**Abstract**

Chagas' disease outcomes depend on several factors including parasite and host genetics, immune response, and route of infection. In this study, we investigate the influence of inoculation route and host genetic background on the establishment and development of Chagas disease in mice, using an isolate of *Trypanosoma cruzi* SC2005 strain (TcII), which was obtained from an oral Chagas' disease outbreak in Santa Catarina, Brazil. Comparative analysis of the immunopathological, histopathological, and hematological profiles of mice was performed demonstrating the influence of the route of infection in disease severity. In outbred mice, intraperitoneal (IP) infection led to higher infection and mortality rates and more severe parasitaemia, when compared with intragastric (IG) infection. Nevertheless, tissue colonization was similar, showing severe damage in the heart, with intense lymphocytic inflammatory infiltrates, regardless of the route of infection. On the other hand, in mice IG-infected, the host genetic background influences the start timing of immune response against *Trypanosoma cruzi*. The susceptible BALB/c inbred mouse strain presented an earlier development of a cytotoxic cellular profile, when compared with A mice. We hypothesize that the cytotoxic response mounted before the parasitaemia increase allowed for a milder manifestation of Chagas' disease in intragastrically infected mice.

**Keywords:** Chagas disease, immunopathology, host genetics, inoculation route, mice
