Rick L. Tarleton

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 up to 18 million people in Latin American and 90 million individuals are 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. cruzi infection and current chemotherapeutic regimens are of limited efficacy.

T. 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 more than 500 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 levels, there is scant evidence that humans or other mammals can completely clear the infection.

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.

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.

Our increased understanding of the mechanisms of immune control and pathogenesis in T. cruzi infection has resulted in the development of a strategy for vaccine discovery and development for T. cruzi and Chagas disease. This project is based upon our belief that disease development in Chagas disease is not the result of anti-self immune responses but rather is due to an ineffectual anti-parasite immune response, and that responses may be potentiated by vaccines which target the induction of strong and appropriate anti-parasite immune responses. The results of proof of principal experiments, employing a variety of vaccine candidates, have supported these hypotheses. These studies thus provide both the justification and the rationale for the further investigation of vaccines to prevent one of the leading causes of heart disease in the world. These latter goals are being pursued using a number of approaches, including a genome-wide computational analysis and experimental screening for potential vaccine candidates by genetic immunization, and DNA microarray analysis to identify stage-specific gene expression, and tandem mass spectrometric sequencing of T. cruzi peptides for gene annotation. This project has the ambitious goals of cloning and testing essentially all T. cruzi genes as vaccines and ultimately selecting a pool of vaccine molecules for field testing. We also develop and make use of additional techniques for functional analysis of T. cruzi genes, including dsRNA inhibition, gene knockout, regulated gene expression, and protein tagging.

Our lab is well supported primarily by the National Institutes of Health. In 1999 the lab was designated a Tropical Disease Research Unit (TDRU) with the funding of a project for discovery and testing of vaccines for T. cruzi infection. The TDRU also funds our project to study the human response in chagasic patients that is headquartered in Buenos Aires, Argentina.