MT, but not blood trypomastigotes, have uniquely specialized functions for mucosal invasion and efficiently enter gastric mucosal epithelium (Hoft 1996, Hoft et al. 1996). This is in accord with the notion that metacyclic and bloodstream trypomastigotes are morphologically similar but are physiologically distinct (Tyler and Engman 2001). Hoft (1996) suggested that MT express stage-specific surface molecules required for adhesion to mucosal epithelial surface receptors and/or for penetration of mucin coat. This hypothesis has been supported by results from experiments of oral infection in mice and in vitro cell invasion assays mimicking the in vivo conditions (Neira et al. 2003, Cortez et al. 2003). Based on these data, the following sequence of events can be visualized (Fig. 6). When MT reach the stomach, they resist destruction because they are protected by protease-resistant gp35/50 mucins, which are abundant on the parasite surface. Pepsin digestion leaves intact the gp82 domain containing both the target cell and the gastric mucin-binding sites. The parasites bind to gastric mucin through gp82 (Fig. 6A) and traverse the mucus to reach the underlying epithelial cells. It has as yet to be demonstrated, but it is possible that T. cruzi has mucinase activity, like Entamoeba histolytica, which expresses cyteine proteinases that disrupt the polymeric structure of colonic mucin (Moncada et al. 2003), or Trichomonas vaginalis, which invades vaginal mucous layer by secreting mucinase (Lehker and Sweeney 1999). Preliminary experiments indicate that T. cruzi secrets an enzyme that acts on gastric mucin.
Once the mucous barrier is overcome, MT of T. cruzi isolates such as CL efficiently invade gastric epithelial cells by engaging gp82 (Fig. 6B) and triggering bidirectional Ca2+ response. MT of G isolate may reach the epithelial cells as effectively as the CL isolate MT, but their entry may be impaired by gp90. Some parasites manage to be internalized by engaging gp35/50 (Fig. 6B).
On the other hand, MT of T. cruzi isolatesexpressing gp30, but deficient in gp82, such as 569 and 588, would have difficulty in penetrating the thick mucin coat, because gp30 binds poorly to gastric mucin. Binding to mucin may be critical for the effective action of mucinase inasmuch as, without binding, the enzyme would be secreted into the medium, not onto the mucin layer. The gp82-deficient parasites that manage to translocate through the mucin coat, and reach the epithelial cells, are then internalized in gp30-mediated manner, probably as efficiently as the gp82-expressing MT.