Pathogenesis of Trypanosoma cruzi infection

描述（由申请人提供）：拉丁美洲与恰加斯病相关的发病率和死亡率超过了众所周知的疾病，如疟疾、结核病或艾滋病。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，而且不是完全有效。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。恰加斯病的病原克氏锥虫最有趣的特征之一是它拥有两个密切相关的细胞器，即酸球体和可收缩的液泡。酸钙体是富含焦磷酸盐（PPi）和聚磷酸盐（polyP）的酸性钙储存体。可收缩的液泡存在于自由生活的原生生物和利什曼原虫中，但在布鲁氏T.中未被描述，而酸球体存在于所有锥虫中。我们的初步结果表明，可收缩的液泡是将克氏锥虫感染致病蛋白转移到质膜的运输枢纽。我们发现反式唾液酸酶在克氏t型病毒感染中起着重要的作用，通过收缩液泡转运到质膜。PolyP是一种由几个到几百个磷酸（Pi）残基通过高能磷酸酐键连接而成的线性聚合物，从细菌到哺乳动物都普遍存在。与在细菌中归因于polyP的几种功能相反，这种聚合物在真核细胞中的功能相对不明确。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，人们对这种分子在含有poly的微生物的毒力中具有潜在的重要性重新产生了兴趣。我们实验室最近的结果表明，息肉和/或PPi可能参与克氏锥虫感染的发病机制。我们建议研究酸细胞体和收缩液泡在克氏锥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.