The Immune Response to Trypanosoma cruzi: Role of Toll-Like Receptors and Perspectives for Vaccine Development

Abstract

In the past ten years, studies have shown the recognition of Trypanosoma cruzi-associated molecular patterns by members of the Toll-like receptor (TLR) family and demonstrated the crucial participation of different TLRs during the experimental infection with this parasite. In the present review, we will focus on the role of TLR-activated pathways in the modulation of both innate and acquired immune responses to T. cruzi infection, as well as discuss the state of the art of vaccine research and development against the causative agent of Chagas disease (or American trypanosomiasis).

Figure 1

T. cruzi-derived PAMPs are recognized by different TLRs. The recognition of different T. cruzi molecules, like parasite surface glycoconjugates and nucleic acids, occurs through distinct Toll-like receptors, which are localized at the cellular plasma or endoplasmic membranes, respectively, and are differentially expressed by various innate immune cell types. GPI anchors of mucin-like glycoproteins activate TLR2/TLR6 heterodimer, GIPL is an agonist for TLR4, genomic DNA activates endosomal TLR9, and TLR7 is involved in parasite RNA recognition. TLRs induce NF-κB and/or IRFs activation via their interaction with different TIR domain-containing adaptor molecules. Of these, MyD88 and Mal/TIRAP are required for TLR2 and TLR4 activation of NF-κB. In a MyD88-independent way, TRIF and TRAM signal downstream TLR4, activating IRF3. TLR7 and TLR9 activate NF-κB and IRF7 via MyD88. NF-κB activation leads to proinflammatory cytokines production, such as TNF-α and IL-12, whereas IRFs are required for type I IFN gene transcription.