Virulence factors in the pathogenesis of Chagas Disease

恰加斯病发病机制中的毒力因素

基本信息

批准号：
7881708
负责人：
Oscar Eduardo Campetella
金额：
$ 8.02万
依托单位：
INSTITUTE/RESEARCH/BIOTECHNOLOGY FDN
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-15 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7881708
关键词：
Acute Adverse effects Affinity Apoptosis Blood Blood Circulation C-terminal Cause of Death Cell surface Cells Cessation of life Chagas Disease Chronic Clinical Communicable Diseases Complex Cytidine Monophosphate N-Acetylneuraminic Acid Cytolysis Cytoplasm Development Disabled Persons Disease Economics Enzymes Event Family Genes Glycobiology Glycoconjugates Goals Health Immune Immune response Immune system Infection Knowledge Latin America Lead Life Cycle Stages Ligands Lymphocyte Lytic Mammals Mass Spectrum Analysis Membrane Molecular Neuraminidase Outcome Ovalbumin Parasites Pathogenesis Pathologic Pattern Peripheral Persons Pharmaceutical Preparations Phase Play Prevalence Prevention Proteins Repetitive Sequence Resistance Resolution Risk Role Rural Serum Sialic Acids Source Surface Thrombocytopenia Toxic effect Transferase Transgenic Mice Trypanosoma cruzi Trypanosoma cruzi trans-sialidase Uterus Vacuole Virulence Factors Work base chemotherapy design economic impact enzyme activity inhibitor/antagonist insight men neutralizing antibody neutralizing monoclonal antibodies novel public health relevance sialylation social sugar thymocyte trans-sialidase

项目摘要

DESCRIPTION (provided by applicant): Trypanosoma cruzi is the causative agent of Chagas disease or American Trypanosomiasis. Chagas Disease continues to be a relevant infectious cause of death in Latin America where at least 50,000 people dies every year and many young men became disabled to rural work with high economic impact to their families. It is estimated that 18,000,000 persons are already infected and 100,000,000 are at risk of infection with 200,000 new cases/year. The disease is also transmitted in uterus and by contaminated blood extending the risk of infection out of the endemic regions. Even though this parasite is unable to synthesize sialic acids de novo, its attachment to, and invasion of host cell as well as its physical protection against serum lytic factors depend upon the sialylation of its membrane-anchored components. To circumvent this gap, the parasite expresses a novel trans-sialidase (TS) activity on its surface, which scavenges sialyl residues from host glycoconjugates and use them to trans- glycosylate its own acceptor molecules. No similar mammal enzyme is described. In addition to the parasite surface-associated role TS is shed into the bloodstream. The systemically distributed enzyme triggers several of the pathologic findings associated to the acute phase of the disease by inducing apoptosis on different cells of the immune system, thrombocytopenia and erythropenia. The control of this virulence factor by neutralizing antibodies results in prevention of all those abnormalities then suggesting a target for chemotherapy This Application points to get novel cellular and molecular insights into the multiple pathogenic roles played by TS during infection and to obtain clues for the rational design of inhibitors that might be used in chemotherapy. The immune cells glycoconjugates involved as targets of the TS will be identified by tagged sugars and mass spectra to gain knowledge on the cellular mechanisms involved. The interaction of the modified surface molecules with the endogenous ligands that leads to the associated mechanisms of death will be also searched. The extent to which the immune system damage induced by the TS is reflected on the ongoing immune response will be determined by using ovalbumin specific TCR transgenic mice. The structural basis of the TS inhibition will be analyzed by the 3D resolution of the binary complex with a high affinity neutralizing monoclonal antibody. PUBLIC HEALTH RELEVANCE: Chagas disease, the American trypanosomiasis, is a chronic parasitic illness that represents a major health, social and economic problem in Latin America. The prevalence of Trypanosoma cruzi infection has been estimated as about 18 million cases, with about 100 million more people at risk and 200,000 new cases/year with about 5 million people having clinical changes attributable to Chagas disease. Treatment is unsatisfactory mainly because dubious outcome and serious adverse effects of the few available drugs.

描述（由申请人提供）：克鲁齐锥虫是chagas病或美国锥虫病的病因。在拉丁美洲，查加斯病仍然是一个相关的传染病死亡原因，每年至少有50,000人死亡，许多年轻人变得残疾，从事对家人的经济影响很大的农村工作。据估计，已经感染了18,000,000人，每年有200,000例新病例感染的风险。该疾病还通过子宫传播，并通过受污染的血液传播，从而扩大了流行区域的感染风险。即使该寄生虫无法合成从头开始的唾液酸，其附着，侵袭宿主细胞及其针对血清裂解因子的物理保护取决于其膜锚定成分的归因性。为了避免这一差距，寄生虫在其表面上表达了一种新型的跨硅酸酶（TS）活性，该酶在其表面上表达了从宿主糖壳中清除siAllyl残基，并使用它们将其转移糖基化其自身的受体分子。没有描述类似的哺乳动物酶。除了寄生虫表面相关的作用外，TS还脱落到血液中。系统分布的酶通过诱导免疫系统，血小板减少症和红细胞减少症的不同细胞的凋亡来触发与疾病急性期有关的几种病理发现。通过中和抗体对这种毒力因子的控制导致预防所有这些异常，然后暗示了化学疗法的靶标这个应用点，以使TS在感染过程中扮演的多种致病作用并获得可能用于化学疗法的抑制剂的新颖性致病作用，从而获得了新颖的细胞和分子见解。标记的糖和质谱将鉴定出涉及TS目标的免疫细胞糖缀合物，以获取有关所涉及的细胞机制的知识。还将搜索改性的表面分子与导致死亡机制的内源配体的相互作用。 TS诱导的免疫系统损伤在正在进行的免疫反应上的程度将通过使用卵蛋白特异性TCR转基因小鼠确定。 TS抑制的结构基础将通过具有高亲和力中和单克隆抗体的二进制复合物的3D分辨率进行分析。公共卫生相关性：美国锥虫病查加斯病是一种慢性寄生疾病，代表了拉丁美洲的主要健康，社会和经济问题。克鲁兹锥虫感染的患病率估计约为1800万例，风险大约有1亿例，每年有200,000例新病例，约有500万人患有临床变化，可归因于夏加斯病。治疗不令人满意，主要是因为少数可用药物的可疑结果和严重的不利影响。