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）：美国锥虫病Chagas病是由鞭毛蛋白酶原生动物锥虫引起的一种慢性残疾寄生疾病。它被认为是一种被忽视的热带疾病。据估计，总共有1亿人处于危险之中，已经感染了约8-1000万，大约有40,000例新病例，恰加斯病代表着拉丁美洲的主要健康，社会和经济问题。感染自然是由从美国南部到南美洲南部的三位角媒介（“接吻虫”）传播的。但是，由于从地方性地区迁移到经济发展的国家，chagasic患者实际上在全球范围内分散。因此，在许多非流行国家（澳大利亚，日本，西班牙等）中，查加斯病正在出现。阿根廷受感染的人估计约为1,600,000，在美国约为300,000-1,000,000。尽管在其生命周期中至关重要，但克鲁齐（T. cruzi）仍无法合成唾液酸。寄生虫从哺乳动物宿主的糖缀合物中清除了它，该酶通过称为跨硅酸盐酶的酶。该酶是促成宿主免疫系统改变的脱落毒力因子，有利于寄生虫定植过程。我们的长期目的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理的相关性，并了解免疫系统生理学的改变。了解病原体对免疫反应的操纵可以更好地抵抗感染，并有助于了解有关免疫系统生理的更多信息，并最终将这些知识转移到其他病理学的治疗处理中（自身免疫性疾病，移植抑制，炎症反应等）。该项目提议在寄生虫和淋巴细胞表面上跨二硅化酶受体分子进行的siALLYL残基的细胞和分子水平上披露与发病机理和寄生虫生物学的相关性。为了实现这些目标，我们将a）使用经过改良转运蛋白转染的遗传改性寄生虫来准确确定TS细胞内贩运； b）遵循非自然的糖接近，作为生物正交化学记者，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小鼠模型搜索已知免疫反应的诱导改变； d）测试遗传改性的寄生虫，以分析TS非活性同工型与毒力因子和发病机理的关联。