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.
