Between 8 and 12 million people are infected with the parasite Trypanosoma cruzi, the causative agent of Chagas disease, and approximately 10,000 die each year. Chagas disease causes cardiomyopathy in up to 30% of those infected and often results in sudden cardiac death. In the context of the HIV epidemic, a new clinical syndrome called reactivation Chagas disease has emerged, characterized by high-level parasitemia, meningoencephalitis, and mortality as high as 80%. Risk factors for reactivation Chagas disease are not well characterized, and studies of the genetic and immunological determinants of reactivation Chagas disease are similarly lacking and urgently needed. The genetic diversity of T. cruzi likely influences clinical presentation and host immune response in Chagas disease. Infections with T. cruzi can be multiclonal, but the frequency of multiclonal infections and the role of specific clones in the manifestations of Chagas disease are not known. In this project, the candidate proposes to improve understanding of the clinical features and pathogenesis of HIV/T. cruzi-coinfection. She will draw upon her epidemiological skills and prior experience studying Chagas disease to address poorly understood aspects of this syndrome while learning cutting-edge laboratory and analytic techniques through a thoughtfully designed educational program and mentorship team. The candidate proposes to address three aspects of HIV/T. cruzi coinfection: (1) to define the immunological deficits that lead to reactivation of T. cruzi, (2) to evaluate the role of T. cruzi genetic diversity in the pathogenesis of reactivation Chagas disease, and (3) to characterize the clinical and laboratory predictors of reactivation Chagas disease and develop an algorithm to distinguish reactivation Chagas disease from cerebral toxoplasmosis. The results will improve understanding of HIV/T. cruzi coinfection, guide the clinical management of HIV/T. cruzi-coinfected patients, and inform future studies into the genetic and immunological determinants of Chagas disease. The candidate is committed to a career in academic medicine and is strongly supported in her goals by her mentors and her division at UNC-Chapel Hill. She has been offered a position as Assistant Professor and guaranteed laboratory and office space as well as 75% protected research time. This proposal includes a comprehensive didactic plan and mentorship team to guide the candidate's research and provide her the subject matter and technical knowledge needed to become an expert in HIV/T. cruzi coinfection. She will build upon her epidemiological skills, clinical experience, and work on malaria with mentors Dr. Steven Meshnick and Dr. Jonathan Juliano. Dr. Robert Gilman and Dr. Caryn Bern, the other members of her mentorship team, are Chagas disease experts and will help her apply these skills to T. cruzi and provide mentorship at the study site in Bolivi. The didactic coursework, mentorship, and practical laboratory, clinical, and field experience obtained over the course of the K23 award will provide the candidate with a diverse skill set that will allow her to be an independent investigator and expert in the pathogenesis vector-borne infectious diseases.
Despite the fact that Chagas disease affects 8 to 12 million people in the Americas, it remains a neglected tropical disease. It disproportionately affects the poor, as does HIV, and reactivation of T. cruzi in HIV-positive patients is fatal in up to 80% of cases. The findings from this project will better define the clinical manifestations and elucidate the pathogenesis of the emerging syndrome of HIV/T. cruzi coinfection, guiding further studies into the disease and helping design better strategies to prevent and treat this serious infection.