Abstract
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects several million people in Latin America. Myocarditis, observed during both the acute and chronic phases of the disease, is characterized by an inflammatory mononuclear cell infiltrate that includes CD4+ T cells. It is known that Th1 cytokines help to control infection. The role that Treg and Th17 cells may play in disease outcome, however, has not been completely elucidated. We performed a comparative study of the dynamics of CD4+ T cell subsets after infection with the T. cruzi Y strain during both the acute and chronic phases of the disease using susceptible BALB/c and non-susceptible C57BL/6 mice infected with high or low parasite inocula. During the acute phase, infected C57BL/6 mice showed high levels of CD4+ T cell infiltration and expression of Th1 cytokines in the heart associated with the presence of Treg cells. In contrast, infected BALB/c mice had a high heart parasite burden, low heart CD4+ T cell infiltration and low levels of Th1 and inflammatory cytokines, but with an increased presence of Th17 cells. Moreover, an increase in the expression of IL-6 in susceptible mice was associated with lethality upon infection with a high parasite load. Chronically infected BALB/c mice continued to present higher parasite burdens than C57BL/6 mice and also higher levels of IFN-γ, TNF, IL-10 and TGF-β. Thus, the regulation of the Th1 response by Treg cells in the acute phase may play a protective role in non-susceptible mice irrespective of parasite numbers. On the other hand, Th17 cells may protect susceptible mice at low levels of infection, but could, in association with IL-6, be pathogenic at high parasite loads.
Highlights
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects approximately 10–12 million people in Latin America and kills more than 15000 each year, representing a major cause of morbidity and mortality in this region [1]
C57BL/6, but not BALB/c mice, showed an efficient clearance of heart parasites by day 17 postinfection. These differences in parasite load and control in the heart may explain the differences in survival between these mouse strains, which agrees with previous results indicating that C57BL/6 are more resistant than BALB/c to infection with the Y parasite strain [24]
The identification of the key factors that determine survival of T. cruzi infection in mice as well as the mechanisms controlling infection in the asymptomatic chronic phase of the infection is crucial in order to develop novel strategies to fight Chagas disease
Summary
Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, affects approximately 10–12 million people in Latin America and kills more than 15000 each year, representing a major cause of morbidity and mortality in this region [1]. T. cruzi has a complex life cycle involving several stages in both vertebrates and insect vectors. It infects and replicates in both macrophages and cardiomyocytes as well as many other cell types. Regulatory T (Treg) cells may help to control T cell responses during infection. Treg cells can be generated in the presence of interleukin (IL)-2 and transforming growth factor (TGF)-b or as induced (i)Treg cells in response to infection by microorganisms. T helper (Th) cells characterized by IL-17 production, are pro-inflammatory cells associated with autoimmune diseases [12] Reciprocal developmental pathways have been described for the generation of both Treg and Th17 cells, with Th17 requiring both TGF-b and IL-6 for differentiation [13]
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