Trypanosoma cruzi Binds to Cytokeratin through Conserved Peptide Motifs Found in the Laminin-G-Like Domain of the gp85/Trans-sialidase Proteins

Background Chagas' disease, caused by the protozoan parasite Trypanosoma cruzi, is a disease that affects millions of people most of them living in South and Central Americas. There are few treatment options for individuals with Chagas' disease making it important to understand the molecular details of parasite infection, so novel therapeutic alternatives may be developed for these patients. Here, we investigate the interaction between host cell intermediate filament proteins and the T. cruzi gp85 glycoprotein superfamily with hundreds of members that have long been implicated in parasite cell invasion. Methodology/Principal Findings An in silico analysis was utilized to identify peptide motifs shared by the gp85 T. cruzi proteins and, using phage display, these selected peptide motifs were screened for their ability to bind to cells. One peptide, named TS9, showed significant cell binding capacity and was selected for further studies. Affinity chromatography, phage display and invasion assays revealed that peptide TS9 binds to cytokeratins and vimentin, and prevents T. cruzi cell infection. Interestingly, peptide TS9 and a previously identified binding site for intermediate filament proteins are disposed in an antiparallel β-sheet fold, present in a conserved laminin-G-like domain shared by all members of the family. Moreover, peptide TS9 overlaps with an immunodominant T cell epitope. Conclusions/Significance Taken together, the present study reinforces previous results from our group implicating the gp85 superfamily of glycoproteins and the intermediate filament proteins cytokeratin and vimentin in the parasite infection process. It also suggests an important role in parasite biology for the conserved laminin-G-like domain, present in all members of this large family of cell surface proteins.
Author Summary Chagas' disease affects millions of people worldwide and is caused by a microorganism called Trypanosoma cruzi. Treatment options for patients with Chagas' disease is still limited to a small number of drugs, all of them very toxic with important side effects that can be debilitating for the health of patients. Understanding the molecular details of how T. cruzi infects humans is an important step toward the development of new drugs for this disease. As part of its life cycle, T. cruzi has to invade cells in order to replicate and produce new parasites. This is a complex event, which involves different proteins produced by both the parasite and the human host cells. Among them, there is a large family of highly polymorphic T. cruzi proteins important to guide the parasite to the target cells. Here we show that notwithstanding their differences, all members of this family share a small region comprised of nine amino acids that is important for cell recognition and infection by the parasite. Exploring these findings may provide researchers with new insights on how to prevent T. cruzi cell invasion and lead to novel therapeutic alternative for this debilitating disease.