The goal of this proposal is to develop the applicant into an independent investigator with a research program that examines the intersection of autoimmunity and antiviral immunity. The principal investigator (PI) previously received his PhD training in biochemistry and molecular biology while studying immune mechanisms of leukocyte trafficking at the Oklahoma Medical Research Foundation. As of 2015, the PI has completed his clinical training in internal medicine and rheumatology and is currently a post-doctoral fellow receiving formal training in immunology and virology at Washington University in Saint Louis. The mentor is Dr. Michael Diamond, Professor of Medicine at Washington University, Associate Director of the Center for Human Immunology and Immunotherapy Programs, and an established leader in the fields of innate immunity and viral pathogenesis. Dr. Diamond has over 270 publications with special expertise in studies of flaviviruses (e.g., West Nile, Dengue, and Zika viruses) and alphaviruses (e.g., Chikungunya virus). Dr. Diamond is an infectious disease specialist who provides a model of a successful physician-scientist to the applicant at Washington University, an internationally recognized premier academic institution. Chikungunya virus (CHIKV) is an arthritogenic alphavirus that causes acute and chronic synovitis in a distribution that mimics seronegative rheumatoid arthritis. Epidemiological studies conducted after the Reunion Island CHIKV outbreak in 2006 suggest that a majority of patients infected with CHIKV progress to chronic arthralgias and arthritis. At present, the role of specific interferon (IFN) stimulated genes and transcription factors during CHIKV infection is still being defined. IFN regulatory factor (IRF)5 is a transcription factor that is activated during viral infection and is known to upregulate expression of IFN stimulated genes, promote production of proinflammatory cytokines, and enhance apoptosis under certain conditions. Polymorphisms resulting in overexpression of human IRF5 are associated with the risk of developing systemic lupus erythematosus and rheumatoid arthritis. We hypothesize that the severity and duration of CHIKV arthritis also may be related to IRF5 polymorphisms that modulate the antiviral immune response during acute infection. Here, we propose to test the contribution of IRF5 expression globally and in specific cell types using an established mouse model of CHIKV arthritis. We also propose to generate knock-in mice that ectopically express IRF5 to test the effect of IRF5 gene dosage on the pathogenesis of CHIKV arthritis. Using these approaches, the applicant will gain expertise in immunology, virology, autoimmunity, and viral arthritis. This will establish a foundation for an independent research program that will study interactions between host genetic risk factors and pathogens that may act to trigger chronic rheumatologic diseases.
This career development proposal will benefit public health in three ways. First, it will develop the principal investigator into an independent physician-scientist who treats patients with rheumatologic disease, identifies important questions, and then designs and conducts basic laboratory research that will advance our knowledge of human disease. Second, the proposed studies also may enhance our understanding of IRF5 in rheumatologic diseases of unknown etiology (e.g., SLE and RA) by defining functions of IRF5 in the context of one type of viral arthritis, a disease with a known etiologic agent (Chikungunya virus (CHIKV)). Lastly, CHIKV has caused epidemics around the world and infected more than 2 million people in the Western Hemisphere since 2013, making CHIKV arthritis a disease of global public health concern.
|Platt, Derek J; Smith, Amber M; Arora, Nitin et al. (2018) Zika virus-related neurotropic flaviviruses infect human placental explants and cause fetal demise in mice. Sci Transl Med 10:|
|Platt, Derek J; Miner, Jonathan J (2017) Consequences of congenital Zika virus infection. Curr Opin Virol 27:1-7|
|Warner, James D; Irizarry-Caro, Ricardo A; Bennion, Brock G et al. (2017) STING-associated vasculopathy develops independently of IRF3 in mice. J Exp Med 214:3279-3292|