Increased Susceptibility of Stat4-Deficient and Enhanced Resistance in Stat6-Deficient Mice to Infection withTrypanosoma cruzi

Abstract

Although Th1-type responses tend to be associated with resistance to Trypanosoma cruzi infection, mixed Th1 and Th2 cytokine responses are generally observed in both resistant and susceptible mice. To help clarify the role of type 1 and type 2 cytokine responses in immunity to T. cruzi, mice with induced deficiencies in the Stat4 or Stat6 genes were infected with T. cruzi. As expected, Stat4−/− mice deficient in type 1 cytokine responses were highly susceptible to infection, exhibiting increased parasitemia levels relative to wild-type mice and 100% mortality. In contrast, parasitemia levels and survival in Stat6-deficient mice were not different from wild type. The type 1 and type 2 cytokine bias of Stat6- and Stat4-deficient mice, respectively, was confirmed by in situ immunocytochemical analysis of cytokine-producing cells in the tissues of infected mice and by subclass analysis of anti-T. cruzi serum Abs. Notably, both Stat4- and Stat6-deficient mice produced substantial amounts of anti-T. cruzi Abs. Tissues from chronically infected Stat6-deficient mice had little to no evidence of inflammation in the heart and skeletal muscle in contrast to wild-type mice, which exhibited substantial inflammation. In situ PCR analysis of these tissues provided evidence of the persistence of T. cruzi in wild-type mice, but no evidence of parasite persistence in Stat6-deficient mice. These data suggest that type 1 T cells are required for the development of immune control to T. cruzi, but that type 2 T cells contribute to parasite persistence and increased severity of disease.

Antigen-Specific Th1 But Not Th2 Cells Provide Protection from Lethal Trypanosoma cruzi Infection in Mice

“…This conclusion is supported by the recent results of Hoft et al (48) demonstrating that immunization of mice under conditions that promote a Th1 response results in protection from challenge infection with T. cruzi. In addition, these results confirm and extend the findings from our laboratory that mice lacking the ability to produce Th2 responses (as a result of targeted knock-of the stat6 gene) develop highly efficient immune responses and less sever disease than wild-type mice (61). Thus, Th2 responses are not necessary and in fact are deleterious in the response to T. cruzi.…”

Immunization with recombinant paraflagellar rod protein induces protective immunity against Trypanosoma cruzi infection

“…Conversely, addition of exogenous IFN-␥ during infection has been shown to ameliorate disease [7]. More recently, it has been shown that mice incapable of developing Th2 immune responses exhibit reduced cardiac pathology from T. cruzi infection compared to animals that may develop a mixed Th1/Th2 response [30], suggesting that a highly polarized Th1 immune response, such as that induced by rPFR immunization, is preferable.…”

Importance of CD8 T cell-mediated immune response during intracellular parasitic infections and its implications for the development of effective vaccines

“…IFN-γ is an important mediator of naturally acquired immunity against the infection. Genetically deficient mice that do not express the IFN-γ receptor or Stat4 are unable to control T. cruzi infection (Holscher et al 1998, Tarleton et al 2000. However, a direct link between IFN-γ secretion by CD8 T cells and the in vivo antiparasitic activity of these cells has not been provided so far.…”