Impaired Production of Proinflammatory Cytokines and Host Resistance to Acute Infection withTrypanosoma cruziin Mice Lacking Functional Myeloid Differentiation Factor 88

Abstract

Studies performed in vitro suggest that activation of Toll-like receptors (TLRs) by parasite-derived molecules may initiate inflammatory responses and host innate defense mechanisms against Trypanosoma cruzi. 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-α, 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.

MyD88 Plays a Unique Role in Host Defense but Not Arthritis Development in Lyme Disease

“…Several recent reports have explored the defective host defense and inflammatory response to several pathogens in MyD88-deficient mice, including S. aureus, L. monocytogenes, T. gondii, M. tuberculosis, and Trypanosoma cruzi (33)(34)(35)(36)(37)53). Similar to the results presented here, these studies demonstrated increased susceptibility to infection evidenced by an inability of MyD88-deficient mice to control pathogen levels.…”

Lack of antigen-specific Th1 response alters granuloma formation and composition inSchistosoma mansoni-infected MyD88-/- mice

“…In Toxoplasma gondi-, Trypanosoma cruzi-and Leishmania major-infected MyD88 -/-mice, the absence of IFN-c production by primed lymphocytes upon recall with the respective antigen correlated with the failure of APC to produce IL-12 upon co-incubation with protozoan antigens [36][37][38][39]. In a recent study, IL-12 and TNF-a production by DC when co-incubated with whole S.…”

A Cellular Micro-RNA, let-7i, Regulates Toll-like Receptor 4 Expression and Contributes to Cholangiocyte Immune Responses against Cryptosporidium parvum Infection

“…Most TLRs, upon recognition of discrete pathogen-associated molecular patterns, activate a set of adaptor proteins (e.g. myeloid differentiation protein 88 (MyD88)) leading to the nuclear translocation of transcription factors, such as NF-B and AP-1, and thus transcriptionally regulate host-cell responses to pathogens, including parasites (3)(4)(5). TLRs may also recognize endogenous ligands induced during the inflammatory response (1)(2)(3)(4).…”

“…Evidence is accumulating that the signaling pathways associated with TLRs not only mediate host innate immunity but are also important to adaptive immune responses to microbial infection (6). Epithelial cells express TLRs and activation of TLRs triggers an array of epithelial defense responses, including production and release of cytokines/chemokines and anti-microbial peptides (1)(2)(3)(4)(5)(6)(7)(8). Expression of TLRs by epithelia is tightly regulated, reflecting the specific microenvironment and function of each epithelial cell type.…”