Regulatory role of Toll-like receptor 2 during infection with Trypanosoma cruzi

Previous studies have emphasized the role of Toll-like receptors (TLRs) and myeloid differentiation factor 88 (MyD88) during infection with protozoan parasites. TLR2 was shown to be important for induction of cytokine synthesis by macrophages exposed to the purified glycosylphosphatidylinositol (GPI)-anchored mucin-like glycoproteins of Trypanosoma cruzi trypomastigotes (tGPIm). On the other hand, MyD88(-/-) mice, but not TLR2(-/-) mice, showed impaired cytokine production and resistance to infection with T. cruzi parasites. Here we evaluate the importance of MyD88 and TLR2 in MAPK activation and cytokine synthesis by macrophages exposed to live T. cruzi parasites and compared to tGPIm. The absence of MAPK phosphorylation in TLR2- and MyD88-deficient macrophages exposed to tGPIm correlated with the incapacity to induce cytokine release in these cells. In contrast, activation of MAPK and synthesis of pro-inflammatory cytokines were not abrogated in TLR2-deficient macrophages exposed to live T. cruzi parasites. We also showed that pretreatment with tGPIm significantly reduces cytokine release by macrophages in response to T. cruzi in a TLR2-dependent manner. Consistently, TLR2(-/-) mice were shown to produce enhanced levels of cytokines upon in vivo challenge with T. cruzi parasites. Together, these results suggest the involvement of additional TLR(s) in the pro-inflammatory response of macrophages to whole parasites, and that, in vivo, TLR2 may have a predominant immunoregulatory role during acute infection with T. cruzi parasites.