Role in pathogenesis and parasite cell biology of the trans-sialidase from Trypan

锥虫转唾液酸酶在发病机制和寄生虫细胞生物学中的作用

基本信息

批准号：
8828547
负责人：
Oscar Eduardo Campetella
金额：
$ 13.32万
依托单位：
INSTITUTE/RESEARCH/BIOTECHNOLOGY FDN
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8828547
关键词：
5&apos Untranslated Regions Antigens Area Argentina Australia Autoimmune Diseases Autoimmunity B-Lymphocytes Biological Biological Assay Biology Blood Circulation Cell Cycle Cell surface Cells Cellular biology Chagas Disease Chemicals Chronic Country Cytolysis Developed Countries Economics Electron Microscopy Enzymes Event Galactose Binding Lectin Galectin 3 Gene Expression Genes Glycobiology Glycoconjugates Goals Graft Rejection Health Immune Immune response Immune system Infection Inflammation Inflammatory Response Japan Kinetics Knowledge Latin America Learning Lectin Leukocytes Life Cycle Stages Link Lymphocyte Mammals Mastigophora Mediating Metabolic Pathway Modeling Molecular Mucins Mus PTPRC gene Parasites Parasitic Diseases Pathogenesis Pathology Pathway interactions Patients Pattern Phenotype Physiological Physiology Process Production Protein Isoforms Proteins Public Health Recombinants Reporter Risk Role Serum Sialic Acids Signal Transduction Site South America Spain Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Staging Surface T-Cell Receptor T-Lymphocyte Testing Th1 Cells Therapeutic Transgenic Mice Transgenic Organisms Transplantation Trypanosoma cruzi Vacuole Variant Virulence Virulence Factors chemotherapy fight against glycosylation migration mouse model neglected tropical diseases neutralizing monoclonal antibodies pathogen response sialylation social sugar tool trafficking trans-sialidase vector

项目摘要

DESCRIPTION (provided by applicant): Chagas disease, the American trypanosomiasis, is a chronic disabling parasitic disease caused by the flagellate protozoon Trypanosoma cruzi. It is considered a neglected tropical disease. With an estimated total of 100 million people at risk, about 8-10 million already infected, and about 40,000 new cases/year, Chagas disease represents a major health, social and economic problem in Latin America. The infection is naturally transmitted by triatomine vectors ("kissing bugs"), from the southern USA to the south of South America. However, chagasic patients are in fact dispersed worldwide due to migration from the endemic region to economically-developed countries. Therefore, Chagas disease is emerging in many non-endemic countries (Australia, Japan, Spain, etc). Infected people in Argentina are estimated at about 1,600,000 and in the USA at about 300,000-1,000,000. Although crucial in its life cycle, T. cruzi is unable to synthesize sialic acids. The parasite scavenges it from the mammalian host glycoconjugates through an enzyme known as trans-sialidase. This enzyme is a shed virulence factor that induces alterations in the host immune system, favoring the parasite colonization process. Our long-term aim is to fully clarify the relevance of this virulence factor to parasite biology, life cycle virulence and pathogenesis, and to understand the alterations induced on the immune system physiology. Understanding the manipulation of the immune response by pathogens allows a better fight against the infection and also helps to learn more about the immune system physiology, and eventually to transfer this knowledge to the therapeutic handling of other pathologies (autoimmune diseases, transplant rejection, inflammatory responses, etc.). This project proposes to disclose the relevance -to pathogenesis and parasite biology, at cellular and molecular levels- of the acquisition process of the sialyl residue performed by the trans-sialidase acceptor molecules on the parasite and lymphocyte surfaces. To achieve these goals we will a) use genetically-modified parasites transfected with modified transporters to accurately determine TS intracellular trafficking; b) follow the unnatural sugars approach as bioorthogonal chemical reporters to clearly identify acceptor molecules and their fate and function on parasite and white cell surfaces; c) search for the induced alterations of known immune responses using T-cell receptor transgenic and KO mice models; and d) test genetically-modified parasites to analyze the association of TS inactive isoforms with virulence factors and pathogenesis.

描述（由申请人提供）：恰加斯病，美洲锥虫病，是一种由鞭毛原生动物克氏锥虫引起的慢性致残性寄生虫病。它被认为是一种被忽视的热带疾病。据估计，南美锥虫病共有 1 亿人面临风险，其中约 8-1000 万人已被感染，每年新增病例约 40,000 例，恰加斯病是拉丁美洲的一个重大健康、社会和经济问题。这种感染通过锥蝽媒介（“接吻虫”）自然传播，从美国南部传播到南美洲南部。然而，由于从流行地区迁移到经济发达国家，恰加斯病患者实际上分散在世界各地。因此，恰加斯病正在许多非流行国家（澳大利亚、日本、西班牙等）出现。阿根廷的感染者估计约为 1,600,000 人，美国约为 300,000-1,000,000 人。尽管克氏锥虫在其生命周期中至关重要，但它无法合成唾液酸。寄生虫通过一种称为反式唾液酸酶的酶从哺乳动物宿主糖复合物中清除它。这种酶是一种脱落的毒力因子，可引起宿主免疫系统的改变，有利于寄生虫的定植过程。我们的长期目标是充分阐明这种毒力因子与寄生虫生物学、生命周期毒力和发病机制的相关性，并了解对免疫系统生理学引起的改变。了解病原体对免疫反应的操纵可以更好地对抗感染，也有助于更多地了解免疫系统生理学，并最终将这些知识转移到其他病理学（自身免疫性疾病、移植排斥、炎症反应）的治疗处理中。， ETC。）。该项目旨在揭示寄生虫和淋巴细胞表面上的转唾液酸酶受体分子所进行的唾液酸残基的获取过程与发病机制和寄生虫生物学在细胞和分子水平上的相关性。为了实现这些目标，我们将 a) 使用经修饰转运蛋白转染的转基因寄生虫来准确确定 TS 细胞内运输； b) 遵循非天然糖方法作为生物正交化学报告分子，以清楚地识别受体分子及其在寄生虫和白细胞表面上的命运和功能； c) 使用 T 细胞受体转基因和 KO 小鼠模型寻找已知免疫反应的诱导改变； d) 测试转基因寄生虫，以分析 TS 无活性亚型与毒力因子和发病机制的关联。