Research in the Tarleton Research Group (TRG) focuses nearly exclusively on Trypanosoma cruzi infection and the resulting disease syndrome known as Chagas disease. T. cruzi is a protozoan parasite that infects 10-20 million people mostly the Americas as well as innumerable other animals. Chagas disease is the 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 to prevent T. cruzi infection and current chemotherapeutic regimens are not consistently curative. Life Cycle of The Chagas Disease 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 on treatment efficacy and immune control. A particularly exciting technical advance has been the use of tissue clearing and light sheet microscopy to carefully track parasite dispersion and immune responses in whole organs. Visualization of infection in a mouse heart with two T. cruzi strains expressing different fluorescent markers. Left: 2D rendering of the entire heart; Right: an optical slice through the same heart. 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. We have recently completed several high quality genomes that shed light on the strain-independent evolution of gene families involved in immune evasion and on the mechanism by which T. cruzi maintains these large and diverse antigen sets. We have also pioneered the use of CRISPR in T. cruzi and are exploiting this technology to attempt genome-wide analysis and modification 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, canines and nonhuman primates, to generate hits, leads and now clinical candidates for treatment of T. cruzi infection. New treatment protocols are using existing drugs are also a focus of ongoing work. We work closely with multiple pharmaceutical groups to take full advantage of the expertise (and especially compound libraries) that 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 antigen arrays 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 track treatment outcomes. Current funding includes multiple NIH grants for both basic and applied research, Wellcome Trust funding for drug discovery and development, 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.