Pathogenesis of Trypanosoma cruzi infection

描述(申请人提供)：拉丁美洲与恰加斯病相关的发病率和死亡率超过疟疾、结核病或艾滋病等更广为人知的疾病。数百万人受到这种锥虫病的影响。没有疫苗可以预防这种疾病，药物治疗有严重的副作用，并不完全有效。对这些寄生虫的代谢途径的研究可能对它们的生存至关重要，但可能在它们的宿主中找不到对应的代谢途径，这可能使开发特定的抑制剂成为可能，作为控制寄生虫而不损害宿主的可能手段。克氏锥虫是查加斯病的病原体，其最有趣的特征之一是它拥有两个紧密相关的细胞器，即酸性钙体和收缩空泡。酸性钙体是富含焦磷酸盐(PPI)和聚磷酸盐(POLIP)的酸性钙库。在自由生活的原生动物和利什曼原虫中都存在可收缩的液泡，但在布氏锥虫中没有描述，而在所有锥虫中都存在酸性钙体。我们的初步结果表明，收缩液泡是将对克氏毛滴虫感染致病重要的蛋白质转移到质膜的运输中心。我们已经发现，反式唾液酸酶是通过收缩液泡运输到质膜的，反式唾液酸酶是建立毛滴虫感染机制的重要因素。息肉是由几个到数百个磷酸(PI)残基通过高能磷酸酸酐键连接而成的线性聚合物，从细菌到哺乳动物无处不在。与细菌中几种被认为是息肉的功能不同，这种聚合物在真核细胞中的功能相对来说是未知的。随着这种聚合物对凝血和炎症的强大调节活性的发现，人们对这种分子重新产生了兴趣，因为它在含有息肉的微生物的毒力方面具有潜在的重要性。我们实验室的最新研究结果表明，息肉和/或PPI可能参与了克氏毛滴虫感染的发病机制。我们建议研究酸性钙体和收缩空泡在毛滴虫感染发病机制中的作用。

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.