Role in pathogenesis and parasite cell biology of the trans-sialidase from Trypanosoma cruzi, the agent of Chagas Disease

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Project Summary Chagas disease affects an estimate of 1,600,000 people in Argentina. This chronic disabling disease also constitutes a major health issue in Latin America. Its causative agent, the protozoan flagellate Trypanosoma cruzi, expresses a virulence factor known as trans-sialidase (TS) that cover the inability of the parasite to perform sialic acids synthesis de novo. TS transfer the sialyl residue from the mammal host proteins to the parasite surface, thus preventing its lysis by serum components and enabling the parasite to invade cells where to replicate. This virulence factor is also shed to the milieu being found in the bloodstream thus acting far from the infectious site/s. TS induce several alterations on the immune system including apoptosis of cellular components and modulation of CD4 T cells both at their elicitation and effector stages. We recently defined the distribution of the parasite surface protein components where the TS and mucins, the main acceptor of the sialyl residue transferred, are located in separate domains. Similarly happens with other unrelated proteins. Some proteins use the contractile vacuole as a pathway to reach the surface while others not. In this project, we propose to study the protein requirements to use this trafficking pathway, or been excluded from it, and the process associated with their final fate on different domains at the parasite surface. Because the TS constitute a central virulence factor of the parasite we will obtain parasites devoid of its expression to assess their ability to invade cells, replicate and induce pathogenesis in mammals. The ability of TSs to modulate the TH1/TH2/TH17 balance will be analyzed at the light of recent findings from our lab that might explain previous results from other researchers and been associated with the outcome of the infection.