TLR-Dependent Induction of IFN- Mediates Host Defense against Trypanosoma cruzi (original) (raw)
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TLR-Dependent Induction of IFN-β Mediates Host Defense against Trypanosoma cruzi
Journal of Immunology, 2006
Host resistance to the intracellular protozoan parasite Trypanosoma cruzi depends on IFN-␥ production by T cells and NK cells. However, the involvement of innate immunity in host resistance to T. cruzi remains unclear. In the present study, we investigated host defense against T. cruzi by focusing on innate immunity. Macrophages and dendritic cells (DCs) from MyD88 ؊/؊ TRIF ؊/؊ mice, in which TLR-dependent activation of innate immunity was abolished, were defective in the clearance of T. cruzi and showed impaired induction of IFN- during T. cruzi infection. Neutralization of IFN- in MyD88 ؊/؊ macrophages led to enhanced T. cruzi growth. Cells from MyD88 ؊/؊ IFNAR1 ؊/؊ mice also showed impaired T. cruzi clearance. Furthermore, both MyD88 ؊/؊ TRIF ؊/؊ and MyD88 ؊/؊ IFNAR1 ؊/؊ mice were highly susceptible to in vivo T. cruzi infection, highlighting the involvement of innate immune responses in T. cruzi infection. We further analyzed the molecular mechanisms for the IFN--mediated antitrypanosomal innate immune responses. MyD88 ؊/؊ TRIF ؊/؊ and MyD88 ؊/؊ IFNAR1 ؊/؊ macrophages and DCs exhibited defective induction of the GTPase IFN-inducible p47 (IRG47) after T. cruzi infection. RNA interference-mediated reduction of IRG47 expression in MyD88 ؊/؊ macrophages resulted in increased intracellular growth of T. cruzi. These findings suggest that TLR-dependent expression of IFN- is involved in resistance to T. cruzi infection through the induction of IRG47.
PLoS pathogens, 2010
The murine model of T. cruzi infection has provided compelling evidence that development of host resistance against intracellular protozoans critically depends on the activation of members of the Toll-like receptor (TLR) family via the MyD88 adaptor molecule. However, the possibility that TLR/MyD88 signaling pathways also control the induction of immunoprotective CD8+ T cell-mediated effector functions has not been investigated to date. We addressed this question by measuring the frequencies of IFN-gamma secreting CD8+ T cells specific for H-2K(b)-restricted immunodominant peptides as well as the in vivo Ag-specific cytotoxic response in infected animals that are deficient either in TLR2, TLR4, TLR9 or MyD88 signaling pathways. Strikingly, we found that T. cruzi-infected Tlr2(-/-), Tlr4(-/-), Tlr9(-/) (-) or Myd88(-/-) mice generated both specific cytotoxic responses and IFN-gamma secreting CD8+ T cells at levels comparable to WT mice, although the frequency of IFN-gamma+CD4+ cells ...
Signaling pathways that regulate Trypanosoma cruzi infection and immune response
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2020
Current understanding of key cellular pathways, which are activated by the interaction between T. cruzi and host immunity, is crucial for controlling T. cruzi infection and also for limiting the development of the immunopathological symptoms of Chagas´disease. Here, we focus on recent advances in the knowledge of modulation of innate receptors such as TLRs and NLRs, especially NLRP3, by T. cruzi in different cells of the immune system. On the other hand, the modulation of macrophage activation may be instrumental in allowing parasite persistence and long-term host survival. In this sense, we discuss the importance of the metabolism of two amino acids: L-arginine and tryptophan, and evaluate the role of iNOS, arginase and IDO enzymes in the regulation of innate and adaptive immune response during this infection; and, finally, we also discuss how T. cruzi exploits the AhR, mTOR and Wnt signaling pathways to promote their intracellular replication in macrophages, thus evading the host's immune response.
European Journal of Immunology, 1994
Interleukin-2 (IL-2) gene expression, a critical early event during T lymphocyte activation, is severely suppressed in mice infected with the protozoan parasite Trypanosoma cruzi, the causative agent of human Chagas' disease. Our previous observation that reduction of IL-2 mRNA inT cells from 7: cruzi-infected mice is not due to an increased degradation of the mRNA suggests a repression of the IL-2 gene at the transcriptional level. In this study, we have measured the level of nuclear factors that bind to specific sites on the IL-2 enhancer. Splenocytes and splenicT cells from acutely infected mice show a marked decrease in the level of AP-1, and a modest decrease in the level of NF-xB and nuclear factor of activated T cells (NF-AT). DNA-binding activity of Oct-1 was least affected inT cells from infected mice. Although the basal level of AP-1 activity is comparable in cells from uninfected and infected mice, mitogen-induced AP-1 activation is absent in the cells from 7: cruzi-infected mice. Sodium deoxycholate treatment slightly enhances NF-xB-binding activity in splenocyte nuclear and whole-cell extracts from infected mice, suggesting that a blockage of the activation of NF-xB is only partially responsible for the decrease in the level of NF-xB in T cells from T cruzi-infected mice. These data identify the molecular basis of IL-2 gene regulation in 7: cruzi infection and suggest that T cells are anergized as a result of the infection.
IFN-γ Plays a Unique Role in Protection against Low Virulent Trypanosoma cruzi Strain
PLOS Neglected Tropical Diseases, 2012
Background: T. cruzi strains have been divided into six discrete typing units (DTUs) according to their genetic background. These groups are designated T. cruzi I to VI. In this context, amastigotes from G strain (T. cruzi I) are highly infective in vitro and show no parasitemia in vivo. Here we aimed to understand why amastigotes from G strain are highly infective in vitro and do not contribute for a patent in vivo infection.
International Journal for Parasitology, 2007
Innate and adaptive immunity collaborate in the protection of intracellular pathogens including Trypanosoma cruzi infection. However, the parasite molecules that regulate the host immune response have not been fully identified. We previously demonstrated that the immunisation of C57BL/6 mice with cruzipain, an immunogenic T. cruzi glycoprotein, induced a strong specific T-cell response. In this study, we demonstrated that active immunisation with cruzipain was able to stimulate nitric oxide (NO) production by splenocytes. Immune cells also showed increased inducible nitric oxide synthase protein and mRNA expression. Spleen adherent cells secreted high levels of IFN-c and IL-12. Microbicidal activity in vitro was mainly mediated by reactive nitrogen intermediaries and IFN-c, as demonstrated by the inhibitory effects of NO synthase inhibitor or by IFN-c neutralisation. Specific T-cells were essential for NO, IFN-c and TNF-a production. Furthermore, we reported that cruzipain enhanced CD80 and major histocompatibility complex-II molecule surface expression on F4/80+ spleen cells. Interestingly, we also showed that cruzipain up-regulated toll like receptor-2 expression, not only in F4/80+ but also in total spleen cells which may be involved in the effector immune response. Our findings suggest that a single parasite antigen such as cruzipain, through adaptive immune cells and cytokines, can modulate the macrophage response not only as antigen presenting cells, but also as effector cells displaying enhanced microbicidal activity with reactive nitrogen intermediary participation. This may represent a mechanism that contributes to the immunoregulatory process during Chagas disease. Ó
The Journal of Immunology, 2004
TLRs function as pattern recognition receptors in mammals and play an essential role in the recognition of microbial components. We found that the injection of glycoinositolphospholipids (GIPLs) from Trypanosoma cruzi into the peritoneal cavity of mice induced neutrophil recruitment in a TLR4-dependent manner: the injection of GIPL in the TLR4-deficient strain of mice (C57BL/ 10ScCr) caused no inflammatory response. In contrast, in TLR2 knockout mice, neutrophil chemoattraction did not differ significantly from that seen in wild-type controls. GIPL-induced neutrophil attraction and MIP-2 production were also severely affected in TLR4-mutant C3H/HeJ mice.
The Journal of Immunology, 2004
Here, we evaluated the impact of TLR2 and myeloid differentiation factor 88 (MyD88) deficiencies in host resistance to infection with T. cruzi. Our results show that macrophages derived from TLR2 ؊/؊ and MyD88 ؊/؊ mice are less responsive to GPI-mucin derived from T. cruzi trypomastigotes and parasites. In contrast, the same cells from TLR2 ؊/؊ still produce TNF-␣, IL-12, and reactive nitrogen intermediates (RNI) upon exposure to live T. cruzi trypomastigotes. Consistently, we show that TLR2 ؊/؊ mice mount a robust proinflammatory cytokine response as well as RNI production during the acute phase of infection with T. cruzi parasites. Further, deletion of the functional TLR2 gene had no major impact on parasitemia nor on mortality. In contrast, the MyD88 ؊/؊ mice had a diminished cytokine response and RNI production upon acute infection with T. cruzi. More importantly, we show that MyD88 ؊/؊ mice are more susceptible to infection with T. cruzi as indicated by the higher parasitemia and accelerated mortality, as compared with the wild-type mice. Together, our results indicate that T. cruzi parasites elicit an alternative inflammatory pathway independent of TLR2. This pathway is partially dependent on MyD88 and necessary for mounting optimal inflammatory and RNI responses that control T. cruzi replication during the early stages of infection.