Host cell proteins that interact with Cryptosporidium

与隐孢子虫相互作用的宿主细胞蛋白

基本信息

批准号：
7690244
负责人：
GUAN ZHU
金额：
$ 18.31万
依托单位：
TEXAS A&M AGRILIFE RESEARCH
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：
2008-09-25 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7690244
关键词：
Acquired Immunodeficiency Syndrome Animals Apicomplexa Babesia Caco-2 Cells Cattle Cell Cycle Regulation Cell Line Cell Surface Proteins Cell membrane Cell physiology Cells Communication Cryptosporidiosis Cryptosporidium Cryptosporidium parvum Cyclospora Development Diarrhea Disease Eimeria Energy Metabolism Extracellular Matrix Extracellular Matrix Protein Gene Extracellular Matrix Proteins Future Genes Goals Health Human Immunocompromised Host In Vitro Individual Infection Integrins Knowledge Laminin Life Matrix Metalloproteinases Membrane Membrane Proteins Methods Molecular Opportunistic Infections Parasites Pathogenesis Pathway interactions Patients Plasmodium Proteins Reverse Transcriptase Polymerase Chain Reaction Role Signal Transduction Testing Toxoplasma Translations Vacuole base biological adaptation to stress effective therapy in vitro Model knock-down member pathogen public health relevance

项目摘要

DESCRIPTION (provided by applicant): Cryptosporidium parvum is a zoonotic pathogen and can cause one of the opportunistic infections in AIDS patients (AIDS-OI). Because of the lack of highly effective treatment against Cryptosporidium infection and the autoinfection potential of this parasite, cryptosporidiosis in immunocompromised individuals can be prolonged and life-threatening. Despite its globally recognized importance in human and animal health, the pathogenesis of cryptosporidiosis in both humans and animals is still poorly understood. It is particularly unclear how the host cell and parasite interact physically and biochemically with each other during infection. The long-term goal of this project is to elucidate the molecular mechanisms involved in the host-pathogen interactions during the Cryptosporidium infection. Our preliminary analysis has identified a number of genes in human cells that are significantly regulated by the C. parvum infection. One noticeable group of the regulated genes are extracellular matrix (ECM) proteins, including integrin, matrix metalloproteinase (MMP) and laminin, that are likely located at the host cell-parasite interface or around the parasite. Additionally, we have also observed that C. parvum-originated membrane proteins can be targeted to the host cell membranes at the parasite-host boundary and parasitophorous vacuole membrane (PVM), suggesting that both the parasite and host cells actively interact with each other at molecular level. Based on these observations, we hypothesize that host cell proteins are actively involved in the interactions and communications with the intracellular parasite during infection. In this exploratory project, we will test our hypothesis by achieving the following two specific aims: Aim 1) Identify host cell molecules that may directly interact with C. parvum during infection using in vitro models of cryptosporidiosis; and Aim 2) Determine the role of the host cell integrin- associated pathway in the host-pathogen interactions. By achieving aim 1, we will identify a list of important host cell surface proteins, particularly those ECM proteins shared in both human and bovine cells, for future studying their potential interactions with Cryptosporidium during invasion and development. By achieving aim 2, we will confirm or refute our hypothesis that host integrin-associated pathway is indeed participated in the establishment of parasite infection. PUBLIC HEALTH RELEVANCE Cryptosporidium parvum is an untreatable opportunistic pathogen in AIDS patients. Little is known on the pathogenesis of cryptosporidiosis, particularly on how the host cell proteins contribute to the infection by this parasite. This exploratory project aims to identify and study the roles of host cell extracellular matrix proteins in infection. The completion of this project will not increase our knowledge on the cause of disease, but also has the potential to find new targets for intervening cryptosporidiosis for which no treatment is yet available in AIDS patients.

描述（申请人提供）：小隐孢子虫是一种人畜共患病原体，可引起艾滋病患者的机会性感染（AIDS-OI）之一。由于缺乏针对隐孢子虫感染的高效治疗方法以及这种寄生虫的自身感染潜力，免疫功能低下个体的隐孢子虫病可能会持续很长时间并危及生命。尽管隐孢子虫病对人类和动物健康的重要性已得到全球公认，但人类和动物隐孢子虫病的发病机制仍知之甚少。目前还不清楚宿主细胞和寄生虫在感染过程中如何在物理和生化方面相互作用。该项目的长期目标是阐明隐孢子虫感染期间宿主与病原体相互作用的分子机制。我们的初步分析已经确定了人类细胞中的许多基因受到微小念珠菌感染的显着调节。一组值得注意的调节基因是细胞外基质（ECM）蛋白，包括整合素、基质金属蛋白酶（MMP）和层粘连蛋白，它们可能位于宿主细胞-寄生虫界面或寄生虫周围。此外，我们还观察到，微小隐孢子虫来源的膜蛋白可以靶向寄生虫-宿主边界和寄生液泡膜（PVM）的宿主细胞膜，这表明寄生虫和宿主细胞在分子水平。基于这些观察，我们假设宿主细胞蛋白在感染过程中积极参与与细胞内寄生虫的相互作用和通讯。在这个探索性项目中，我们将通过实现以下两个具体目标来检验我们的假设：目标 1) 使用隐孢子虫病体外模型识别在感染过程中可能与微小隐孢子虫直接相互作用的宿主细胞分子；目标 2) 确定宿主细胞整合素相关途径在宿主-病原体相互作用中的作用。通过实现目标 1，我们将确定一系列重要的宿主细胞表面蛋白，特别是在人类和牛细胞中共享的 ECM 蛋白，以便将来研究它们在入侵和发育过程中与隐孢子虫的潜在相互作用。通过实现目标2，我们将证实或反驳我们的假设，即宿主整合素相关途径确实参与了寄生虫感染的建立。公共卫生相关性小隐孢子虫是艾滋病患者中一种无法治疗的机会性病原体。人们对隐孢子虫病的发病机制知之甚少，特别是宿主细胞蛋白如何促进这种寄生虫的感染。该探索性项目旨在识别和研究宿主细胞胞外基质蛋白在感染中的作用。该项目的完成不会增加我们对疾病病因的认识，但也有可能为艾滋病患者尚无治疗方法的隐孢子虫病的干预找到新的靶点。