Jason Whitmire, PhD

Jason Whitmire, PhD

Associate Professor
Department of Genetics
5062 GMB
CB#7292
919-843-7081



Research

There is a significant need to improve vaccine-induced immunity against infectious diseases. Memory T cells are induced by vaccines and infections and play a key role in long-term immune protection. My lab studies the underlying mechanisms that stimulate long-term immunity so that this information can be used to better design protective vaccines. We use in vivo models of live virus infection to examine T cell and B cell responses following acute or chronic virus infections. We typically work with lymphocytic choriomeningitis virus (LCMV) infection in mice as our model system. We have several ongoing projects.

To identify and characterize the molecular pathways that promote antiviral T cell responses and memory. My lab’s research has highlighted the critical role of interferons and co-stimulatory molecules in establishing T cell memory and protection against disseminated infection. Our studies show that IFNab and IFNg signals enhance primary and memory cell development. We are currently examining the molecular and cellular mechanisms by which interferons propel T cell responses and methods to deliver these signals to increase memory.

To examine the role of B cells in CD4 T cell memory. CD4 T cells interact with antigen-specific B cells that express viral peptide on MHCII and promote their differentiation into antibody secreting cells and plasma cells. We have shown that B cells are actively involved in sustaining CD4 T cell memory following acute infection and are needed to protect mice against disseminating virus infection. Currently, we are identifying the molecular interactions between B cells and CD4+ T cells that sustain CD4+ T cell memory.    

To understand the underlying mechanisms of NK cell-mediated regulation of T cell responses. Our lab discovered that Natural Killer (NK) cell activity inhibits immune control of a disseminated virus infection. We found that NK cell depletion improves virus-specific T cell and B cell responses, leading to rapid control of the infection. We are investigating the underlying mechanisms whereby NK cells limit the T cell and B cell responses to disseminated infection.

To understand the genetic mechanisms regulating immunity and viral pathogenesis. People vary tremendously in their immune responses to infections and vaccines, but the underlying genetic basis for this variation is not known. Working in the mouse model, we are utilizing several approaches to better understand the genetic underpinnings of immunity and pathogenesis. 

To identify mutations associated with severe viral pathogenesis. We identified a line of mice that undergo a severe immunopathological response to systemic LCMV infection that is associated with severe weight loss, elevated cytokines, elevated liver damage, and tissue hemorrhaging. In collaboration with Professors Fernando Pardo-Manuel de Villena and Beverly Koller (Dept. Genetics), we are using forward genetics to map the mutations responsible for this severe outcome and then investigate the underlying mechanistic basis of pathogenesis.

To identify novel genes & pathways involved in immune defense against virus infection. In collaboration with Professors Fernando Pardo-Manuel de Villena, Mark Heise, Ralph Baric, and Marty Ferris (all at UNC), we are examining the role of genetic diversity on immunity by utilizing the Collaborative Cross resource. These mice are genetically diverse and vary tremendously in how they respond to LCMV and can be used to map regions that control T cell responses. We anticipate that the genetic pathways governing immune responses and causing phenotypic variability between mouse strains will correspond to conserved immune-defense pathways in people.

To characterize the role of histone demethylases in adaptive immune responses to viral infection. Histone methylation regulates gene expression and affects cell differentiation and function. In an interdisciplinary collaboration with Professors Maureen Su (Dept. Pediatrics) and Terry Magnuson (Dept. Genetics), we are examining the role of histone demethylases in immune defense against disseminated virus infection. We identified a demethylase that plays a critical role in protection against chronic infection. We are currently characterizing specific genes that are regulated by this enzyme in T cells and extending our observations in mice to humans with chronic virus infection.

 

To understand the 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-associated pathogenesis, which may be applicable to other picornavirus infections.

Selected publications:

Cook, K.D., H.C. Kline, J.K. Whitmire §. 2015. NK cells inhibit humoral immunity by reducing the abundance of CD4+ T follicular helper cells during a chronic virus infection. J. Leukocyte Biol. –In press.

Misumi, I. and J.K. Whitmire §. 2014. IFN-lambda exerts opposing effects on T cell responses depending on the chronicity of the virus infection. J. Immunol. 192: 3596-3606.

Misumi, I. and J.K. Whitmire §. 2014. B cell depletion curtails CD4+ T cell memory and reduces protection against disseminating virus infection. J. Immunol. 192: 1597-1608.

Misumi, I., M. Alirezaei, B. Eam, M.A. Su, J.L. Whitton, J.K. Whitmire §. 2013. Differential T cell responses to residual viral antigen prolongs CD4+ T cell contraction following the resolution of infection. J. Immunol. 191:5655-5668.

Cook, K.D. and J.K. Whitmire §. 2013. The depletion of NK cells prevents T cell exhaustion to efficiently control disseminating virus infection. J. Immunol. 190: 641-649. 

Complete list of publications

Affiliations

Department of Microbiology & Immunology
Department of Genetics
Carolina Vaccine Institute

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