Functional Characterization of the Schistosome Tegument

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 DESCRIPTION (provided by applicant): Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting over 200 million people in over 70 countries. The parasite live for years, sometimes decades, in what should be a very hostile environment - the blood of vertebrates - yet they appear to elicit little if any overt reaction from the host's hemostatic system. We hypothesize that proteins at the host-interactive surface, identified in the previous funding cycle, are central to the parasites ability to impede host hemostasis. In this competing renewal, we propose to test several key hypotheses concerning: 1) the role of tegumental ecto-enzymes in blocking platelet activation and aggregation, 2) the ability of tegumental protease(s) to cleave key coagulation proteins, and 3) the role of tegumental plasminogen-binding proteins in activating plasmin and promoting thrombolysis. These studies will yield significant new information on the molecular mechanisms used by schistosomes to blunt the host thrombotic response. In addition, the work may identify tegumental proteins critical for parasite survival leading to subsequent screens to discover potential schistosome-killing drugs that inhibit these molecules and/or to trials testing their vaccine potential. In this way, our planned experiments have the potential to reveal novel and valid targets, as well as new treatments, for intervention in a parasite that remains a widespread and major cause of human disease. Additionally, given wide interest in understanding the mechanisms governing coagulation control, knowing how schistosomes regulate this process will be of keen interest beyond the field of eukaryotic pathogen research.