<i>Trypanosoma cruzi</i> Infection through the Oral Route Promotes a Severe Infection in Mice: New Disease Form from an Old Infection?

<div><p>Oral transmission of Chagas disease has been documented in Latin American countries. Nevertheless, significant studies on the pathophysiology of this form of infection are largely lacking. The few studies investigating oral route infection disregard that inoculation in the oral cavity (Oral infection, <b>OI</b>) or by gavage (Gastrointestinal infection, <b>GI</b>) represent different infection routes, yet both show clear-cut parasitemia and heart parasitism during the acute infection. Herein, BALB/c mice were subjected to acute <b>OI</b> or <b>GI</b> infection using 5x10⁴ culture-derived <i>Trypanosoma cruzi</i> trypomastigotes. <b>OI</b> mice displayed higher parasitemia and mortality rates than their <b>GI</b> counterparts. Heart histopathology showed larger areas of infiltration in the <b>GI</b> mice, whereas liver lesions were more severe in the <b>OI</b> animals, accompanied by higher Alanine Transaminase and Aspartate Transaminase serum contents. A differential cytokine pattern was also observed because <b>OI</b> mice presented higher pro-inflammatory cytokine (IFN-γ, TNF) serum levels than <b>GI</b> animals. Real-time PCR confirmed a higher TNF, IFN-γ, as well as IL-10 expression in the cardiac tissue from the <b>OI</b> group compared with <b>GI</b>. Conversely, TGF-β and IL-17 serum levels were greater in the <b>GI</b> animals. Immunolabeling revealed macrophages as the main tissue source of TNF in infected mice. The high mortality rate observed in the <b>OI</b> mice paralleled the TNF serum rise, with its inhibition by an anti-TNF treatment. Moreover, differences in susceptibility between <b>GI</b><i>versus</i><b>OI</b> mice were more clearly related to the host response than to the effect of gastric pH on parasites, since infection in magnesium hydroxide-treated mice showed similar results. Overall, the present study provides conclusive evidence that the initial site of parasite entrance critically affects host immune response and disease outcome. In light of the occurrence of oral Chagas disease outbreaks, our results raise important implications in terms of the current view of the natural disease course and host-parasite relationship.</p></div