PURPOSE OF REVIEW The severe acute respiratory syndrome (SARS)-coronavirus 2 (CoV2)/COVID-19 pandemic has reminded us of the fundamental and nonredundant role played by the innate and adaptive immune systems in host defense against emerging pathogens. The study of rare 'experiments of nature' in the setting of inborn errors of immunity (IEI) caused by monogenic germline variants has revealed key insights into the molecular and cellular requirements for immune-mediated protection against infectious diseases. This review will provide an overview of the discoveries obtained from investigating severe COVID-19 in patients with defined IEI or otherwise healthy individuals. RECENT FINDINGS Genetic, serological and cohort studies have provided key findings regarding host defense against SARS-CoV2 infection, and mechanisms of disease pathogenesis. Remarkably, the risk factors, severity of disease, and case fatality rate following SARS-CoV2 infection in patients with IEI were not too dissimilar to that observed for the general population. However, the type I interferon (IFN) signaling pathway - activated in innate immune cells in response to viral sensing - is critical for anti-SARS-CoV2 immunity. Indeed, genetic variants or autoAbs affecting type I IFN function account for up to 20% of all cases of life-threatening COVID-19. SUMMARY The analysis of rare cases of severe COVID-19, coupled with assessing the impact of SARS-CoV2 infection in individuals with previously diagnosed IEI, has revealed fundamental aspects of human immunology, disease pathogenesis and immunopathology in the context of exposure to and infection with a novel pathogen. These findings can be leveraged to improve therapies for treating for emerging and established infectious diseases.
Mechanisms underlying host defense and disease pathology in response to severe acute respiratory syndrome (SARS)-CoV2 infection: insights from inborn errors of immunity.