Virulence factors in the pathogenesis of Chagas Disease

恰加斯病发病机制中的毒力因素

• 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
• 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

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(申请人提供)：克氏锥虫是恰加斯病或美国锥虫病的病原体。恰加斯病仍然是拉丁美洲每年至少50000人死亡的相关传染病原因，许多青年男子因在农村工作而致残，对其家庭造成很大的经济影响。据估计，已有1800万人感染，1亿人面临感染风险，每年新增病例20万例。这种疾病还会在子宫内传播，并通过受污染的血液传播，从而使感染的风险扩大到流行地区之外。尽管这种寄生虫不能从头合成唾液酸，但它对宿主细胞的附着和入侵以及对血清裂解因子的物理保护依赖于其膜锚定成分的唾液酸化。为了绕过这一缺口，寄生虫在其表面表达一种新的反式唾液酸酶(TS)活性，该活性从宿主糖结合物中清除唾液酸基残基，并用它们来反式糖基化自己的受体分子。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还被释放到血液中。这种系统分布的酶通过诱导免疫系统不同细胞的凋亡、血小板减少和红细胞减少，触发了与疾病急性期相关的几种病理结果。通过中和抗体控制这种毒力因子，可以预防所有这些异常，然后提出一个化疗的靶点。本申请旨在获得对TS在感染过程中所起的多种致病作用的新的细胞和分子方面的见解，并为合理设计可能用于化疗的抑制剂提供线索。作为TS靶标的免疫细胞糖偶联物将通过标记的糖和质谱图进行鉴定，以获得有关细胞机制的知识。修饰的表面分子与内源性配体的相互作用也将导致相关的死亡机制。TS引起的免疫系统损害在正在进行的免疫反应中的反映程度将通过使用卵蛋白特异性TCR转基因小鼠来确定。TS抑制的结构基础将通过与高亲和力中和单抗的二元络合物的3D分辨来分析。公共卫生相关性：恰加斯病是美洲锥虫病，是一种慢性寄生虫病，是拉丁美洲的一个主要健康、社会和经济问题。据估计，克氏锥虫感染的流行率约为1800万例，风险人群增加约1亿人，每年新增病例20万例，约有500万人因恰加斯病而出现临床变化。治疗不令人满意的主要原因是少数可用药物的疗效不确定和严重的不良反应。