Department of Pathobiological Sciences
Titles and Education
- Professor of Immunology
- DVM, Veterinary College, Univ. Agri. Sci. Bangalore, India
- MVSc., Veterinary College, Univ. Agri. Sci. Bangalore, India
- Ph.D, University of Minnesota, Twin Cities
- Postdoctoral Fellowship, Emory University School of Medicine, Atlanta, GA.
Cell-Mediated Immunity to Acute and Chronic Viral Infections
CD8 T cells play a critical role in defense against viral, intracellular bacterial, and protozoon infections. We are interested in studying the regulation of T-cell responses and immunity to acute (influenza A virus, vaccinia virus and lymphocytic choriomeningitis virus) and chronic viral infections.
1. Mechanisms of T-Cell Memory to Viral Infections
Establishment and maintenance of protective memory B and T cells is fundamental to the development of effective vaccines. The overarching goal of our research therefore, is to understand the cellular and molecular basis of T cell memory. Specifically, we are interested in elucidating the signaling and transcriptional mechanisms that regulate the quantity and quality of memory T cells. In line with this theme, we and others have discovered that the PI3K/AKT signaling pathway governs T cell memory by regulating the activity of the transcription factors FoxO1 and FoxO3. While FoxO3 restrains the clonal expansion and the number of memory T cells, FoxO1 promotes the functional maturation and regenerative capacity of long-lived memory T cells. An ongoing project is investigating whether FoxO1 promotes the regenerative potential of memory T cells by regulating the activity or expression of mTOR, Bach2 and p16INK4a.
2. Adjuvants to Induce Systemic and Mucosal Cellular Immunity
Despite decades of research, very few adjuvants are licensed for use in humans. Unlike live vaccines, current inactivated/subunit vaccines formulated with the licensed adjuvants often confer shorter duration of immunity, largely induce antibody responses, require multiple immunizations to maintain protective immunity, and trigger poor cell-mediated immunity (CMI; TH1 and CD8 T cell memory). Therefore, there is a critical need to identify adjuvants that engender balanced antibody and CMI to protect against both extracellular and intracellular pathogens. Carbomers are polymers of acrylic acid cross-linked with polyalkenyl ethers, and are extensively used as bioadhesives in the pharmaceutical industry and as adjuvants in veterinary and experimental vaccines. We have identified a carbomer-class adjuvant, Adjuplex (ADJ) that elicits potent systemic and mucosal CD4 TH1 and CD8 T cell responses, like a live viral vaccine. We are investigating a combination adjuvant to leverage the CD4/CD8 T cell responses induced by ADJ to balance and potentiate the immune responses triggered by clinically tested TLR agonists, glucopyranosyl lipid A (GLA) and CpG. We hypothesize that combining ADJ with GLA and CpG constitutes a novel adjuvant that couples the effective antigen delivery and immune modulatory properties of ADJ with the immune potentiating effects of GLA and CpG to concomitantly activate multiple innate signaling pathways.Our goal is to identify a novel combination adjuvant that will engage multiple signaling pathways in immune cells and harness the unique immune stimulating properties of individual components to engender a balanced and durable humoral and CMI response that protects against mucosal and systemic infections.
Singh, A., A. Jatzek, E. H. Plisch, R. Srinivasan, J. Svaren, and M. Suresh (2010) Regulation of memory CD8 T cell differentiation by CDK inhibitor p27Kip1. Mol. Cell. Biol. (Accepted).
Hatta, Y, K. Hershberger, K. Shinya, S. C. Proll, R. D. Dubielzig, M. Hatta, M. G. Katze, Y. Kawaoka, and M. Suresh (2010) Viral replication rate regulates clinical outcome and CD8 T cell responses during highly pathogenic H5N1 Influenza virus infection. PLOS Pathogens. (Accepted).
Nakayama, Y., E. H. Plisch, J. A. Sullivan, C. J. Czuprynski, B. R. J. Williams, and M. Suresh (2010). PKR and Type I IFNs are dispensable for memory T cell expansion but required for viral control during primary and secondary infections. PLOS Pathog. 6(6):e1000966 Link.
Nakayama, Y., S. Kim, E. Kim, M. Sandor, and M. Suresh (2009) C3 promotes expansion of CD8+ and CD4+ T cells in a Listeria monocytogenes infection. J. Immunol. 183: 2921-31 Link.
Ito, Y., K. Shinya, M. Kiso, T. Watanabe, Y. Sakoda, M. Hatta, Y. Muramoto, D. Tamura, Y. Sakai-Tagawa, T. Noda, S. Sakabe, M. Imai, Y. Hatta, S. Watanabe, C. Li, S. Yamada, K. Fujii, S. Murakami, H. Imai, S. Kakugawa, M. Ito, R. Takano, K. Iwatsuki-Horimoto, M. Shimojima, T. Horimoto, H. Goto, K. Takahashi, A. Makino, H. Ishigaki, M. Nakayama, M. Okamatsu, K. Takahashi, D. Warshauer, P. A. Schult, R. Saito, H. Suzuki, Y. Furuta, M. Yamashita, K. Mitamura, K. Nakano, M. Nakamura, R. Brockman-Schneider, H. Mitamura, M. Yamazaki, N. Sugaya, M. Suresh, M. Ozawa, G. Neumann, J. Gern, H. Kida, K. Ogasawara, and Y. Kawaoka (2009) In vitro and in vivo characterization of new swine-origin H1N1 influenza viruses. Nature: 460:102