Immunoregulation of cellular immunity and tissue homeostasis during Chagas' disease

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PROJECT SUMMARY/ABSTRACT Chagas disease, caused by the protozoan Trypanosoma cruzi, is endemic in Latin America but cases are increasing in non-endemic countries, becoming a global concern. It affects 6 million people and imposes a major economic burden due to early mortality and physical disabilities. Disease progression, from symptomless to severe, is linked to parasite heterogeneity and a variable host immune response. Development of robust CD8+ T cell immunity is a key element of host resistance and T. cruzi persistence and chronic Chagas disease has been associated to suboptimal CD8+ T cell responses. Despite this, the knowledge about pathways that promote robust protective CD8+ T cell immunity to T. cruzi remains incomplete and for instance, the metabolic hurdles faced by effector CD8+ T cells for expansion and differentiation have been barely explored. Also, the progression of T. cruzi infection is thought to be significantly modulated by regulatory immune responses that limit parasite-specific immunity as well as infection-associated immunopathology by mechanisms poorly understood. In this context, defining how effector and regulatory pathways intertwined to allow the generation of optimal cellular immunity against T. cruzi preserving of tissue homeostasis is crucial to understand Chagas disease pathogenesis. In this direction, our published data showed that Treg cells became activated during T. cruzi infection and acquired phenotypic attributes that markedly changed along the infection. Thus, Treg cells acquired features linked to the regulation of type 1 responses and limited CD8+ T cell immunity during the infection acute phase, likely delaying parasite control and favoring chronicity. In contrast, preliminary data demonstrate that Treg cells with tissue repair ties, which were disfavored during the acute phase, accumulated during the chronic phase in nonlymphoid tissues considered targets of T. cruzi and reduced tissue damage. Altogether, our findings highlight numerous changes in the phenotypic and functional profile as well as main location of specialized Treg cells in the transition from acute to chronic phase, suggesting that Treg cell roles switch from deleterious to protective in the course of this infection. A comprehensive characterization of phenotype, function and transcriptional program of Treg cells in different tissues, together with the manipulation of this regulatory subset by different strategies will allow us to define the mechanisms underlying Treg cell mediated regulation of effector immunity and immunopathology in acute and chronic experimental T. cruzi infection. These approaches will guide our evaluation of effector and regulatory pathways and their association to the clinical severity in samples of patients with chronic Chagas disease in order to translate our finding to human health. Altogether, our studies will provide meaningful data about different interacting pathways and, possibly, new mediators that participate in the regulation of effector cellular immunity to T. cruzi and the development of chronic pathology. This information will identify potential new targets for the rational design of therapies for Chagas´ disease and, likely, other chronic infections.