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Abstract
The prolonged persistence of Trypanosoma cruzi in most infected hosts, despite highly functional parasite-specific immune responses, signifies the remarkable success of this parasite in evading immune destruction. One potential strategy that favors the persistence of T. cruzi is its failure to trigger pathogen pattern recognition sensors upon host cell invasion. Activation of innate host sensors by pathogens is the earliest response of hosts to infection and is crucial to driving and directing the pathogen control immune program. Host cell invasion by T. cruzi is accompanied by a limited induction of an almost exclusively type I interferon (IFN-I) dependent response, which drives a modest activation of IFN-I dependent genes. The first part of this thesis demonstrates that T. cruzi- driven IFN-I production is dependent on the activation of cGAS-STING cytosolic DNA sensing pathway in host cells, though the parasite stimulus for pathway activation was not identified. At the initial site of infection in the skin, STING activation and IFN-I production promoted parasite expansion. In skeletal muscle tissue, the primary sites of T. cruzi persistence, STING activation was inconsequential while in cardiac tissue STING activation contributed to acute parasite control independently of IFN-I, together displaying a tissue-dependent impact of STING on the infection outcome. Although innate immune recognition is essential to initiate immune control, adaptive responses are generally required to control and eliminate pathogens. T. cruzi persistence is also likely enabled by the generation of CD8+ T cell responses that are largely focused on a few epitopes, including those encoded by the the strain variant trans-sialidase genes. The second part of this thesis reports the characterization of a newly described immunodominant response in infected C57BL/6 mice against the peptide MUCKb25, an epitope within a predicted glycosylphosphatidylinositol signal sequence of members of the large mucin family of proteins. Like previously identified immunodominant responses in T. cruzi infection, the MUCKb25-specific response does not appear to contribute strongly to immune control of the infection as deletion of the response in mice failed to alter the course of the infection. Together this thesis work demonstrates that through the combination of stealth invasion and eliciting CD8+ T cell responses that are largely focused on epitopes that are non-protective, T. cruzi can potentially evade immune detection and resist complete immune clearance.