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: 8118170
• 负责人: Oscar Eduardo Campetella
• 金额: $ 7.94万
• 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 2013-03-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8118170
• 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; 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洲锥虫病的病原体。在拉丁美洲，恰加斯病仍然是造成死亡的一个相关传染病，每年至少有50 000人死亡，许多青年男子因从事农村工作而致残，对其家庭造成严重的经济影响。据估计，已有1 800万人受到感染，1亿人面临感染风险，每年新增病例20万。该病还可通过子宫和受污染的血液传播，将感染风险扩大到流行地区以外。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溶解因子的物理保护取决于其膜锚定成分的唾液化。为了避免这种间隙，寄生虫在其表面表达一种新的反式唾液酸酶（TS）活性，它清除宿主糖缀合物上的唾液酸残基，并利用它们来反式糖基化其自身的受体分子。没有类似的哺乳动物酶被描述。除了与寄生虫表面相关的作用外，TS还会进入血液。这种全身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，引发与疾病急性期相关的几种病理表现。通过中和抗体来控制这种毒力因子，可以预防所有这些异常，从而为化疗提供了一个靶点。该应用旨在获得新的细胞和分子视角，了解TS在感染过程中所起的多种致病作用，并为合理设计可能用于化疗的抑制剂提供线索。免疫细胞糖缀合物作为TS的靶标将通过标记糖和质谱进行鉴定，以了解所涉及的细胞机制。修饰的表面分子与内源性配体的相互作用导致死亡的相关机制也将被搜索。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应答中，将通过使用卵清蛋白特异性TCR转基因小鼠来确定。通过高亲和中和单克隆抗体的三维分辨率分析TS抑制的结构基础。公共卫生相关性：恰加斯病，即美洲锥虫病，是一种慢性寄生虫病，是拉丁美洲的一个重大卫生、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，另有约1亿人面临感染风险，每年新增病例约20万例，约500万人因恰加斯病出现临床变化。治疗不理想的主要原因是结果不确定和少数可用药物的严重不良反应。

项目成果

Identification of glycoproteins targeted by Trypanosoma cruzi trans-sialidase, a virulence factor that disturbs lymphocyte glycosylation.

克氏锥虫转唾液酸酶（一种干扰淋巴细胞糖基化的毒力因子）靶向的糖蛋白的鉴定。

• DOI: 10.1093/glycob/cwq037
• 发表时间: 2010
• 期刊: Glycobiology
• 影响因子: 4.3
• 作者: Muia,RominaP;Yu,Hai;Prescher,JenniferA;Hellman,Ulf;Chen,Xi;Bertozzi,CarolynR;Campetella,Oscar
• 通讯作者: Campetella,Oscar

Continuous nonradioactive method for screening trypanosomal trans-sialidase activity and its inhibitors.

筛选锥虫转唾液酸酶活性及其抑制剂的连续非放射性方法。

• DOI: 10.1093/glycob/cwq056
• 发表时间: 2010
• 期刊: Glycobiology
• 影响因子: 4.3
• 作者: Sartor,PaulaA;Agusti,Rosalia;Leguizamon,MariaS;Campetella,Oscar;deLederkremer,RosaM
• 通讯作者: deLederkremer,RosaM