The pandemic of SARS-coronavirus 2 (CoV2)/COVID-19 has highlighted the critical and nonredundant function of the innate and adaptive immune systems in host defense against emerging infections. The investigation of uncommon “natural experiments” in the context of inborn errors of immunity (IEI) induced by monogenic germline variations yielded important insights into the molecular and cellular needs for immune-mediated protection against infectious illnesses. For a review, researchers sought to provide an overview of the findings from studying severe COVID-19 in patients with specified IEI or otherwise healthy persons.

Key insights of host resistance against SARS-CoV2 infection and disease etiology came from genetic, serological, and cohort research. Surprisingly, the risk factors, the severity of illness, and case fatality rate after SARS-CoV2 infection in IEI patients were not significantly different from those seen in the general community. The type I interferon (IFN) signaling pathway, which is triggered in innate immune cells in response to viral detection, is crucial for anti-SARS-CoV2 immunity. Indeed, genetic variations or autos altering type I IFN function accounted for up to 20% of all COVID-19 cases.

The study of rare cases of severe COVID-19, as well as the impact of SARS-CoV2 infection in people who had previously been diagnosed with IEI, had revealed fundamental aspects of human immunology, disease pathogenesis, and immunopathology in the context of exposure to and infection with a novel pathogen.