The Role of ADAM9 in the Innate Immune Response to SARS-CoV-2 Infection - PROJECT ABSTRACT Immune dysregulation is a hallmark of severe COVID-19 caused by infection with severe acute respiratory syndrome coronavirus 2 (SCoV2). The pathogenesis of immune dysregulation in COVID-19 is thought to involve a dysfunctional host innate immune response, including a discordant type I interferon (T1IFN) response relative to viral replication and an exaggerated inflammatory response creating an imbalance between viral clearance and excessive inflammation ultimately resulting in acute lung injury (ALI), multiorgan failure, and even death. Despite extensive investigation, the precise mechanisms underlying the immune dysfunction during SCoV2 infection remain a mystery. We recently discovered a novel innate immune pathway mediated by A Disintegrin and Metalloproteinase 9 (ADAM9) critical for the host response to positive, single-stranded RNA (+ssRNA) viruses, including SCoV2. Specifically, we demonstrated that ADAM9 is essential for melanoma differentiation- associated protein 5 (MDA5)-mediated T1IFN response to cytosolic SCoV2 viral RNA (vRNA). Our preliminary results in SCoV2-infected mice revealed a profound difference in clinical disease severity based on ADAM9 expression alone, suggesting that ADAM9 is associated with the development of severe disease, consistent with published data; however, the mechanisms by which ADAM9 drives disease pathology are unknown. The current proposal builds logically on our preliminary data that revealed a critical role for ADAM9 in MDA5-mediated innate immune activation and aims to define the role of ADAM9 in the immunopathogenesis of severe COVID-19 and determine the impact of ADAM9 on SCoV2-induced acute lung injury. Successful completion of these studies will provide further insight into the novel ADAM9/MDA5 innate immune pathway and the role of this pathway in the pathogenesis of SCoV2-mediated immune dysregulation and its impact on lung pathology. This project builds logically on the candidate’s previous postdoctoral research and new compelling preliminary data and will serve as a career development mechanism. The candidate will receive mentorship from Dr. Fitzgerald and Dr. Kurt-Jones on experimental design, data interpretation, grant and manuscript preparation, lab protocol development, training/mentoring of graduate students, seminar preparation and presentation skills, and additional support to ensure a seamless transition to an independent investigator. Data generated from this proposal will lay the foundation for an R01 that builds upon the current study to further investigate virus-host interactions regulating innate immune mechanisms and determine immune correlates of protection versus pathogenesis that can be leveraged to develop novel strategies to treat or prevent lethal disease. These studies will be conducted at the UMass Chan Medical School, a leading institution for research in innate immunity and viral pathogenesis.
