Pathogenesis of Trypanosoma cruzi infection

克氏锥虫感染的发病机制

基本信息

批准号：
8710952
负责人：
ROBERTO DOCAMPO
金额：
$ 35.02万
依托单位：
UNIVERSITY OF GEORGIA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-15 至 2014-09-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8710952
关键词：
Acquired Immunodeficiency Syndrome Address Adverse effects Affect Animals Bacteria Blood coagulation Calcium Cations Cell membrane Chagas Disease Characteristics Complex Cyclophosphamide Development Diphosphates Disease Drug Targeting EF Hand Motifs Enzymes Eukaryotic Cell Immunosuppression In Vitro Infection Inflammation Laboratories Latin America Leishmania Length Life Link Malaria Mammals Metabolic Pathway Molecular Chaperones Morbidity - disease rate Mus Organelles Osmoregulation Parasite Control Parasitemia Parasites Pathogenesis Pharmaceutical Preparations Polymers Polyphosphates Polyps Proteins Regulation Role Stress Trypanosoma brucei brucei Trypanosoma cruzi Trypanosomiasis Tuberculosis Vaccines Vacuole Virulence in vivo inhibitor/antagonist inorganic phosphate interest microorganism mortality mouse model mutant overexpression prevent pyrophosphatase research study trafficking uptake water channel

项目摘要

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.

描述（由申请人提供）：拉丁美洲与夏加斯病有关的发病率和死亡率超过了疟疾，结核病或艾滋病等众所周知的疾病。数以百万计的人受到这种锥虫病的影响。没有疫苗可预防这种疾病，药物治疗具有严重的副作用，并且没有完全有效。这些寄生虫中代谢途径的研究可能对它们的生存至关重要，但可能没有发现其宿主中的同等对应物可以使特定抑制剂的发展成为可能控制寄生虫而不会损害宿主的方法。 Cruzi的最有趣的特征之一是Chagas疾病的病因学剂，它拥有两个密切相关的细胞器，即酸离子，酸离子和收缩液泡。酸性钙的酸性钙储存富含焦磷酸（PPI）和聚磷酸盐（息肉）的酸性钙。收缩液泡存在于自由生存的生物中，也存在于利什曼尼亚属中，但尚未在t. brucei中进行描述，而所有锥虫中都存在酸离子。我们的初步结果表明，收缩液泡是转移蛋白质对Cruzi感染的病原体至关重要的蛋白质的贩运中心。我们发现，对于建立克鲁兹感染至关重要的跨硅酸盐酶在通往质膜的路上被收缩液泡贩运。息肉是数百至数百种磷酸盐（PI）残基的线性聚合物，这些残基由高能磷酸甘蔗键键连接，并且从细菌到哺乳动物无处不在。与细菌中息肉归因于息肉的几个功能相反，该聚合物在真核细胞中的功能相对不确定。随着该聚合物对血液凝结和炎症的有效调节活性的发现，对该分子的兴趣重新引起了人们对含息肉微生物的毒力的重要性。我们实验室的最新结果表明，息肉和/或PPI可能参与t. cruzi感染的发病机理。我们建议研究酸性藻异构体的作用和收缩液泡在T. Cruzi感染的发病机理中的作用。