Nonimmune Cells Contribute to Crosstalk between Immune Cells and Inflammatory Mediators in the Innate Response to Trypanosoma cruzi Infection

Abstract

Chagas myocarditis, which is caused by infection with the intracellular parasite Trypanosoma cruzi, remains the major infectious heart disease worldwide. Innate recognition through toll-like receptors (TLRs) on immune cells has not only been revealed to be critical for defense against T. cruzi but has also been involved in triggering the pathology. Subsequent studies revealed that this parasite activates nucleotide-binding oligomerization domain- (NOD-)like receptors and several particular transcription factors in TLR-independent manner. In addition to professional immune cells, T. cruzi infects and resides in different parenchyma cells. The innate receptors in nonimmune target tissues could also have an impact on host response. Thus, the outcome of the myocarditis or the inflamed liver relies on an intricate network of inflammatory mediators and signals given by immune and nonimmune cells. In this paper, we discuss the evidence of innate immunity to the parasite developed by the host, with emphasis on the crosstalk between immune and nonimmune cell responses.

Figure 1

TLR-dependent innate immune responses. T. cruzi-derived components are recognized by TLR2, TLR4, and TLR9, triggering the production of proinflammatory cytokines and microbicidal effectors. Thus, parasite antigens and the cytokines locally released act together to promote the development of protective Th1 response, which lead to parasite growth control. Moreover, TLR2 signaling also has immunoregulatory properties essential to hinder the immune response induced by the parasite. Regarding the T. cruzi entry process, TLR2 but not TLR4 is involved in the activation of Rab-5, fusion of early endosomes, and phagocytosis of trypomastigotes. Furthermore, it is plausible to think that others unexplored TLRs and/or parasite antigens could be involved in the induction of the innate immune responses against T. cruzi.

Figure 2

TLR-independent innate immune responses. Infection triggers increased intracellular Ca²⁺ concentration through interaction of bradykinin with the bradykinin B2 receptor (B2-R) among other mechanisms. Target innate immune cells utilize Ca²⁺ to activate the Ca-dependent signaling pathway leading to the activation of NFATc1. Intracellular T. cruzi is recognized by NOD1, activating NF-κB. T. cruzi is also recognized by unknown molecules leading to the activation of TBK1 and IRF3. Altogether the mechanisms participate in the induction of an effective immune response against the parasite.

Figure 3

Comparative analysis of hepatic injury, inflammation and TLR expression in Trypanosoma cruzi-infected B6 and BALB/c mice. The parasitemia was higher in BALB/c than B6 mice. However infected B6 mouse strain showed stronger and injurious inflammatory environment (increased NO and ROS) associated with high levels of TLR2, TLR4, and TLR9 in hepatic leukocytes. In contrast, BALB/c mice displayed more balanced proinflammatory/immunoregulatory cytokines profile during the acute infection. Furthermore, TLR2 and TLR4 were upregulated in infiltrating leukocytes and hepatocytes as well, while TLR9 expression was low in hepatic leukocytes of infected BALB/c mice. Altogether the results suggested that the strong inflammatory environment elicited in infected B6 mice plus the loss of TLR2 signaling may be responsible for the severity of the hepatic injury and higher mortality of this mouse strain [19, 23].