Intra-host strain dynamics shape disease progression: the missing link in Chagas disease pathogenesis.

Chronic Chagasic cardiomyopathy develops years after infection in 20-40% of patients, but disease progression is poorly understood. Here, we assessed parasite dynamics and pathogenesis over a 2.5-year period in naturally infected rhesus macaques. Individuals with better control of parasitemia were infected with a greater diversity of parasite strains compared to those with increasing parasitemia over time. Also, the parasite multiplication rate decreased with increasing parasite diversity, suggesting competition among strains or a stronger immune response in multiple infections. Significant differences in electrocardiographic (ECG) profiles were observed in Chagasic macaques compared to uninfected controls, suggesting early conduction defects, and changes in ECG patterns over time were observed only in macaques with increasing parasitemia and lower parasite diversity. Disease progression was also associated with plasma fibronectin degradation, which may serve as a biomarker. These data provide a novel framework for the understanding of Chagas disease pathogenesis, with parasite diversity shaping disease progression.IMPORTANCEChagas disease progression remains poorly understood, and patients at increased risk of developing severe cardiac disease cannot be distinguished from those who may remain asymptomatic. Monitoring of strain dynamics and pathogenesis over 2-3 years in naturally infected macaques shows that increasing parasite diversity in hosts is detrimental to parasite multiplication and Chagasic cardiomyopathy disease progression. This provides a novel framework for the understanding of Chagas disease pathogenesis.