Pivotal Role of Interleukin-12 and Interferon-γ Axis in Controlling Tissue Parasitism and Inflammation in the Heart and Central Nervous System during Trypanosoma cruzi Infection

Abstract

The role of cytokines in the control of tissue parasitism and pathogenesis of experimental Chagas' disease was investigated. Wild-type and different cytokine as well as inducible nitric oxide synthase (iNOS) knockout mice were infected with the Colombian strain of Trypanosoma cruzi, and the kinetics of tissue parasitism, inflammatory reaction, parasitemia, and mortality were determined. We demonstrate the pivotal role of the interleukin (IL)-12/interferon (IFN)-gamma/iNOS axis and the antagonistic effect of IL-4 in controlling heart tissue parasitism, inflammation, and host resistance to acute infection with T. cruzi. Further, the heart and central nervous system were shown the main sites of reactivation of T. cruzi infection in mice lacking functional genes for IFN-gamma and IL-12, respectively. Our results also show that in contrast to IFN-gamma knockout (KO) mice, splenocytes from IL-12 KO mice infected with T. cruzi produced low levels of IFN-gamma upon stimulation with antigen. Consistently, high levels of anti-T. cruzi IgG2a antibodies were detected in the sera from IL-12 KO, but not from IFN-gamma KO mice, infected with the Colombian strain of T. cruzi. Thus, our results suggest that the level of IFN-gamma deficiency is a major determinant of the site of reactivation of T. cruzi infection in immunocompromised host.

TNF/TNFR1 signaling up-regulates CCR5 expression by CD8+ T lymphocytes and promotes heart tissue damage during Trypanosoma cruzi infection: beneficial effects of TNF-α blockade

“…TNFR1 -/-mice treated from 10-17 dpi with a subcurative dose of Benznidazole survived the acute infection and exhibited reduced heart inflammation during the chronic phase, contrasting with IFN-γ -/-and IL12 -/-mice, which succumbed shortly after treatment cessation with intense parasitemia, parasitism, and inflammatory processes (Michailowsky et al 2001). Therefore, though important, TNF-α is not crucial for the control of parasite dissemination.…”

“…Parasitemia was estimated using 5 µl of blood obtained from the tail vein, and employed as a parameter to establish acute and chronic phases (dos Santos et al 2001). In some experiments, the animals were treated with a subcurative dose of Benznidazole (100 mg/kg/day) from days 10 to 17 after infection (Michailowsky et al 2001).…”

IL-17 Is Necessary for Host Protection against Acute-Phase Trypanosoma cruzi Infection

“…Interestingly, the production of IFN-g, which is a critical cytokine for achieving antitrypanosoma immunity (18,19), was lower in IL-17A 2/2 mice during T. cruzi infection compared with WT mice (Fig. 5A-C).…”

“…Production of IL-12 by macrophages is triggered by the invasion of blood trypomastigotes of T. cruzi early postinfection, and IL-12 induces Th1 differentiation and subsequent IFN-g production (16,17). IFN-g is a critical cytokine in host resistance to T. cruzi infection (18,19); it is produced by NK cells at the early phase of infection and by CD4 + and CD8 + T cells later during the infection (20,21). IFN-g, synergistically with TNF-a, induces NO synthesis by macrophages, a critical mediator for killing of causal organisms during the acute phase of infection (22,23).…”

Immunological and non-immunological effects of cytokines and chemokines in the pathogenesis of chronic Chagas disease cardiomyopathy

“…Upon activation, such cells secrete pro-inflammatory cytokines and chemokines, upregulate expression of co-stimulatory receptors and increase endocytosis and intracellular killing of parasites through release of reactive oxygen and nitrogen species. Pro-inflammatory cytokines, such as IL-1, IL-6, IL-12, IL-18, IL-27, and TNF-α are promptly released, and further activate other inflammatory cells (Michailowsky et al 2001. Macrophages and dendritic cells that have endocytosed the parasite subsequently elicit a strong T cell and antibody response against T. cruzi.…”