Determining the role of the cytokine interleukin-22 (IL-22) in SARS-CoV-2 infection

PROJECT SUMMARY SARS-CoV-2 infection often has lasting, long-term effects on people's health. Post-acute sequelae SARS-CoV- 2 infection (PASC), informally called "Long COVID", is a clinically heterogenous disease with different patients having different affected tissues. In addition to the lungs, the site of primary infection, PASC patients also report issues with other tissues, including the gastrointestinal (GI) tract. Although we still do not understand the mechanisms for PASC, there is an urgent need to identify therapeutics to prevent and/or treat PASC patients. Early in the pandemic, COVID-19 patients were described as having a cytokine storm that is likely one of the major complications leading to PASC. Although many of these cytokines contribute to tissue damage and destruction, interleukin-22 (IL-22) is well-described to be protective to inflamed tissues in diseases such as airway inflammation and inflammatory bowel disease. IL-22 stimulation alters the transcriptional profile of epithelial cells within the target tissues to increase cellular proliferation and decrease sensitivity to apoptosis. IL- 22 can also aid in wound repair and recombinant IL-22-Fc is in clinical trials for the treatment of flares in ulcerative colitis patients and tissue repair in patients with acute graft versus host disease. There is a gap in our knowledge of how individual cytokines may affect patient outcomes and if they can be used for preventing or repairing tissue damage. Our hypothesis is that IL-22 is a protective cytokine to tissues during SARS-CoV-2 infection. In this proposal we will examine the role of IL-22 in vitro in respiratory and GI cells and in an in vivo mouse model of SARS-CoV-2 infection. Our overall objective is to determine if IL-22 is a protective cytokine in this disease and can be beneficial to the lung and GI tissues during infection. Upon completion of these aims, the expected outcome is a new understanding of the critical role of the cytokine IL-22 in SARS-CoV-2 infection. This breakthrough will have a positive impact on our understanding of immune responses to SARS-CoV-2 infection as they may provide strong evidence-based rationale for further development of IL-22 biology targeted therapies in the prevention and/or treatment of PASC.