Research in the Tarleton Research Group (TRG) focuses exclusively on Trypanosoma cruzi infection and the resulting disease syndrome known as Chagas disease. T. cruzi is a protozoan parasite that infects approximately >10 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. cruzi infection and current chemotherapeutic regimens are of limited efficacy.
Historically the TRG approached T. cruzi infection from a primarily immunological perspective, attempting to address broad questions such as how is immune control initiated and maintained during the infection, and how does T. cruzi manage to avoid immune clearance and maintain an infection for decades in hosts, and what is the relationship between immunity, parasite persistence, and disease development? We approach these questions not only from the angle of host responses but also from the parasite side, where we strive to understand the unique biology of T. cruzi that impinges on its interaction with its many host species. An example of this approach is our discovery of dormancy in T. cruzi and the impact this ability may have treatment efficacy and immune control.
In the course of attempting to answer these and other questions and to translate the knowledge acquired into interventions, our focus has necessarily expanded beyond immunology. Development of tools to make the study of T. cruzi infection and Chagas disease more facile has been a high priority. The TRG participated in the sequencing and assembly of the current reference genome of T. cruzi and provided transcriptomic and proteomic data for that genome. Current efforts include providing a more complete reference genome and understanding genome complexity, particularly with respect to the multiple large and variant gene families that are the focus of most immune responses. We have also pioneered the use of CRISPR in T. cruzi and are exploiting this technology for genome-wide analysis of gene function in T. cruzi, among other applications.
The TRG has also stepped aggressively into drug discovery for T. cruzi infection, developing and exploiting the excellent animal model systems, including rodents, canine and nonhuman primates, to generate hits, leads and now clinical candidates for treatment of T. cruzi infection. We work closely with multiple pharmaceutical groups to take full advantage of the expertise we lack and we attempt to disseminate information with the Chagas community by, for example, organizing the Chagas Drug Discovery Consortium. One NIH-funded consortium involving three additional U.S.-based laboratories and three groups in Brazil and Argentina is developing a high-density array format for assessing treatment outcomes. The TRG also maintains a >20 yr collaboration with the Susana Laucella’s group in Buenos Aires where we study the immunology of human Chagas disease and tracking treatment outcomes.
Current funding includes multiple NIH grants for both basic and applied research, Wellcome Trust funding for drug discovery, and collaborative drug discovery projects with several pharmaceutical groups.
The TRG believes that Chagas Disease is a solvable problem and is working on multiple levels to provide solutions.
See the full list of publications at PubMed.
- Sánchez-Valdéz FJ, Padilla A, Wang W, Orr D, Tarleton RL. Spontaneous dormancy protects Trypanosoma cruzi during extended drug exposure. Elife. 2018 Mar 26;7. pii: e34039. doi: 10.7554/eLife.34039. PMID: 29578409. PMCID: PMC5906098
- Soares Medeiros LC, South L, Peng D, Bustamante JM, Wang W, Bunkofske M, Perumal N, Sanchez-Valdez F, Tarleton RL. Rapid, Selection-Free, High-Efficiency Genome Editing in Protozoan Parasites Using CRISPR-Cas9 Ribonucleoproteins. mBio. 2017; 8(6). doi: 10.1128/mBio.01788-17. PMID: 29114029 PMCID: PMC5676044
- Peng D, Tarleton R. EuPaGDT: a web tool tailored to design CRISPR guide RNAs for eukaryotic pathogens. MGen. 2015;1(4). doi: 10.1099/mgen.0.000033. PMID: 28348817 PMCID: PMC5320623
- Peng D, Kurup SP, Yao PY, Minning TA, Tarleton RL. CRISPR-Cas9-mediated single-gene and gene family disruption in Trypanosoma cruzi. MBio. 2014 Dec 30;6(1):e02097-14. doi: 10.1128/mBio.02097-14. PMID: 25550322; PMCID: PMC4281920.
- Weatherly DB, Peng D, Tarleton RL (2016) Recombination-driven generation of the largest pathogen repository of antigen variants in the protozoan Trypanosoma cruzi. BMC Genomics. 17(1):729. doi: 10.1186/s12864-016-3037-z. PMID: 27619017. PMCID: PMC5020489
- Kurup SP, Tarleton RL. The Trypanosoma cruzi flagellum is discarded via asymmetric cell division following invasion and provides early targets for protective CD8⁺ T cells. Cell Host Microbe. 2014 Oct 8;16(4):439-49. doi: 10.1016/j.chom.2014.09.003. PMID: 25299330; PMCID: PMC4194031.
- Kurup SP, Tarleton RL. Perpetual expression of PAMPs necessary for optimal immune control and clearance of a persistent pathogen. Nature Communications. 2013;4:2616. Epub 2013/10/24. doi: 10.1038/ncomms3616. PMID: 24149620. PMCID: PMC4161029
- Laucella SA, Mazliah DP, Bertocchi G, Alvarez MG, Cooley G, Viotti R, Albareda MC, Lococo B, Postan M, Armenti A, Tarleton RL. Changes in Trypanosoma cruzi-specific immune responses after treatment: surrogate markers of treatment efficacy. Clin Infect Dis. 2009 Dec 1;49(11):1675-84. doi: 10.1086/648072. PMID: 19877967; PMCID: PMC2805187.
- Cooley G, Etheridge RD, Boehlke C, Bundy B, Weatherly DB, Minning T, Haney M, Postan M, Laucella S, Tarleton RL. High throughput selection of effective serodiagnostics for Trypanosoma cruzi PLoS Negl Trop Dis. 2008 Oct 8;2(10):e316. doi: 10.1371/journal.pntd.0000316. PMID: 18841200; PMCID: PMC2556098.
- Bustamante JM, Craft JM, Crowe BD, Ketchie SA, Tarleton RL. New, combined, and reduced dosing treatment protocols cure Trypanosoma cruzi infection in mice. J Infect Dis. 2014 Jan 1;209(1):150-62. doi: 10.1093/infdis/jit420. Epub 2013 Aug 14. PMID: 23945371; PMCID: PMC3864384.
- Tarleton RL. 2016. Chagas Disease: A Solvable Problem, Ignored. (2016) Trends Mol Med. Aug 11. pii: S1471-4914(16)30094-6. doi: 10.1016/j.molmed.2016.07.008. PMID: 27523778. PMCID: PMC5748248
- Tarleton RL, Gürtler RE, Urbina JA, Ramsey J, Viotti R. Chagas disease and the London declaration on neglected tropical diseases. PLoS Negl Trop Dis. 2014 Oct 9;8(10):e3219. doi: 10.1371/journal.pntd.0003219. eCollection 2014 Oct. PMID: 25299701; PMCID: PMC4191937.
- Tarleton RL, Reithinger R, Urbina JA, Kitron U, Gürtler RE. The challenges of Chagas Disease– grim outlook or glimmer of hope. PLoS Med. 2007 Dec;4(12):e332. doi: 10.1371/journal.pmed.0040332. PMID: 18162039; PMCID: PMC2222930.