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Background   Trypanosoma cruzi , the agent of Chagas disease, is a protozoan parasite transmitted to humans by blood-sucking triatomine vectors. However, and despite its utmost biological and epidemiological relevance,  T .  cruzi  development inside the digestive tract of the insect remains a poorly understood process.    Methods/Principle findings  Here we showed that Gp35/50 kDa mucins, the major surface glycoproteins from  T .  cruzi  insect-dwelling forms, are involved in parasite attachment to the internal cuticle of the triatomine rectal ampoule, a critical step leading to its differentiation into mammal-infective forms. Experimental evidence supporting this conclusion could be summarized as follows: i) native and recombinant Gp35/50 kDa mucins directly interacted with hindgut tissues from  Triatoma infestans , as assessed by indirect immunofluorescence assays; ii) transgenic epimastigotes over-expressing Gp35/50 kDa mucins on their surface coat exhibited improved attachment rates (~2–3 fold) to such tissues as compared to appropriate transgenic controls and/or wild-type counterparts; and iii) certain chemically synthesized compounds derived from Gp35/50 kDa mucins were able to specifically interfere with epimastigote attachment to the inner lining of  T .  infestans  rectal ampoules in  ex vivo  binding assays, most likely by competing with or directly blocking insect receptor(s). A solvent-exposed peptide (smugS peptide) from the Gp35/50 kDa mucins protein scaffolds and a branched, Gal f -containing trisaccharide (Gal f β1–4[Gal p β1–6]GlcNAcα) from their  O -linked glycans were identified as main adhesion determinants for these molecules. Interestingly, exogenous addition of a synthetic Gal f β1–4[Gal p β1–6]GlcNAcα derivative or of oligosaccharides containing this structure impaired the attachment of Dm28c but not of CL Brener epimastigotes to triatomine hindgut tissues; which correlates with the presence of Gal f  residues on the Gp35/50 kDa mucins’  O -glycans on the former but not the latter parasite clone.    Conclusion/Significance  These results provide novel insights into the mechanisms underlying  T .  cruzi- triatomine interplay, and indicate that inter-strain variations in the  O -glycosylation of Gp35/50 kDa mucins may lead to differences in parasite differentiation and hence, in parasite transmissibility to the mammalian host. Most importantly, our findings point to Gp35/50 kDa mucins and/or the Gal f  biosynthetic pathway, which is absent in mammals and insects, as appealing targets for the development of  T .  cruzi  transmission-blocking strategies.

Trypanosoma cruzi surface mucins are involved in the attachment to the Triatoma infestans rectal ampoule