Thromboinflammatory consequences of infection-induced autoimmunity

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.