Immune mechanisms that determine outcome of “New world” cutaneous and visceral leishmaniasis.
The leishmaniases comprise several diseases caused by intracellular protozoan parasites belonging to Leishmaniaspecies leading to a wide spectrum of clinical manifestations and a global health problem. Among the parasitic infections, this disease is responsible for the highest number of DALYs (Disability adjusted life years; a measure of health burden) after malaria. “Old world” cutaneous leishmaniasis usually manifests as a localized self-healing skin lesion with long-term protective immunity in humans. In contrast, some forms of “New world” cutaneous leishmaniasis manifests as a chronic infection that is associated with mutilation of ear and disfiguring scars or as a severe mucocutaneous disease involving nasal and oropharyngeal mucosa with extensive tissue destruction. Visceral leishmaniasis is the most severe clinical form, characterized by hepatosplenomegaly, fever, abdominal pain and weight loss.
Our laboratory is interested in understanding the immune mechanisms that determine outcome of “New world” cutaneous and visceral leishmaniasis caused by L. mexicana and L. donovani respectively. We are particularly interested in studying the role of cytokines in regulation of immune responses during these two species of Leishmaniaand the use of cytokine and cytokine receptor gene deficient mice has been a very powerful tool in these studies. As cytokines can modulate functions of several cells of the immune system in vivo, we are now using cell-specific gene deficient mice lacking specific cytokine receptors on specific immune cells such as macrophages and T cells. These mice are generated using cre/lox technology that enables us to delete a gene in cell-specific manner. We believe that these studies will enable us to determine how cytokines regulate immune responses in vivo during leishmaniasis. With regards to L. donovani, our studies have focused on understanding the regulation of effector cell responses in murine visceral leishmaniasis caused by L. donovani. Of particular interest to our group is the determining the immune mechanisms that mediate protection and/or induce immunopathology during VL. More recently, in collaboration with the McGill University, we have initiated studies that focus on the development of amastigote-specific single candidate vaccine against visceral and “New world” cutaneous leishmaniasis that cause considerable morbidity and mortality in humans. Another area of research in our laboratory is understanding the immunological basis of gender-related differences in susceptibility to Leishmania. In these studies, we are interested in determining the roles of sex-hormones in modulation of immune response and determining the outcome of Leishmania infection. Our long-term goal is to identify the basic mechanisms by which cytokines regulate T cell responses and host immunity to cutaneous leishmaniasis caused by L. mexicana and visceral leishmaniasis caused by L. donovani and utilize this knowledge to develop a vaccine against these diseases.
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Parish, CL, Finkelstein, DI, Tripanichkul, W, Satoskar, AR, Drago, J, and Horn, MK. The role of Interleukin-1, Interleukin-6 and glia in inducing growth of neuronal terminal arbors in mice. J. Neurosci. 2002; 22:8034.
Wurster, AL, Rodgers, VL, Satoskar, AR., Whitters, MJ, Young, DA, Collins, M, and Grusby, MJ. Interleukin-21 is a T helper (Th) cell 2 cytokine that specifically inhibits the differentiation of naïve Th cells into interferon gamma-producing Th1 cells. J. Exp. Med. 2002; 196: 969.
Pien, GC, Nguyen, KB, Malmgaard, L, Satoskar, AR, and Biron, CA. A unique mechanism for innate cytokine promotion of T cell responses to viral infections. J. Immunol. 2002; 169:5827.
Rodriguez-Sosa, M, Rosas, LE, David, JR, Bojalil, R, Satoskar, AR*, and Terrazas, LI*. Macrophage migration inhibitory factor plays a critical role in mediating protection against the helminth parasite Taenia crassiceps. (*Joint senior co-authors) Infect. Immun. 2003; 71:1247.
Rodriguez-Sosa, M, Rosas, LE, Terrazas, LI, Lu, B, Gerard, C, and Satoskar, AR*. CC chemokine receptor 1 enhances susceptibility to Leishmania major during early phase of infection. Immunol. Cell Biol. 2003; 80:114.
Rodriguez-Sosa, M, Satoskar, AR, David, JR, and Terrazas, LI. Altered T helper responses in CD40 and interleukin-12 deficient mice reveal a critical role for Th1 responses in eliminating the helminth parasite Taenia crassiceps. Int. J. Parasitol. 2003; 33: 701.
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Pan, J.H., Sukhova, G.K., Satoskar, A.R., David, J.R., Yang, J.T., Fu, H., Metz, C., Baugh, J.A., Bucala, R., Fang, K., Libby, P. and Shi, G.P. Regulation of cysteine protease expression by macrophage migration inhibitory factor. Circulation. 2004; 109:3149-3153.
Rodriguez-Sosa, M., Rosas, L.E., Saavedra, R., Satoskar, A.R. and Terrazas, L.I. STAT4-dependent IL-12 signaling pathway is required for resistance to the helminth parasite Taenia crassiceps. Infect. Immun. 2004; 71:1247-1254.
Wang, N., Satoskar, A.R., Faubion, W., Howie, D., Okamoto. S., Feske, S., Gullo, C., Clarke, K., Rodriguez Sosa, M., Sharpe, A.H. and Terhorst, C. SLAM controls T cell and macrophage functions. J. Exp. Med. 2004; 199:1255-1264.
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Howie, D., Laroux, F.S., Morra, M., Satoskar, A.R., Rosas, L.E., Faubion, W.A., Julien, A., Rietdijk, S., Coyle, A.J., Fraser, C., and Terhorst, C. The SLAM family receptor Ly108 controls T cell and neutrophil functions. J. Immunol. 2005; 174:5931-5935.
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Powell, N.D., Papenfuss, T.L., McClain, M.A., Gienapp, I.E., Shawler, T.M., Satoskar, A.R., and Whitacre, C.C. Macrophage migration inhibitory factor is necessary for progression of experimental autoimmune encephalomyelitis. J. Immunol. 2005; 175:5611-5614.
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Rosas, L.E., Keiser, T., Barbi, J., Satoskar, A.A., Septer, A., Kcazmarek, J., Lezama-Davila, C.M., and Satoskar, A.R. Genetic background influences immune responses and disease outcome of cutaneous L. mexicana infection in mice. Int. Immunol. 2005; 17:1347-1357.
Hattori, H., Okano, M., Kariya, S., Nishizaki, K. and Satoskar, A. R. CD40-CD40L interaction is involved in pathogenesis of SEA induced allergic rhinitis. Amer. J. Rhinol. 2006; 20:165-169.
Liang, S.C., Greenwald, R.J., Latchman, Y.E., Rosas, L., Satoskar, A. R, Freeman, G.J. and Sharpe, A.H. PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis. Eur. J. Immunol. 2006; 36:58-64.
Reyes, J., Terrazas, L.I., Espinoza, B., Gomez-Garcia, L., Cruz-Robles, D., Rivera-Montoya, I., Snider, H., Satoskar, A. R. and Rodriguez-Sosa, M. Macrophage migration inhibitory factor (MIF) plays a critical role in host defense against acute Trypanosoma cruzi infection. Infect. Immun. 2006; 74:3170-3179.
Rosas, L.E., Barbi, J., Snider, H., Satoskar, A.A., Lugo-Villarino, G., Keiser,T., Papenfuss, T, Durbin, J, Radzioch, D, Glimcher, LH and Satoskar, A. R. Cutting edge: STAT1 and T-bet play distinct roles in determining outcome of visceral leishmaniasis caused by Leishmania donovani J. Immunol. 2006; 177:22-25.
Rosas, L.E., Satoskar, A.A., Roth, K., Keiser, T., Barbi, J., Hunter, C.A, de Sauvage, F. and Satoskar, A. R. IL-27R (WSX-1/TCCR) gene deficient mice display enhanced resistance to Leishmania donovani infection but develop severe liver immunopathology. Am. J. Pathol. 2006; 168:158-169.