Determination of mucosal immune responses to, and infection of the gastrointestinal tract by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2)

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PROJECT SUMMARY In approximately 6 months, the Coronavirus Disease 2019 (COVID-19) pandemic, caused by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has resulted in >6 million cases and led to >350K deaths worldwide, with over 100K of these deaths in the USA alone. Although the major pathologies leading to these deaths are cardiovascular and pulmonary in nature, COVID-19 is a multi-system disease and gastrointestinal (GI) symptoms are frequently reported. While animal studies and in-vitro experiments demonstrate that enterocytes can be infected by SARS-CoV-2, analyses of the GI tract in humans have been limited to viral RNA detection in feces or suggestions of enteric inflammation as measured by elevated levels of fecal calprotectin in a subset of patients. Being at the forefront of COVID-19 cases in New York City, we have recruited a cohort of >60 individuals. With a strong collaborative infra-structure supported by the parent R01 grant focusing on host-viral (HIV-1 associated) interactions in the GI tract, we are well-poised for detailed analyses of intestinal tissues in COVID-19 patients. Specifically, as evidenced in the submitted application, we have already generated a strong body of data, demonstrating for the first time, human enterocyte infection by SARS-CoV-2 that is in some cases associated with evidence of intestinal inflammation as measured by fecal calprotectin and numerous fecal cytokines. We are in the process of determining how these inflammatory responses modulate SARS-CoV-2 specific immune responses as measured by fecal IgA. The supplementary funds as requested will allow us to continue with the analyses of specimens that are already banked and will enable further recruitment of patients with active and convalescent COVID-19 disease. With the proposed studies, we aim to a) further characterize infection of GI tissues; b) determine viral persistence in the gut during convalescence; and c) determine the generation and evolution of inflammatory and antigen-specific mucosal immune responses. Altogether, through further development and analyses of this unique cohort, we aim to provide important insights into the role played by the GI tract in COVID-19 pathogenesis and transmission.