutations result in increased proinflammatory cytokines leading to disease. This discovery can improve molecular diagnosis of children at risk for developing a rare complication of SARS-CoV-2 infection. They also provide scientific rationale for molecular targeting of a pathway whose dysregulation is central to this condition. Finally, ongoing work led by our research group is investigating the potential role of genetic variants of dsRNA sensors in COVID-19 outcome.