Cardiomyocyte transcriptomic signatures in response to Trypanosoma cruzi infection underpin Chagas cardiomyopathy progression.

Abstract

Chagas disease can lead to life-threatening cardiac manifestations that occur more frequently in geographic areas more prevalent with the TcI/II circulating genetic strains. To elucidate the differential transcriptomic signatures of the cardiomyocyte resulting from infection with TcI/II or TcVI T. cruzi strains and explore their relationships with pathogenesis, HL-1 rodent cardiomyocytes were infected with TcI/II or TcVI T. cruzi trypomastigotes. RNA was isolated serially post-infection for microarray analysis. Enrichment analyses of differentially expressed genes (fold-change [&ge;]2 or [&le;] 0.5) highlighted the over-represented biological pathways. We found that Oxidative stress-related GO terms, Hypertrophy model, Apoptosis, and MAPK signaling pathways (all with p<0.01) were upregulated. Glutathione and one-carbon metabolism pathway, and Cellular nitrogen compound metabolic process GO term (all with p <0.001) were upregulated exclusively in the cardiomyocytes infected with the TcI/II strains. Upregulation in the oxidative stress-related and hypertrophic responses are shared hallmarks with viral myocarditis, another inflammatory cardiac pathology. Nitrogen metabolism upregulation and Glutathione metabolism imbalance may implicate the relation of nitrosative stress and poor oxygen radicals scavenging in the unique pathophysiology of chagasic cardiomyopathy development. ImportanceChagas disease affects more than 6 million people worldwide. One-third of those chronically infected will develop the life-threatening condition Chagas Cardiomyopathy (CCM). Trypanosoma cruzi (T. cruzi), grouped based on their genetic variability into six discrete typing units (DTU), are associated with DTU-specific clinical phenotypes. The diverse genetic make-up of parasite virulence factors shall evoke unique host defense responses of variable magnitude, collectively affecting the phenotypic expression of CCM. To address this, we performed a transcriptome analysis of cardiomyocytes infected with three different T. cruzi strains each belonging to a different DTU. As a result, we were able to point out dysregulation in nitrogen metabolic processes, Glutathione, and one-carbon metabolism pathways as main features in the host response against cardiomyopathy-prone T. cruzi strains. Further research on these pathways could serve not only in the lookout for progression biomarkers but also in the lead toward the discovery of new therapeutic targets.