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Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi with clinical presentations ranging from asymptomatic to cardiac and/or gastrointestinal complications. The mechanisms of pathogenesis are still poorly understood, but T. cruzi strain diversity may be associated with disease progression. Therefore, we evaluated the transcriptomic response of PBMCs from macaques with natural chronic infections and tested for heterogeneity in their gene signatures. Remarkably, transcriptomic response to T. cruzi infection matched parasite strain profiles, indicating that parasite diversity is a key determinant of host response. While differences in adaptive immune responses were identified, more striking alterations of innate immune processes were detected. Thus, initial innate response to T. cruzi infection may be conditioned by parasite strain diversity, resulting in different profiles of trained immunity modulating subsequent adaptive responses, allowing parasite control or its persistence during the chronic phase. These results call for further characterization of the cross-talk between innate and adaptive immunity according to parasite diversity, and how altered trained immunity contributes to pathogenesis, as this may lead to better treatments and vaccines.