Reaching for the Holy Grail: insights from infection/cure models on the prospects for vaccines for Trypanosoma cruzi infection

Abstract

Prevention of Trypanosoma cruzi infection in mammals likely depends on either prevention of the invading trypomastigotes from infecting host cells or the rapid recognition and killing of the newly infected cells by T. cruzi-specific T cells. We show here that multiple rounds of infection and cure (by drug therapy) fails to protect mice from reinfection, despite the generation of potent T cell responses. This disappointing result is similar to that obtained with many other vaccine protocols used in attempts to protect animals from T. cruzi infection. We have previously shown that immune recognition of T. cruzi infection is significantly delayed both at the systemic level and at the level of the infected host cell. The systemic delay appears to be the result of a stealth infection process that fails to trigger substantial innate recognition mechanisms while the delay at the cellular level is related to the immunodominance of highly variable gene family proteins, in particular those of the trans-sialidase family. Here we discuss how these previous studies and the new findings herein impact our thoughts on the potential of prophylactic vaccination to serve a productive role in the prevention of T. cruzi infection and Chagas disease.

CD8+ T cells in Trypanosoma cruzi infection

“…Unfortunately, no anti- T. cruzi vaccine developed to date generates immune protection that is as good as, much less better than that achieved by the active infection. We have recently used an infection and cure model to study the development of immune protection in mice infected with fully virulent wild-type T. cruzi followed by drug-induced cure of that infection (38). Previous studies using benznidazole treatment to cure T. cruzi infection in mice demonstrated the development of central memory (Tcm) T cells in the cured mice that were capable of transferring a degree of early protection from T. cruzi infection to recipient mice (26).…”

“…Previous studies using benznidazole treatment to cure T. cruzi infection in mice demonstrated the development of central memory (Tcm) T cells in the cured mice that were capable of transferring a degree of early protection from T. cruzi infection to recipient mice (26). However, subsequent studies employing multiple rounds of infection and drug cure showed that the protection afforded by this “vaccination” protocol (where Tcm CD8 + T cells dominate) was always inferior to that provided by an active chronic infection where T effector (Teff) cells dominate (38). One interpretation of these studies is that the Teff cells in actively infected mice (24, 25) are more protective than the exclusively Tcm CD8 + T cells retained in mice cured of infection.…”

Chagas Disease Diagnostic Applications

“…Both are nitroheterocyclic, oral compounds that require prolonged administration, may display severe adverse effects, cannot be used to treat pregnant women due to their uncertain teratogenic risks and, most importantly, show high efficacy solely if administered at the onset of infection (Carlier and Truyens, 2015; Rassi, Rassi and Marin-Neto, 2010; Viotti et al, 2006). The prospects for the development of an effective vaccine for prophylactic and/or therapeutic purposes, on the other hand are still clouded by substantial scientific and socioeconomic challenges (Beaumier et al, 2016; Bustamante and Tarleton, 2015). …”

Wnt Signalling Orchestrates the Immune Response and Cardiac Damage DuringTrypanosoma cruziInfection

“…Both treatments have several side effects and current data indicate that in established cardiac disease, the treatment unlikely change clinical outcomes (38,39). Thus, drugs inefficiency, the lack of an effective vaccine able to prevent the establishment of the infection and the persistence of insect vector in endemic areas, are all factors that increase the prevalence of the disease (40).…”