Research in the Tarleton laboratory focuses on the immunology and pathogenesis of Trypanosoma cruzi infection and the resulting disease syndrome known as Chagas disease. T. cruzi is a protozoan parasite that infects approximately 18 million people in Latin American with 90 million more at risk of infection. Chagas disease is the single most common cause of congestive heart failure and sudden death in the world and the leading cause of death among young-to-middle age adults in endemic areas of South America. There are no vaccines for prevention of T. cruziinfection and current chemotherapeutic regimens are of limited efficacy.
Three broad questions are being addressed by the research in the Tarleton lab: 1) How is immune control initiated and maintained during the infection, and 2) How does T. cruzi manage to avoid immune clearance and maintain an infection for decades in hosts, and 3) What is the relationship between immunity, parasite persistence, and disease development?
The ultimate goals of these investigations are to provide insights into the immunologic basis of parasite control and pathogenesis in T. cruzi infection and to use this information to design methods for prevention of infection or intervention in chronic disease.cruzi is a blood-borne parasite with an extracellular non-replicative trypomastigote stage that circulates throughout the body and an obligate intracellular stage capable of replication within a variety of types of host cells. Soon after invasion of host cells, the trypomastigotes move from the phagolysosome into the host cell cytoplasm during their differentiation into amastigote forms. Within the host cell, the amastigotes undergo a series of divisions resulting in the production of 500 or more progeny from a single invading parasite over the span of 4-5 days. Amastigotes then convert back into trypomastigotes and are released from the host cell, resulting in that cell’s destruction, and repeat the cycle of invasion, replication and release. Although the host immune response generally limits the parasite load, there is scant evidence that humans or other mammals can completely clear the infection.
Our lab developed the initial evidence that infected host cells are targets of immune recognition and control via their recognition by host cytotoxic CD8+ T lymphocytes (CTL). We are continuing to investigate the mechanisms by which CD8+ T cells exert this control and the identity of the parasite antigens recognized by these cells, in both murine models and in human infections. We are also investigating how T cell responses develop against an antigenically complex pathogen like T. cruzi, and how T cell memory is maintained, or not, the presence of parasite persistence, as well as how T. cruzi evades immune clearance, potentially through the production of altered peptide ligands or by residing in the muscle microenvironment. Finally, the role of the immune response and parasite persistence in determining the severity of Chagas disease is being investigated by following disease progression and immune responses in human patients in Argentina.
- Bustamante, J.M., L.M. Bixby and R.L. Tarleton. 2008. Drug-induced cure drives conversion to a stable and protective CD8+ T central memory response in chronic Chagas disease. Nat. Med. 14:542-50.
- Martin DL, Postan M, Lucas P, Gress R, Tarleton RL. 2007. TGF-beta regulates pathology but not tissue CD8+ T cell dysfunction during experimental Trypanosoma cruzi infection. Eur J Immunol. 37(10):2764-71.
- Tarleton R.L, Reithinger R, Urbina JA, Kitron U, Gürtler RE. 2007. The challenges of Chagas Disease– grim outlook or glimmer of hope. PLoS Med. Dec;4(12):e332.
- Kotner J, Tarleton R. Endogenous CD4+CD25+ Regulatory T Cells Have Limited Role in Control of Trypanosoma cruziInfection in Mice. Infect Immun. 2007 75: 861-869.
- Tarleton R.L. Immune system recognition of Trypanosoma cruzi. Curr Opin Immunol. 2007.Aug;19(4):430-4
- Martin DL, Weatherly DB, Laucella SA, Cabinian MA, Crim MT, Sullivan S, Heiges M, Craven SH, Rosenberg CS, Collins MH, Sette A, Postan M, Tarleton RL. CD8+ T-Cell responses to Trypanosoma cruzi are highly focused on strain-variant trans-sialidase epitopes. 2006. PLoS Pathog. (8):e77.
- Laucella, S.A., D. Martin, M.C. Albareda, B.H. Fralish, N. Prado, A.H. Armenti, R.J. Viotti, S.N. Torres, B. Loccoco, M. Postan, R.L. Tarleton. 2004. Frequency of IFN-gamma-producing T cells specific for Trypanosoma cruzi inversely correlates with disease severity in chronic human Chagas disease. Journal of Infectious Diseases, 89(5): 909-918.
- Atwood JA III, DB Weatherly, TA Minning, B Bundy, C Cavola, FR Opperdoes, R Orlando, RL Tarleton. 2005. The Trypanosoma cruzi proteome. Sciences; 309(5733): 473-476.