Oral Exposure to Trypanosoma cruzi Elicits a Systemic CD8⁺T Cell Response and Protection against Heterotopic Challenge

Abstract

Trypanosoma cruzi infects millions of people in Latin America and often leads to the development of Chagas disease. T. cruzi infection can be acquired at or near the bite site of the triatomine vector, but per os infection is also a well-documented mode of transmission, as evidenced by recent microepidemics of acute Chagas disease attributed to the consumption of parasite-contaminated foods and liquids. It would also be convenient to deliver vaccines for T. cruzi by the oral route, particularly live parasite vaccines intended for the immunization of reservoir hosts. For these reasons, we were interested in better understanding immunity to T. cruzi following oral infection or oral vaccination, knowing that the route of infection and site of antigen encounter can have substantial effects on the ensuing immune response. Here, we show that the route of infection does not alter the ability of T. cruzi to establish infection in muscle tissue nor does it impair the generation of a robust CD8؉ T cell response. Importantly, oral vaccination with attenuated parasites provides protection against wild-type (WT) T. cruzi challenge. These results strongly support the development of whole-organismbased vaccines targeting reservoir species as a means to alleviate the burden of Chagas disease in affected regions.

The Trypanosoma cruzi Flagellum Is Discarded via Asymmetric Cell Division following Invasion and Provides Early Targets for Protective CD8+ T Cells

“…To test this hypothesis, we infected mice with TcPAR4 or Tcwt parasites and then drug-cured the infection using benznidazole to simulate vaccination (Bustamante et al, 2008). These mice were then challenged in each footpad with tdTomato fluorescent proteinexpressing T. cruzi (CL strain) (Canavaci et al, 2010), and parasite load at the site of infection was monitored by in vivo imaging (Collins et al, 2011) and by PCR for detection of parasite DNA in tissues (Fig 6A). By day 4 post-infectionTcPAR4-immunized mice displayed a significant decline in parasite numbers, as reflected in fluorescence signal, compared to Tcwt vaccinated or the control non-vaccinated (primi-infection) mice (Figure 6B,C).…”

Advances and challenges towards a vaccine against Chagas disease

“…31 These cells are stimulated following oral infection, which is supposed to be a common route of infection for several animal reservoir species. 32 Thus, there is now a growing consensus that a protective immune response against T. cruzi requires the activation of a Th1 immune profile, with the stimulation of CD8 + T cells, while antibodies may play a rather secondary role.…”

“…Nonetheless, there is a renewed interest in a live attenuated vaccine approach and recent studies have described the generation of T. cruzi mutants for specific genes such as LYT1 or ECH1 and 2, which can provide good protection against infection in mice, including through oral administration. 32,38 Early attempts at immunizing mice with more defined preparations were based on proteins purified from parasite culture, including cruzipain, the paraflagellar rod protein or trypomastigote excretory-secretory antigens. [39][40][41] As expected, the outcome of such vaccines is critically dependent on the formulation used, and the orientation of the immune response that is induced.…”

Tc52 Amino-Terminal-Domain DNA Carried by Attenuated Salmonella enterica Serovar Typhimurium Induces Protection against a Trypanosoma cruzi Lethal Challenge

“…Potential sources of food contamination are triatomine bugs or triatomine feces, raw meat from infected animals, and gland secretions of infected opossums (Didephis marsupalis) (44). When the infection occurs by the oral route, metacyclic trypomastigotes invade the epithelium of the oral, esophageal, gastric, and intestinal mucosae and rapidly become systemic (48). In this work we focus on the development of an oral vaccine that could confer mucosal and systemic immunity, and the challenge was conducted intraperitoneally as a heterologous route for a more rigorous test of vaccine efficacy.…”