Immune mechanisms that determine outcome of “New world” cutaneous and visceral leishmaniasis.

Abhay Satoskar

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Associate Professor
M.B.B.S., University of Bombay (India), 1989
M.D., University of Bombay (India), 1992
PhD., University of Strathclyde, Glasgow (U.K.), 1996

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.

Recent Publications

Xu D, McSorley SJ, Tetley L, Chatfield S, Dougan G, Chan WL, Satoskar, AR, David JR, Liew FY. Protective effect on Leishmania major infection of MIF, TNF-alpha and IFN-gamma administered orally via attenuated Salmonella typhimurium. J. Immunol. 1998; 160: 1285-1289.

Satoskar AR, Khamis Al-Q, Alexander J. Sex-determined resistance against Leishmania mexicana is associated with the preferential induction of a Th1-like response and IFN-gamma production by female but not male DBA/2 mice. Immun Cell Biol. 1998; 76: 159-166.

Satoskar, AR, Okano M, Connaughton S, David JR, Labow M. Enhanced Th2-like responses in IL-1 type 1 receptor-deficient mice. Europ J Immunol.1998; 28: 2066-2074.

Stamm L, Raisanen-Solokowski A, Okano M, Russell M, David JR, Satoskar AR. Mice with STAT6-targeted disruption develop a Th1 response and control cutaneous leishmaniasis. J. Immunol. 1998; 161: 6180-6188.

Bozza M, Soares M, Bozza P, Satoskar AR, Brombacher F, Titus R, Shoemaker C, David JR. The selective PACAP-type I receptor agonist Maxadilan from Sand fly saliva protects mice against lethal endotoxemia. Europ J Immunol. 1998; 28: 3120-3127.

Bozza M, Satoskar AR, Lin G, Lu B, Humbles AA, Gerard C, David JR. Targeted disruption of migration inhibitory factor gene reveals its critical role in sepsis. J. Exp. Med. 1999; 189: 341-346.

Satoskar AR, Stamm LM, Zhang, XM, Satoskar, AA, Okano, M, David JR, Terhorst C, Wang B. Mice lacking natural killer (NK) cells develop an efficient Th1 response and control cutaneous L. major infection. J. Immunol. 1999; 162:6747-6754.

Satoskar, AR, Stamm, LM, Zhang, X., Okano, M, David, JR, Terhorst, C., and Wang, B. NK cell deficient mice develop Th1-like response but fail to mount an efficient antigen-specific IgG2a antibody response. J. Immunol. 1999; 163: 5298-5302.

Stamm, LM, Satoskar, AA, Ghosh, S, David, JR and Satoskar, AR. STAT4-mediated IL-12 signaling pathway is critical for the development of protective immunity in cutaneous leishmaniasis. Europ. J. Immunol. 1999; 29:2524-2529.

Alexander, J, Satoskar AR and Russell, DG. Leishmania species: models of intracellular parasitism. J. Cell Sci.1999; 112:2993-3002. (Review).

Satoskar, AR, Rodig, S, Telford, SR, Satoskar, AA, Ghosh, S., von Lichtenberg, F., and David, JR. Interleukin 12 gene deficient mice are susceptible to L. donovani infection but have diminished hepatic immunopathology. Europ. J. Immunol. 2000; 30:834-839..

Monteforte, G., Takeda, K., Akira, S, David, JR and Satoskar, AR. Interleukin-18 is not critical for the development of Th1 response and control of cutaneous L. major infection. J. Immunol. 2000; 164: 5890-5893.

Alexander, J., Carter, KC., Al-Fasi, N., Satoskar, AR, and Brombacher, F. Effective drug therapy against visceral leishmaniasis is dependent on endogenous IL-4. Europ. J. Immunol. 2000; 30:2935-2943.

Hattori, H, Okano, M, Yoshino, T, Akagi, T, Nakayama, E, Saito, C, Satoskar, AR, Ogawa, T, Azuma, M and Nishizaki, K. Expression of co-stimulatory CD80/CD86-CD28/CD152 molecules in the nasal mucosa of patients with perennial allergic rhinitis. Clin. Exp. Allergy. 2001; 31:1242.

Okano, M, Azuma, M, Yoshino, T, Hattori, H, Nakada, M, Satoskar, AR, Harn Jr, DA, Nakayama, E, Akagi, T, and Nishizaki, K. Differential role of CD80 and CD86 molecules in the induction and the effector phases of allergic rhinitis in mice. Am. J. Res. Crtic. Care Med. 2001; 164: 1501.

Szabo, SJ, Sullivan, BM, Stemmann, C., Satoskar, AR, Sleckman, BP, and Glimcher, LH. Distinct effects of T-bet in Th1 lineage commitment and IFN-γ production in CD4 and CD8 T cells. Science. 2002; 295:338.

Greenwald, RJ, McAdam, AJ, Van der Woude, D, Satoskar, AR, and Sharpe, AH. Inducible co-stimulator protein regulates both Th1 and Th2 responses to cutaneous leishmaniasis. J. Immunol. 2002; 168: 991.

Rodriguez-Sosa, M, David, JR, Bojalil, R., Satoskar, AR, and Terrazas, LI. Susceptibility to the larval stage of the helminth parasite Taenia crassiceps is mediated by the Th2 response induced via STAT6 signaling. J. Immunol. (Cutting Edge) 2002; 168:3135.

Brown, JA, Greenwald, RJ, Scott, S, Schweitzer, A.N, Satoskar, AR, Chung, C, Schopf, LR, van der Woude, D, Sypek, JP, and Sharpe, AH. T helper differentiation in resistant and susceptible B7-deficient mice infected with Leishmania major. Eur. J. Immunol. 2002; 32:1764.

Hattori H, Okano M, Yamamoto T, Yoshino T, Yamashita Y, Watanabe T, Satoskar, AR, Harn DA, and Nishizaki K. Intranasal application of purified protein derivative suppresses the initiation but not the exacerbation of allergic rhinitis in mice. Clin. Exp. Allergy. 2002; 32:951.

Costa, CH, Stewart, JM, Gomes, RBB, Garcez, LM, Ramos, PK, Bozza, M, Satoskar, AR, Dissennayake, S, Santos, RS, Silva, MRB, Shaw, JJ, David, JR, and Maguire, JH. Asymptomatic human carriers of Leishmania chagasi. Am. J. Trop. Med. Hyg. 2002; 66:334-337.

Rodriguez-Sosa, M, Satoskar, AR, Calderon, R., Gomez-Garcia, L, Saaverda, R., Bojalil, R., and Terrazas, LI. Chronic helminth infection induces alternatively activated macrophages expressing high levels of CCR5 with low interleukin-12 production and Th2-biasing ability. Infect. Immun. 2002; 70:3656.

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.

Rosas, L, Keiser, T, Pyles, R, Durbin, J, and Satoskar, AR*. Development of protective immunity against cutaneous leishmaniasis is dependent on STAT1-mediated IFN signaling pathway. Eur. J. Immunol. 2003; 33: 1799.

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.

Bhardwaj, N., Rosas, L.E., Lafuse, W.P., and Satoskar, A.R. Leishmania inhibits STAT1-mediated IFN-γ signaling in macrophages: Increased tyrosine phosphorylation of dominant negative STAT1β by Leishmania mexicana. Int. J. Parasitol. 2005; 35:7582.

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.

Morra, M., Barrington, R.A., Abadia-Molina, A., Okamoto, S., Julien, A., Gullo, C., Kalsy, A., Edwards, M.J., Chen, G., Spolski, R., Leonard, W.J., Huber, B.T., Borrow, P., Biron, C.A., Satoskar, A.R., Carroll, M.C., and Terhorst, C. Defective B cell responses in the absence of SH2D1A. Proc. Natl Acad. Sci. USA. 2005; 102:4819-4823.

Okano, M., Hattori, H., Yoshino, T., Sugata, Y., Yamamoto, M., Fujiwara, T., Satoskar, A.A., Satoskar, A.R., and Nishizaki, K.Nasal exposure to Staphylococcal enterotoxin enhances the development of allergic rhinitis in mice. Clin. Exp. Allergy. 2005; 35:506-514.

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.

Rosas, L.E., Barbi, J., Lu, B., Fujiwara, N., Gerard, C., Sanders, V.M., and Satoskar A.R. CXCR3-/- mice mount an efficient Th1 response but fail to control L. major infection. Eur. J. Immunol. 2005; 35:515-523.

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.

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