Abstract
ABSTRACTSuccessful infection by Trypanosoma cruzi, the agent of Chagas' disease, is critically dependent on host cell invasion by metacyclic trypomastigote (MT) forms. Two main metacyclic stage-specific surface molecules, gp82 and gp90, play determinant roles in target cell invasion in vitro and in oral T. cruzi infection in mice. The structure and properties of gp82, which is highly conserved among T. cruzi strains, are well known. Information on gp90 is still rather sparse. Here, we attempted to fill that gap. gp90, purified from poorly invasive G strain MT and expressing gp90 at high levels, inhibited HeLa cell lysosome spreading and the gp82-mediated internalization of a highly invasive CL strain MT expressing low levels of a diverse gp90 molecule. A recombinant protein containing the conserved C-terminal domain of gp90 exhibited the same properties as the native G strain gp90: it counteracted the host cell lysosome spreading induced by recombinant gp82 and exhibited an inhibitory effect on HeLa cell invasion by CL strain MT. Assays to identify the gp90 sequence associated with the property of downregulating MT invasion, using synthetic peptides spanning the gp90 C-terminal domain, revealed the sequence GVLYTADKEW. These data, plus the findings that lysosome spreading was induced upon HeLa cell interaction with CL strain MT, but not with G strain MT, and that in mixed infection CL strain MT internalization was inhibited by G strain MT, suggest that the inhibition of target cell lysosome spreading is the mechanism by which the gp90 molecule exerts its downregulatory role.
Highlights
Successful infection by Trypanosoma cruzi, the agent of Chagas’ disease, is critically dependent on host cell invasion by metacyclic trypomastigote (MT) forms
As the low invasion capacity of G strain MT is attributed to its property in downregulating the host cell signaling pathways that lead to lysosome spreading, we asked whether G strain MT could exert an inhibitory effect on CL strain MT internalization in a mixed infection
Our findings indicate that the T. cruzi MT-specific surface molecule gp90 exerts a downregulatory role in parasite internalization mainly through its ability to inhibit host cell lysosome spreading
Summary
Successful infection by Trypanosoma cruzi, the agent of Chagas’ disease, is critically dependent on host cell invasion by metacyclic trypomastigote (MT) forms. Assays to identify the gp sequence associated with the property of downregulating MT invasion, using synthetic peptides spanning the gp C-terminal domain, revealed the sequence GVLYTADKEW These data, plus the findings that lysosome spreading was induced upon HeLa cell interaction with CL strain MT, but not with G strain MT, and that in mixed infection CL strain MT internalization was inhibited by G strain MT, suggest that the inhibition of target cell lysosome spreading is the mechanism by which the gp molecule exerts its downregulatory role. Unknown is the degree of similarity between the diverse gp molecules or whether there is a common motif recognized by target cells To address these questions, we analyzed in this study the structure and properties of gp that are relevant for interaction with host cells and MT invasion
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