Abstract
Host cell invasion and dissemination within the host are hallmarks of virulence for many pathogenic microorganisms. As concerns Trypanosoma cruzi, which causes Chagas disease, the insect vector-derived metacyclic trypomastigotes (MT) initiate infection by invading host cells, and later blood trypomastigotes disseminate to diverse organs and tissues. Studies with MT generated in vitro and tissue culture-derived trypomastigotes (TCT), as counterparts of insect-borne and bloodstream parasites, have implicated members of the gp85/trans-sialidase superfamily, MT gp82 and TCT Tc85-11, in cell invasion and interaction with host factors. Here we analyzed the gp82 structure/function characteristics and compared them with those previously reported for Tc85-11. One of the gp82 sequences identified as a cell binding site consisted of an α-helix, which connects the N-terminal β-propeller domain to the C-terminal β-sandwich domain where the second binding site is nested. In the gp82 structure model, both sites were exposed at the surface. Unlike gp82, the Tc85-11 cell adhesion sites are located in the N-terminal β-propeller region. The gp82 sequence corresponding to the epitope for a monoclonal antibody that inhibits MT entry into target cells was exposed on the surface, upstream and contiguous to the α-helix. Located downstream and close to the α-helix was the gp82 gastric mucin binding site, which plays a central role in oral T. cruzi infection. The sequences equivalent to Tc85-11 laminin-binding sites, which have been associated with the parasite ability to overcome extracellular matrices and basal laminae, was poorly conserved in gp82, compatible with its reduced capacity to bind laminin. Our study indicates that gp82 is structurally suited for MT to initiate infection by the oral route, whereas Tc85-11, with its affinity for laminin, would facilitate the parasite dissemination through diverse organs and tissues.
Highlights
Host cell invasion and dissemination within the host are required for many pathogenic microorganisms to establish infection
P7, the sequence identified as the main gp82 gastric mucin-binding site that is associated with the metacyclic trypomastigotes (MT) capacity to migrate through the gastric mucin layer [4], had its counterpart in Tc85-11 and exhibited five amino acid substitutions, two of which were conservative (Fig. 2C)
Assays were performed in which the ability of MT and tissue culture-derived trypomastigotes (TCT) to traverse a gastric mucin layer was compared
Summary
Host cell invasion and dissemination within the host are required for many pathogenic microorganisms to establish infection. Different pathogens may employ common tactics as well particular strategies for interaction with host components and for cell invasion. Enteropathogenic bacteria rely on their ability to bind to mucins, the main component of the mucus layer that protects the gastrointestinal mucosa, in order to reach the target cells. For instance, adheres preferentially to colonic mucin as the first step to gain access to the colonic epithelial cells, within which it replicates after invasion [1,2]. Trypanosoma cruzi, the protozoan parasite that causes Chagas disease, binds selectively to gastric mucin as a prelude to traverse the mucus layer towards the underlying target cells [4].
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