Pathogenesis of Trypanosoma cruzi infection

描述（由申请人提供）：在拉丁美洲，与恰加斯病相关的发病率和死亡率超过了疟疾、结核病或艾滋病等更知名的疾病。数百万人受到这种锥虫的影响。没有疫苗可以预防这种疾病，药物治疗有严重的副作用，而且不完全有效。研究这些寄生虫的代谢途径可能对它们的生存至关重要，但在它们的宿主中可能找不到相应的代谢途径，这可能使开发特异性抑制剂成为控制寄生虫而不损害宿主的可能手段。克氏锥虫是南美锥虫病的病原体，其最有趣的特征之一是具有两个密切相关的细胞器，即酸钙体和收缩泡。酸钙体是富含焦磷酸盐（PPi）和聚磷酸盐（polyP）的酸性钙储存体。收缩泡存在于自由生活的原生生物中，也存在于利什曼原虫属，但在T.布氏锥虫，而酸钙体存在于所有锥虫。我们的初步结果表明，收缩泡是一个运输枢纽的蛋白质转移的重要性，T。cruzi感染到质膜。我们已经发现，转唾液酸酶，这是建立T。cruzi感染，通过收缩泡运输到质膜。PolyP是由高能磷酸酐键连接的几个到数百个磷酸（Pi）残基的线性聚合物，并且从细菌到哺乳动物无处不在。与细菌中聚P的几种功能相反，这种聚合物在真核细胞中的功能相对不确定。随着这种聚合物对血液凝固和炎症的有效调节活性的发现，人们对这种分子重新产生了兴趣，因为它在含polyP的微生物的毒力中具有潜在的重要性。我们实验室的最新研究结果表明，polyP和/或PPi可能参与了T的发病机制。克氏感染我们拟研究酸钙体和收缩泡在T.克氏感染

DESCRIPTION (provided by applicant): Morbidity and mortality associated with Chagas disease in Latin America exceed better-known conditions such as malaria, tuberculosis, or AIDS. Millions of people are affected by this trypanosomiasis. No vaccines are available to prevent this disease and drug treatments have serious side effects and are not completely effective. The study of metabolic pathways in these parasites that may be essential for their survival but may not find an equivalent counterpart in their host could make possible the development of specific inhibitors as possible means of controlling the parasites without damaging the hosts. One of the most interesting characteristics of Trypanosoma cruzi, the etiologic agent of Chagas disease, is its possession of two closely associated organelles, the acidocalcisomes and the contractile vacuole. Acidocalcisomes are acidic calcium stores rich in pyrophosphate (PPi) and polyphosphate (polyP). The contractile vacuole is present in free-living protists and also in Leishmania spp., but has not been described in T. brucei, while acidocalcisomes are present in all trypanosomatids. Our preliminary results suggest that the contractile vacuole is a trafficking hub for the transfer of proteins important for the pathogenesi of T. cruzi infection to the plasma membrane. We have found that trans-sialidases, which are important for the establishment of T. cruzi infection, are trafficked through the contractile vacuole in their way to the plasma membrane. PolyP is a linear polymer of a few to many hundreds of phosphate (Pi) residues linked by high-energy phosphoanhydride bonds and is ubiquitous from bacteria to mammals. In contrast to several functions ascribed to polyP in bacteria, the functions of this polymer in eukaryotic cells are relatively undefined. With the discovery of the potent modulatory activity of this polymer on blood coagulation and inflammation there has been renewed interest in this molecule as of potential importance in virulence of polyP-containing microorganisms. Recent results from our laboratory suggest that polyP and/or PPi could be involved in the pathogenesis of T. cruzi infection. We propose to study the roles of acidocalcisomes and the contractile vacuole in the pathogenesis of T. cruzi infection.