Enhancing immunity to Trypanosoma cruzi with transgenic expression of exogenous PAMPs and endogenous parasite proteins
Kurup, Samarchith P.
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Trypanosoma cruzi establishes an indefinitely persistent infection in mammalian hosts and causes Chagas disease in humans. Adaptive cell mediated immune responses- including CD8+ T cell responses- are critical in controlling this infection, making it a priority in the field to understand the dynamics of this response and ways to manipulate immune responses to potentially clear the infection. Compared to most other pathogens, T. cruzi has a relative deficiency in the expression of immunologically relevant pathogen associated molecular patterns (PAMPs), the molecules that allow the innate immune system to detect and initiate responses to invading pathogens. This relative absence of PAMPs in T. cruzi may aid in its ability to establish and persist in hosts. Heterologous expression of bacterial PAMPs in T. cruzi led to a more rapid and consistently stronger adaptive immune responses. Although co-inoculating with, or temporarily anchoring exogenous PAMPs on T. cruzi also resulted in initially stronger parasite-specific CD8+ T cell responses, only the continuous expression of heterologous PAMPs sustained these responses and ultimately resulted in clearance of the infection. However, the CD8+ T cell responses in T. cruzi infection are often directed at members of large gene families, including trans-sialidase-like proteins that are highly diverse and vary widely among T. cruzi strains. We hypothesized that CD8+ T cell responses directed against sub-dominant, invariant, non gene-family proteins may impart better cross-strain protection from T. cruzi infection. On observing that T. cruzi sacrifices its flagellum during entry of host cells, transgenic T. cruzi over-expressing the abundant flagellar protein PAR4 were generated, that induced stronger and more effective PAR4-specific CD8+ T cell response, conferring better protection from subsequent T. cruzi challenges. These findings demonstrate that, the efficiency and strength of specific immune responses may be affected at and beyond their initiation by PAMPs, as well as by the over-expression of chosen target epitopes, to effect the overall improved immune control of a pathogen.