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
Sa, Q., Ochiai, E., Crutcher, S., Michie, S. A., Xu, B., Payne, L., Wang, X., Suzuki, Y. VCAM-1/a4b1 integrin interaction is crucial for prompt recruitment of immune T cells into the brain during the early stage of reactivation of chronic infection with Toxoplasma gondii to prevent toxoplasmic encephalitis Infect. Immun. April 21, 2014. (Epub ahead of print).
Sullivan, A. M., Zhao, X., Suzuki, Y., Ochiai, E., Crutcher, S., and Gilchrist, M. A. Evidence for finely-regulated asynchronous growth of Toxoplasma cysts based on data-driven model selection. PLoS Computational Biol. 9(11): e1003283, 2013. doi:10.1371/journal.pcbi.1003283.
Sa, Q., Woodward, J., and Suzuki, Y. IL-2 production by CD8+ immune T cells can augment their IFN-g production independently from their proliferation in the secondary response to an intracellular pathogen. J. Immunol. 190:2199-2207, 2013.
Suzuki, Y., Sa, Q., Ochiai, E., Mullins, J., Yolken, R. and Halonen, S. Cerebral toxoplasmosis: Pathogenesis, host resistance and behavioural consequences. In Toxoplasma gondii: The Model Apicomplexan (second edition). Weiss, L. M., and Kim, K., eds., Elsevier, pp. 755-796, 2013.
Hester, J., Mullins, J., Sa, Q., Payne, L., Mercier, C., Cesbron-Delauw, M. F., and Suzuki, Y. Toxoplasma gondii antigens recognized by IgG antibodies differ between mice with and without active proliferation of tachyzoites in the brain during the chronic stage of infection. Infect. Immun. 80: 3611-3620, 2012.
Cong, H., Mui, E.J., Witola, W.H., Sidney, J., Alexander J., Sette, A., Maewal, A., El Bissati, K., Zhou, Y., Suzuki, Y., Lee, D., Woods, S., Sommerville, C., Henriquez, F.L., Roberts, C.W., and McLeod, R. Toxoplasma gondii HLA-B*0702-restricted GRA7 (20-28) peptide with adjuvants and a universal helper T cell epitope elicits CD8+ T cells producing interferon-gamma and reduces parasite burden in HLA-B*0702 mice. Hum Immunol. 73:1-10, 2012.
Suzuki, Y., Sa, Q., Gehman, M., and Ochiai, E. Interferon-gamma- and perforin-mediated immune responses in the brain against Toxoplasma gondii. Expert Rev Mol Med Oct 4; 13:e31, 2011.
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. 12:1252-1257, 2010.
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. 30:653-660, 2010.
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.