Simultaneous Infection With Genetically Distinct Trypanosoma cruzi Isolates Is Associated With Distinct Myocardial Innate Immune Transcriptional Profiles During Acute Infection in Mice

ABSTRACT Innate immune receptors are central to host resistance against Trypanosoma cruzi infection, yet how parasite genetic diversity is associated with these responses remains poorly understood. Here, we characterized acute infection outcomes and myocardial innate immune transcriptional profiles in mice subjected to single and mixed infections with genetically distinct T. cruzi parasites (DTUs TcII, TcIII, and TcVI). Swiss mice were infected with RN2, RN23, Y, or CL‐Brener individually or in combination, and parasitemia, survival, and cardiac gene expression were assessed. The Y strain, CL‐Brener clone, and RN2 + RN23 + CL‐Brener condition exhibited a high‐severity profile, with marked parasitemia (8000–28,000 trypomastigotes/5 μL), mortality of 74%–100%, reduced myocardial transcription of Tlr2 , Tlr4 , Tlr9 , Trif , and Myd88 , and increased transcription of Nlrp3 , Casp1 , Il1β , and Tnfα . In contrast, RN2 and RN23 single infections exhibited low‐severity profiles and higher transcription of innate immune mediators associated with parasite control. Mixed‐infection groups displayed transcriptional and infection profiles differing from the corresponding single‐infection groups under a standardized total inoculum. Together, these findings identify distinct myocardial innate immune transcriptional profiles across single and mixed T. cruzi infection conditions and support further investigation of the contributions of parasite population composition and dose to acute infection outcomes.