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：
7656872
负责人：
Oscar Eduardo Campetella
金额：
$ 8.1万
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/7656872
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）：克氏锥虫是恰加斯病或美洲锥虫病的病原体。恰加斯病仍然是拉丁美洲相关的传染病死亡原因，每年至少有 50,000 人死亡，许多年轻人无法从事农村工作，这对其家庭造成了巨大的经济影响。据估计，已有 18,000,000 人被感染，1 亿人面临感染风险，每年新增病例 200,000 例。该疾病还在子宫内传播，并通过受污染的血液传播，从而增加了流行地区感染的风险。尽管这种寄生虫无法从头合成唾液酸，但其对宿主细胞的附着和入侵以及其针对血清溶解因子的物理保护取决于其膜锚定成分的唾液酸化。为了规避这一间隙，寄生虫在其表面表达一种新型的转唾液酸酶（TS）活性，该酶从宿主糖缀合物中清除唾液酸残基，并利用它们对其自身的受体分子进行转糖基化。没有描述类似的哺乳动物酶。除了与寄生虫表面相关的作用外，TS 还会流入血流中。全身分布的酶通过诱导免疫系统不同细胞凋亡、血小板减少症和红细胞减少症，引发与疾病急性期相关的一些病理结果。通过中和抗体控制这种毒力因子，可以预防所有这些异常，然后提出化疗靶点。本申请指出，可以对 TS 在感染过程中发挥的多种致病作用获得新的细胞和分子见解，并获得合理设计的线索可能用于化疗的抑制剂。作为 TS 靶标的免疫细胞糖缀合物将通过标记糖和质谱进行识别，以获得有关细胞机制的知识。还将研究修饰的表面分子与内源性配体的相互作用，从而导致相关的死亡机制。 TS 诱导的免疫系统损伤在多大程度上反映在正在进行的免疫反应上，将通过使用卵清蛋白特异性 TCR 转基因小鼠来确定。 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元复合物的 3D 分辨率进行分析。公共卫生相关性：查加斯病（美洲锥虫病）是一种慢性寄生虫病，是拉丁美洲的一个重大健康、社会和经济问题。据估计，克氏锥虫感染的患病率约为 1800 万例，其中约 1 亿人处于危险之中，每年新增 20 万例，其中约 500 万人因恰加斯病而出现临床变化。治疗效果不理想主要是因为少数可用药物的结果可疑且副作用严重。