Intra-host Trypanosoma cruzi parasite dynamics in naturally-infected macaques and Chagas disease progression - PROJECT SUMMARY Intra-host Trypanosoma cruzi parasite dynamics in naturally-infected macaques and Chagas disease progression Chagas disease is a major vector borne parasitic disease cause by the protozoan parasite Trypanosoma cruzi, with over 6 million cases in the Americas. Chronic chagasic cardiomyopathy (CCC) is the most common and life-threathening manifestation of Chagas disease, which develops many years after the initial infection in 20-40% of patients. However, disease progression is still poorly understood, due to the need for prolonged follow-up, the lack of precise biomarkers, extensive parasite genetic and biological diversity, among others. A major gap is that patients at increased risk of developing severe disease cannot be distinguished from those who may remain in the asymptomatic chronic stage, making any prognosis uncertain and complicating patient care and treatment. Importantly, there is growing evidence that a large proportion of infections are caused by multiple parasite strains. The implications of such multiple infections on disease progression and clinical manifestations are unclear, but interactions among strains are likely to occur, that may shape disease progression. Therefore, our general objective is to determine the effects of T. cruzi parasite diversity on disease progression during the chronic phase by monitoring a cohort of naturally- infected rhesus macaques. We will follow naturally-infected Chagasic macaques from a well established cohort of animals that have been infected for 1-6 years. Sequential blood samples will be used to measure parasite burden by qPCR and parasite genotyping through NGS to assess parasite strain dynamics over 24 months of follow- up. These will be associated with ECG recordings to assess cardiac function. We will also perform bulk and single cell RNA-sequencing of PBMCs to assess differences in transcriptional profiles according to parasite diversity. This system immunology approach will inform on immune correlates for disease progression. Finally, we will measure plasma fibronectin degradation and other candidate biomarkers, to correlate with disease progression as measured by parasite burden and ECG alterations. These studies will be key to better understand Chagas disease progression in naturally-infected hosts, and test for the role of parasite genetic diversity in shaping disease progression. Together with the validation of potential biomarkers, this work is expected to have an important translational impact by leading to better treatments and prognosis for Chagasic patients.
