UTMB Department of Pathology

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Pathogenic Mechanisms of Cutaneous Leishmaniasis

Leishmania parasites can cause localized cutaneous, diffuse cutaneous and visceral leishmaniasis in humans. These parasites are distributed in at least 88 countries and are transmitted to mammalian hosts via the bite of infected sand flies. The long-term goal of our research is to understand parasite-host-vector interactions and to use this knowledge for the control of the disease. To achieve this, I am currently using murine models to dissect and to define the key components that are involved in these interactions. Areas of my research include:

Pathogenic mechanisms of cutaneous leishmaniasis: Some inbred strains of mice are genetically resistant or susceptible to Leishmania parasites, and allow us to examine the roles of innate and acquired immunity in the control of the infection. Given that this parasite mainly infects and grows within macrophages and dendritic cells, I have been focusing my attention on cellular immune responses and would like to address several important questions. What are the major differences between protective and pathogenic T helper cells? How are these T cell subsets primed and activated in infected animals? What parasite antigens are recognized by these T cell subsets? How are the interactions among parasites, DCs, and T cells regulated in vivo? Since conversations between different cell populations are mediated by cell surface molecules, cytokines, chemokines, and their corresponding receptors, I can examine the role of these molecules using gene-targeted knockout mice, neutralizing monoclonal antibodies, or antagonists. This study is funded by a NIH R01 grant and the UTMB McLaughlin Fellowship Fund.

Identification of target antigens of the parasite: Leishmania parasites are complex organisms containing approx. 10,000 genes. To identify genes/proteins that can been "seen" by the host immune system or are essential for the intracellular survival of the parasite, I am taking following approaches: 1) screening for relevant targets using parasite-specific T cell clones or sera from infected animals; 2) searching for protective antigens via cDNA expression library immunization; and 3) identifying genes preferentially expressed in the intracellular stage of the parasite by 2-D gel and 2-D Western blot analyses. This study is partially supported by UTMB Sealy Funds and the UTMB McLaughlin Fellowship Fund.

Role of sand fly saliva in leishmanial pathogenesis: Sand flies are more efficient in transmitting parasites than syringes; however, the mechanism that underlies this is not entirely clear. In collaboration with Dr. Greg Lanzaro's group at UC Davis, I am examining host immune responses to a defined salivary protein, and the impact of these responses on vector fitness and the outcome of Leishmania infection. Information learned from this study would help us understand the pathogenesis of other vector-born diseases. This study is supported by a NIH R01 grant.

1. Razik-Desouky, A., C. A. Specht, L. Soong, and J. M. Vinetz. 2001. Leishmania donovani: Expression and enzymological characterization of the chitinase LdCHT1. In press
2. Ji, J., J. Sun, H. Qi, and L. Soong. Analysis of T helper responses during infection with Leishmania amazonensis. Am. J. Trop. Med. Hyg . In Press
3. Qi, H., V. L. Popov, and L. Soong. Leishmania amazonensis-dendritic cell interactions in vitro and the priming of parasite-specific CD4+ T cells in vivo. J. Immunol. 167:4534-4542
4. Qi, H., V. L. Popov, and L. Soong. Leishmania amazonensis-dendritic cell interactions in vitro and the priming of parasite-specific CD4+ T cells in vivo. J. Immunol. 167:4534-4542
5. Soong, L.*, S. Kar*, M. Colmenares, K. Goldsmith-Pestana, and D. McMahon-Pratt. The immunologically protective P-4 antigen of Leishmania amastigotes: A developmentally regulated single-strand specific nuclease associated with the endoplasmic reticulum. J. Biol. Chem. 275:37789-37797
6. Haberer, J. E., A. M. Da Cruz, L. Soong, M. P. Oliveira-Neto, L. Rivas, D. McMahon-Pratt, and S. G. Continho. Leishmania pifanoi arnastigote antigen P-4: Epitopes involved in T-cell responsiveness to human cutaneous leishmaniasis. Infect. Immun. 66:3100-3105
7. McMahon-Pratt, D., P. Kima, and L. Soong. Leishmania amastigote target antigens: the challenge of a stealthy intracellular parasite. Parasitol. Today. 14:31-34
8. Sacca, R., S. Turley, L. Soong, 1. Mellman, and N. H. Ruddle. Transgenic expression of lymphotoxin restores lymph nodes to lymphotoxin-a-deficient mice. J. Immunol. 159:4252-4260
9. Soong, L., C-H. Chang, J. Sun, B. J. Longley Jr., N. H. Ruddle, R. A. Flavell, and D. McMahon-Pratt. Role of CD4+ T cells in pathogenesis associated with Leishmania amazonensis infection. J. Immunol. 158:5374-5383
10. Hodgkinson, V. H. and L. Soong. In vitro maintenance of Leishmania amastigotes directly from lesions: advantages and limitations. J. Parasitol. 83:953-957
11. Silveira, F. T., J. M. Blackwell, E. A. Ishikawa, R. Braga, J. J. Shaw, R. J. Quinnell, L. Soong, P. Kima, D. McMahon-Pratt, G. F. Black, and M.-A. Shaw. T cell responses to crude and defined leishmanial antigens in patients from the lower Amazon region of Brazil infected with different species of Leishmania of the subgenera Leishmania and Viannia. Parasite Immunol. 20:19-26
12. Kima, P., L. Soong, C. Chincaro, N. H. Ruddle, and D. McMahon-Pratt. Sequestration in Leishmania-infected macrophages of endogenously synthesized parasite antigen from presentation to CD4+ T cells. Eur. J. Immunol. 26:3163-3169
13. Hodgkinson, V. H., L. Soong, S. M. Duboise, and D. McMahon-Pratt. Leishmania amazonensis: cultivation and characterization of axenic amastigotes-like organisms. Exp. Parasitol. 83: 94-105
14. Soong, L., J-C. Xu, 1. Grewal, P. Kima, J. Sun, B. J. Longley Jr., N. H. Ruddle, D. McMahon-Pratt, and R. A. Flavell. Disruption of CD40/CD40 ligand interactions results in an enhanced susceptibility to Leishmania amazonensis infection. Immunity. 4: 263-273
15. Continho, S. G., M. P. de Oliveira, A. M. da Cruz, P. D. Luca, S. C. F. Mendonca, A. L. Bertho, L. Soong, and D. McMahon-Pratt. T-cell responsiveness of American cutaneous leishmaniasis patients to purified Leishmania pifanoi amastigote antigens and Leishmania braziliensis promastigote antigens. Immunologic patterns associated with cure. Exp. Parasitol. 84:144-155
16. Campos-Neto, A., L. Soong, J. Cordova, D. Saint'Angelo, Y. Skeiky, N. H. Ruddle, S. G. Reed, C. Janeway Jr., and D. McMahon-Pratt. Cloning and expression of a Leishmania donovani gene instructed by a peptide isolated from MHC class II molecules of infected macrophages. J. Exp. Med. 182: 1423-1433
17. Soong, L., S. M. Duboise, P. Kima, and D. McMahon-Pratt. Leishmania pifanoi amastigote antigens protect mice against cutaneous leishmaniasis. Infect. Immun. 63: 35593566
18. Soong, L. and R. L. Tarleton. Trypanosoma cruzi infection suppresses nuclear factors that bind to specific sites on the IL-2 enhancer. Eur. J. Immunol. 24:16-23
19. Soong, L. and R. L. Tarleton. Selective suppressive effects of Trypanosoma cruzi infection on IL-2, c-myc and c-fos gene expression. J. Immunol. 149: 2095-2102

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