Yasuhiro Suzuki, Ph.D.
Professor
Doctoral Studies: University of Tokyo.
Visiting Scientist: Stanford University
Research Statement:
We are interested in analyzing the mechanisms of the host immune responses to pathogens and the immunopathogenesis of infectious diseases. The pathogen that we are working with is Toxoplasma gondii, an intracellular protozoan parasite. Acute infection with the parasite is characterized by proliferation of tachyzoites and can cause various diseases including lymphadenitis and congenital infection of fetuses. Interferon-gamma (IFN-g)-dependent, cell-mediated immune responses and, to a lesser degree, humoral immunity limit proliferation of tachyzoites, but the parasite establishes chronic infection by forming cysts primarily in the brain. Chronic infection with T. gondii is one of the most common parasitic infections in humans worldwide. The tissue cyst remains largely quiescent for the life of host, but can reactivate and cause life-threatening toxoplasmic encephalitis (TE) in immunocompromised host. Patients with AIDS, and those with a variety of neoplastic diseases including Hodgkin’s and non-Hodgkin’s lymphoma, and organ transplantation patients on immunosuppressive therapy are at risk of developing this disease. We have developed murine models of TE that mimic the development of the disease in immunocompromised patients. These murine models have provided us an excellent opportunity to analyze how the immune system functions to control the pathogen in the brain, which is isolated from the periphery by the blood-brain barrier. We have shown that IFN-g is essential for maintaining the latency of the chronic infection and prevention of TE. Of interest, in addition to T cells, cells other than T cells need to produce IFN-g in the brain to prevent the disease. A depletion study suggested that the IFN-g-producing non-T cells required for the resistance are not NK cells. We are interested in the mechanisms of collaborations between T cells and brain-specific cells in the IFN-g-mediated resistance that requires two different sources of the cytokine. We are also trying to develop a vaccine to prevent T. gondii infection and toxoplasmosis.
Selected Recent Publications:
Singh, J., Graniello, C., Ni, Y., Payne, L., Sa, Q., Hester, J., Shelton, B.J., Suzuki, Y. Toxoplasma IgG and IgA, but not IgM, antibody titers increase in sera of immunocompetent mice in association with proliferation of tachyzoites in the brain during the chronic stage of infection. Microbes Infect. 2010 Aug 10. [Epub ahead of print].
Wen, X., Kuod, T., Payne, L., Wang, X., Rodgers, L., and Suzuki, Y. Predominant IFN-g-mediated expression of CXCL9, CXCL10, and CCL5 proteins in the brain during chronic infection with Toxoplasma gondii in BALB/c mice resistant to development of toxoplasmic encephalitis. J. Interferon Cytokine Res. 2010 Jul 13. [Epub ahead of print].
Suzuki, Y., Wang, X., Jortner, B. S., Payne, L., Ni, Y., Michie, S. A., Xu, B., Kudo, T., and Perkins, S. Removal of Toxoplasma gondii cysts from the brain by perforin-mediated activity of CD8+ T cells. Am. J. Pathol. 176:1607-1613, 2010.
Hermes, G., Ajioka, J.W., Kelly, K.A., Mui, E., Roberts, F., Kasza, K., Mayr, T., Kirisits, M.J., Wollman, R., Ferguson, D.J.P., Roberts, C.W., Hwang, J.H., Trendler, T., Kennan, R.P., Suzuki, Y., Reardon, C., Hickey, A.W., Chen, L., and McLeod, R. Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection. J. Neuroinflamation 5:48-85, 2008.
Wang, X., and Suzuki, Y. Microglia produce IFN-g independently from T cells during acute toxoplasmosis in the brain. J Interferon Cytokine Res. 27:599-605, 2007.
Wang, X., Michie, S.A., Xu, B., and Suzuki, Y. Importance of IFN-g-mediated expression of endothelial VCAM-1 on recruitment of CD8+ T cells into the brain during chronic infection with Toxoplasma gondii. J Interferon Cytokine Res. 27:329-338, 2007.
Miller, R., Wen, X., Dunford, B., Wang, X. and Suzuki, Y. Cytokine production of CD8+ immune T cells, but not of CD4+ T cells, from Toxoplasma gondii-infected mice is polarized to a type-1 response following stimulation with tachyzoite-infected macrophages. J Interferon Cytokine Res. 26:787-92, 2006.
Rodgers J, Wang X, Wen X, Dunford B., Miller R and Suzuki Y. Strains of Toxoplasma gondii used for tachyzoite antigens to stimulate spleen cells of infected mice in vitro affect cytokine responses of the cells in the culture. Parasitol Res 97:332-335, 2005.
Wang X, Claflin J, Kang H and Suzuki Y. Importance of CD8+Vb8+ T cells in IFN-g-mediated prevention of toxoplasmic encephalitis in genetically resistant BALB/c mice. J Interferon Cytokine Res. 25:338-344, 2005.
Suzuki Y, Claflin J, Wang X, Lengi A and Kikuchi T. Microglia and macrophages as innate producers of interferon-gamma in the brain following infection with Toxoplasma gondii. Int J Parasitol 35:83-90, 2005.
Wang X, Kang H, Kikuchi T and Suzuki Y. Gamma interferon production, but not perforin-mediated cytolytic activity, of T cells is required for prevention of toxoplasmic encephalitis in BALB/c mice genetically resistant to the disease. Infect Immun 72:4432-4438, 2004.
Kang H, Liesendfeld O, Remington JS, Claflin J, Wang X and Suzuki Y. TCR Vb8+ T cells prevent development of toxoplasmic encephalitis in BALB/c mice genetically resistant to the disease. J Immunol 170:4254-4259, 2003.
Grigg ME, Bonnefoy S, Hehl AB, Suzuki Y*,and Boothroyd JC*. Success and virulence in Toxoplasma as the results of sexual recombination between two distinct ancectries. Science 294:161-165, 2001. *joint corresponding authors.
Kang H, and Suzuki Y. Requirement of non-T cells that produce interferon-gamma for prevention of reactivation of Toxoplasma gondii infection in the brain. Infect Immun 69:2920-2927, 2001.
Suzuki Y, Sher A, Yap G, Park D, Ellis Neyer L, Liesenfeld O, Fort M, Kang H and Gufwoli E. IL-10 is required for prevention of necrosis in the small intestine and mortality in both genetically resistant BALB/c and susceptible C57BL/6 mice following peroral infection with Toxoplasma gondii. J Immunol 154:5375-5382, 2000.
Kang H, Remington JS, and Suzuki, Y. Decreased resistance of B cell-deficient mice to infection with Toxoplasma gondii despite unimpaired expression of IFN-g, TNF-a and inducible nitric oxide synthase. J Immunol 164:2629-2634, 2000.
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