Functional Characterization of the Schistosome Tegument

点击翻译按钮获取中文摘要

Schistosomes are parasitic flatworms that cause a chronic, debilitating disease afflicting >200 million people in >70 countries. The parasites live for years in what should be a very hostile environment – the blood of vertebrates – yet they appear to elicit little if any damaging responses from the host’s hemostatic systems. We hypothesize that proteins at the host-interactive surface, identified in the previous funding cycle, are central to this ability. In this competing renewal, we propose to test several key hypotheses concerning: 1) the hemostatic roles of tegumental ectoenzymes SmNPP5 & SmATPDase in vitro and in vivo, 2) the ability of tegumental ectoenzymes SmAP & NACE to generate key nutrients - adenosine and nicotinamide respectively - that are vital for schistosome survival and growth and 3) the ability of tegumental calpain to impede coagulation, promote thrombolysis and to block local thrombus formation in vivo. These studies aim to reveal the physiological functions of these proteins and will yield significant new information on the molecular mechanisms used by schistosomes to blunt the host thrombotic response while maintaining access to vital nutrients. 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.