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Innate immune response in T. cruzi infection

Soluble components of the innate system

When invading its vertebrate host, the parasite is facing soluble microbicidal factors such as the complement system, natural antibodies, and antimicrobial peptides rapidly produced by epithelial cells and infiltrating leucocytes. T. cruzi trypomastigotes and amastigotes activate the lectin and/or the alternative pathways of the complement.4 They however express various molecules rendering them resistant to complement lysis, allowing them to invade cells. Natural antibodies produced by B-1 B cells are also involved in early protection against T. cruzi.5 In humans, part of natural Abs, called anti-Gal Ab, can lyse trypomastigotes by binding to surface a-galactosyl residues.6 Infected epithelial cells rapidly produce the antimicrobial peptide defensin a-1 able to induce irreversible damages to trypomastigotes and amastigotes.7

Innate recognition of T. cruzi infection

Pattern recognition receptors (PRRs) recognize molecular motifs shared by different types of microbes and activate the transcription of genes involved in inflammation and antimicrobial responses.8 TLR2, TLR4 (surface receptors), TLR7, and TLR9 (endosomal receptors) have to date been implicated in the recognition of T. cruzi. TLR2 (in association with TLR6) recognizes the glycosylphosphatidylinositol (GPI) anchors of surface mucins of blood trypomastigotes (tGPI).9 How their lipid moiety buried in the plasma membrane are accessible for TLR recognition is not clear. Structural requirements are incompatible with the site of cleavage by the parasite GPI- PLC, which in addition is not expressed by trypomastigotes.10 tGPI anchors might be released with vesicles shed by trypomastigotes.11 TLR2 also recognizes Tc52 shed by trypomastigotes and amastigotes.12 TLR4 recognizes surface ceramide-containing GPI- anchors known as glycoinositolphospholipids (GIPLs),13 and may also be activated by the parasite trans-sialidase (TS) independently of GIPL recognition.14 TLR7 is involved in T. cruzi recognition, though no more information is available.15 TLR9 recognizes unmethylated CpG sequences of T. cruzi DNA.16

T. cruzi also engages other PRRs such as the surface mannose receptor, the lectin-like receptor mMGL,17 and the cytosolic NLRs NOD-1 and NOD-2.18 The parasites have recently been shown to also activate the inflammasome NLRP3.19

TLRs and NOD-1 significantly contribute to control the acute infection. TLR9 plays a dominant role, TLR2 exerts an activating or immunoregulatory role depending on cell type, while TLR4 seems to play a minor role,13,20-22 whereas the TRIF pathway synergizes with the Myd88 one.23 Importantly, when the parasite invades its vertebrate host, several days are needed before parasite TLR-ligands become available for TLR recognition, delaying potent innate immune recognition.24

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