Thromboinflammatory consequences of infection-induced autoimmunity

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PROJECT SUMMARY/ABSTRACT A growing body of evidence suggests that COVID-19 emulates many aspects of inflammatory and autoimmune diseases. Circulating autoantibodies have been detected in serum of COVID-19 patients where they have an antigen profile reminiscent of the lupus-associated thrombophilia known as antiphospholipid syndrome. While the association between infection, critical illness, and the induction of autoantibodies has long been recognized, pathogenesis and persistence of these antibodies—and most importantly the extent to which they may be therapeutic targets—have not been well defined. This award will play a critical role in helping me achieve my long-term career goals, which include: (1) Establishing a unique niche in the area of infection- associated autoimmunity; (2) Becoming an independent investigator at a leading medical research institution; and (3) Mentoring and fostering the development of trainees. These objectives will be reached by incorporating both a strong mentorship environment and a formal instructional plan. Mentorship Environment: I am currently an Assistant Professor in the Division of Rheumatology at the University of Michigan with 75% of my effort protected for research. Over the past two years, I have received strong training from Dr. Jason Knight in antiphospholipid syndrome pathogenesis. With this proposal, I am seeking support for a new research endeavor, as I turn my attention to the thromboinflammatory consequences of infection-associated autoimmunity. I have assembled a strong team of advisors, all experts in their respective fields and carefully selected to compliment the proposed project and career development. Formal Instruction: My scientific goals for this proposal include: (1) To expertly assess relevant measures of thromboinflammation; (2) To effectively manipulate and characterize mouse models; and (3) To develop laboratory skills in support of the study of autoantibodies and NETs in sepsis. Equally important are my career development goals, which include: (1) To learn to write innovative proposals in support of ethically-conducted research in humans and animals; (2) To enhance leadership, mentoring, and team-building skills; and (3) To continue to improve my written and oral communication. These goals will be achieved through a combination of mentorship, formal didactic instruction, and experimentation. Research: I plan to use COVID-19 and other severe infections as a window into the origins of autoimmunity and—in doing so—determine thromboinflammatory mechanisms of infection-associated autoantibodies. Aim 1 will elucidate the durability and clinical interactions of antiphospholipid antibodies and anti-NET antibodies in patients hospitalized with either COVID-19 or non-COVID sepsis. Aim 2 will characterize pathogenic and protective functions of infection-associated autoantibodies.