Host cell proteins that interact with Cryptosporidium

与隐孢子虫相互作用的宿主细胞蛋白

• 批准号: 7540134
• 负责人: GUAN ZHU
• 金额: $ 21.98万
• 依托单位: TEXAS A&M AGRILIFE RESEARCH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-25 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7540134
• 关键词: Acquired Immunodeficiency Syndrome; Animals; Apicomplexa; Babesia; Bos taurus; 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; Numbers; Opportunistic Infections; Parasites; Pathogenesis; Pathway interactions; Patients; Plasmodium; Propionibacterium acnes; Proteins; Public Health; Reverse Transcriptase Polymerase Chain Reaction; Role; Signal Transduction; Testing; Therapeutic Corynebacterium Parvum; Toxoplasma; Translations; Vacuole; base; biological adaptation to stress; in vitro Model; knock-down; member; pathogen

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（由申请人提供）：隐孢子虫是一种人畜共患病原体，可能引起艾滋病患者的机会性感染之一（AIDS-OI）。由于缺乏针对隐孢子虫感染的高度有效治疗以及该寄生虫的自发性感染潜力，因此可以延长免疫强化病人的隐孢子虫病，并威胁生命。尽管它在人类和动物健康中具有全球认可的重要性，但人类和动物中隐孢子虫病的发病机理仍然很少了解。尤其尚不清楚宿主细胞和寄生虫在感染过程中如何在身体和生物化学上相互作用。该项目的长期目标是阐明隐孢子虫感染期间宿主 - 病原体相互作用所涉及的分子机制。我们的初步分析已经确定了人类细胞中的许多基因，这些基因受parvum C. parvum感染显着调节。一个明显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，帕尔瓦姆梭状芽胞杆菌的膜蛋白可以靶向寄生虫宿主边界的宿主细胞膜和寄生虫液泡膜（PVM），这表明寄生虫和宿主细胞均以分子水平与彼此相互作用。基于这些观察结果，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信。在这个探索性项目中，我们将通过实现以下两个特定目的来检验我们的假设：目标1）确定使用隐孢子虫病的体外模型在感染过程中可能直接与Parvum C. parvum相互作用的宿主细胞分子；目标2）确定宿主细胞整合素途径在宿主 - 病原体相互作用中的作用。通过实现AIM 1，我们将确定重要的宿主细胞表面蛋白的列表，尤其是在人和牛细胞中共有的ECM蛋白，以便将来研究其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，我们将确认或驳斥我们的假设，即宿主结合相关的途径确实参与了寄生虫感染的建立。公共卫生相关性隐孢子虫Parvum是艾滋病患者的一种无法治疗的机会病原体。关于隐孢子虫病的发病机理知之甚少，特别是宿主细胞蛋白如何促进该寄生虫感染。该探索性项目旨在识别和研究宿主细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原因的了解，但也有可能找到用于干预隐孢子虫病的新目标，而艾滋病患者尚无治疗。