Project 3: Serological Interactions with the Mucosal Innate Immune System Regulates COVID-19 Associated Tissue Damage.

Abstract. The UNC Center for Excellence in SARS-CoV2 Serologic Research uses basic and applied research strategies to improve our understanding of the molecular and cellular mechanisms driving serological and humoral immune responses after SARS-CoV2 infection. COVD-19 pathogenesis can take a mild course with few or no symptoms or it can progress to a more severe state requiring hospitalization and often results in respiratory distress, secondary bacterial infections and death. It is clear the severity is due to the type and magnitude of the immunological response to SARS-CoV2 infection. There is very little information about the independent and cooperative effects of all phases of the immune response: innate and adaptive, namely humoral (B cell/serologic), and cellular (T cell) and their clinical sequelae in COVID-19. However, clinical outcomes (pulmonary hyper-inflammatory responses with concurrent immune suppression) of COVID-19 are strikingly similar to that which we have studied with lung inhalation injuries and unresolved oronasalpharyngeal inflammatory responses. Indeed, we and others have defined that the nature and magnitude of an innate immune response to a pathogen directly affects the nature and magnitude of the specific humoral response systemically and in the pathogen-tropic tissue (i.e. oronasopharynx/lung). Resulting antibodies (Ab) also shape many subsequent innate immune functions of canonical immune cells such as neutrophils and macrophages, as well as barrier functions of mucosal cells such as epithelial cells. The additive effect of these interactions directly impacts the short- and long-lived Ab repertoire. Taken together, this Project will focus our investigations on defining unique and overlapping mechanisms of the mucosal immune-mediated pathogenesis of COVID-19 which lead to mild and severe disease. We hypothesize that the bi-directional interactions between the innate immune response and the serologic immune response regulate and shape the severity of COVID-19. We will test this hypothesis by 1) revealing pulmonary and systemic innate immune signatures, as a function of serology across the span of natural disease in human patients, to identify indices which promote development of protective versus pathogenic Ab repertoires, while 2) delineating mechanisms of polyclonal and monoclonal Ab mediated activation and suppression of innate immune and mucosal cell function which drive severe versus mild disease in murine models of COVID-19. Taken together, these data will inform us both mechanistically and therapeutically, defining antibody repertoires that can interrupt or ameliorate disease. The integrated expertise of our Team and the Center as a whole is necessary and sufficient to address the novel cross-cutting hypotheses put forth which will improve our understanding of SARS-CoV2 serological and humoral immunity.