Jason Whitmire, PhD

My lab studies the underlying mechanisms that stimulate immune responses to virus infections. We characterize the molecular and host-genetic pathways that lead to antiviral T cell responses, as well as pathogenic outcomes to infection. We work with lymphocytic choriomeningitis virus (LCMV) and HAV infections in mouse models. We have several ongoing projects.

Histone demethylases and T cell responses to infection

Histone methylation regulates gene expression and affects antiviral T cell differentiation and function. We are examining the role of UTX, a histone demethylase, in immune defense against disseminated virus infection. We are currently characterizing specific genes and pathways that are regulated by UTX in T cells and extending our observations in mice to humans with chronic virus infection.

Host genetics and viral pathogenesis

Arenaviruses can cause hemorrhagic disease in humans though the outcome to infection varies by person. We identified a line of mice that undergoes severe immunopathological response to systemic LCMV infection that is associated with weight loss, elevated cytokines, thrombocytopenia, and lung edema, features resembling human arenavirus infection. We are using forward genetics to map the mutations responsible for this severe outcome and then investigate the underlying mechanistic basis of pathogenesis.

Obesity, T cell responses, and pathogenesis

Obesity is associated with worsened outcomes to virus infection in people. We identified a novel population of virus-specific T cells that is present in adipose tissue of infected mice. Obesity greatly increases the abundance of these cells, but results in an unusual form of pathogenesis upon re-infection, characterized by fat necrosis and pancreatitis. We are investigating how T cells are recruited to adipose, how obesity increases memory T cell numbers, and how T cells contribute to pathogenesis during infection.

Innate and adaptive immune defenses of a human hepatropic virus infection

In close collaboration with Stan Lemon’s lab (UNC), we have developed the first small vertebrate model of human hepatitis A virus infection. The infected mice replicate virus to high titers and develop lesions in the liver. We have identified several innate virus-sensing pathways that are critical for immune defense against this infection. With this new model in hand, we can now (1) dissect how HAV disarms immune defenses and (2) evaluate the cellular and molecular mechanisms associated with HAV pathogenesis, which may be applicable to other picornavirus infections.

Mentor Training:

• Bias 101
• Faculty Mentoring Workshop for Biomedical Researchers

Training Program Affiliations:

• Genetics and Molecular Biology
• Microbiology and Immunology

Publications

PubMed Link

Selected publications:

• Misumi, I., K.D. Cook, J.E. Mitchell, S.C. Vick, R.H. Lee, T. Uchimura, W. Bergmeier, P. Mieczkowski, F.P-M. de Villena, J.P.Y. Ting, and J.K. Whitmire . 2019. “Identification of a locus in mouse that regulates the collateral damage and lethality of virus infection”. Cell Reports. 27(5).
• Misumi, I. J. Starmer, M.A. Beck, T. Magnuson, and J.K. Whitmire . 2019. “Obesity expands a distinct population of adipose-resident T cells and increases vulnerability to infection”. Cell Reports 27: 514-524.
• Hirai-Yuki, Asuka, L. Hensley, A. Das, H. Feng, L. Sun, J.E. Wilson, F. Hu, Z. Feng, W. Lovell, I. Misumi, J. P-Y Ting, S. Montgomery, J. Cullen, J.K. Whitmire, and S.M. Lemon. 2016. “MAVS-dependent host species range and pathogenicity of a human hepatitis virus”. Science 353: 1541-1545.
• Cook, K.D., K.B. Shpargel, J. Starmer, F. Whitfield-Larry, B. Conley, D.E. Allard, J.E. Rager, R.C. Fry, M.L. Davenport, T. Magnuson, J.K. Whitmire , M.A. Su §. 2015. “Tfh-dependent clearance of a persistent virus infection requires T cell expression of the histone demethylase UTX”. Immunity 43: 703-714.