A natural host model for microsporidia pathogenesis in the intestine

肠道微孢子虫发病机制的自然宿主模型

• 批准号: 8204946
• 负责人: Emily R Troemel
• 金额: $ 38.24万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-15 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8204946
• 关键词: Acquired Immunodeficiency Syndrome; Address; Animal Model; Animals; Binding; Biochemical; Biological Process; Caenorhabditis; Caenorhabditis elegans; Cell physiology; Cells; Cellular Structures; Cessation of life; Characteristics; Child; Complement; Cues; Detection; Development; Diarrhea; Disease; Epidemic; Epithelial Cells; Fingers; Genes; Genetic; Genome; Genomics; Goals; Human; Image; Imaging Device; Immune; Immune response; Infection; Infection Control; Internet; Intestines; Invaded; Label; Libraries; Life; Medical; Microsporidia; Mission; Modeling; Molecular; Names; Natural Resistance; Natural regeneration; Nematoda; Organ; Parasites; Paris, France; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Physiological; Plague; Predisposition; Property; Proteins; RNA Interference; Reproduction spores; Research; Resistance; Resistance to infection; Signal Pathway; Staging; Structure; Subcellular structure; System; Techniques; Testing; Transgenic Organisms; Transplant Recipients; Variant; cellular microvillus; defense response; fungus; in vivo; innovation; insight; molecular imaging; novel; pathogen; public health relevance

DESCRIPTION (provided by applicant): The primary goal of this project is to understand how microsporidia cause disease. Microsporidia are eukaryotic intracellular pathogens that can infect a wide variety of hosts but are poorly understood. These pathogens can cause serious infections in humans, particularly in AIDS patients. Understanding the pathogenic properties of microsporidia is relevant to the NIH's mission because it promises to help reduce the burden of human illness. Very little is known about the molecular interactions between microsporidia and their host intestinal cells, although several observations suggest that there is an intimate dynamic between them. Our long-term goal is to better understand the strategies that microsporidia use to exploit host intestinal cells, as well as the strategies hosts use to control these infections. The objective of this proposal is to investigate the molecular interactions between the nematode C. elegans and its natural microsporidian pathogen, N. parisii. N. parisii infects C. elegans intestinal cells, which are transparent, facilitating direct imaging of the infection. C. elegans intestinal cells share many features with mammalian intestinal cells, such as finger-like microvilli, which are anchored into a cytoskeletal structure called the terminal web. Intriguingly, N. parisii can specifically manipulate the terminal web, probably as part of an exit strategy. The central hypothesis of this proposal is that there are specific molecular interactions between host and pathogen that allow N. parisii to directly target host cell components, and that allow C. elegans to regulate resistance to infection. We will pursue two specific aims to address this hypothesis: 1) determine the mechanisms used by N. parisii to restructure and modify C. elegans intestinal cells; and 2) identify the pathways that are important for regulating resistance/susceptibility to N. parisii infection. To accomplish the first aim we will use in vivo imaging of N. parisii infection in animals expressing fluorescently-labeled cytoskeletal and subcellular markers in the C. elegans intestine. These studies will be complemented with physiological and biochemical analyses of the consequences of infection. Under the second aim we will use a combination of genetic and genomic techniques to identify which pathways are important for control of N. parisii infection. The approach is innovative because it utilizes a natural host/pathogen model that offers genetic, molecular, and imaging tools to better understand molecular interactions between microsporidia and their hosts. The proposed research is significant because it is expected to provide insights into the molecular interactions between microsporidia and their human hosts. PUBLIC HEALTH RELEVANCE: Microsporidia are responsible for a wide variety of infections, including severe intestinal infections in AIDS patients. However, the molecular mechanisms used by microsporidia to infect host cells, and the host innate immune response to these infections, are poorly understood. This proposal employs a natural nematode host model for microsporidia pathogenesis in the intestine that has potential applicability to understanding the pathogenesis of microsporidian infections in the human intestine.

描述（由申请人提供）：该项目的主要目标是了解微孢子虫是如何引起疾病的。微孢子虫是真核的细胞内病原体，可以感染各种宿主但知之甚少。这些病原体会引起人类的严重感染，尤其是在艾滋病患者中。了解微孢子虫的致病特性与NIH的使命有关，因为它有望帮助减轻人类疾病的负担。关于微孢子虫与其宿主肠细胞之间的分子相互作用知之甚少，尽管有几种观察结果表明它们之间存在着私密的动态。我们的长期目标是更好地了解微孢子虫用于利用宿主肠细胞的策略，以及宿主用于控制这些感染的策略。该提案的目的是研究线虫C.秀隐杆菌与其天然微孢子病原体N. parisii之间的分子相互作用。北孢菌感染了秀丽隐杆线虫肠细胞，它们是透明的，可促进感染的直接成像。秀丽隐杆线虫肠细胞与哺乳动物肠细胞（例如手指样微壁）具有许多特征，这些细胞被固定在称为末端网的细胞骨架结构中。有趣的是，Parisii可以专门操纵终端网，这可能是退出策略的一部分。该提议的中心假设是，宿主和病原体之间存在特定的分子相互作用，使帕里西氏菌能够直接靶向宿主细胞成分，并允许秀丽隐杆线虫调节对感染的耐药性。我们将追求两个具体的目的来解决这一假设：1）确定帕里西氏菌用于重组和修改秀丽隐杆线虫肠道细胞的机制； 2）确定对于调节对巴西猪笼草感染的耐药性/敏感性很重要的途径。为了实现第一个目标，我们将在表达荧光秀丽隐杆线虫肠中表达荧光标记的细胞骨架和亚细胞标记的动物中使用猪笼草感染的体内成像。这些研究将与感染后果的生理和生化分析相辅相成。在第二个目标下，我们将使用遗传和基因组技术的组合来确定哪些途径对于控制脑乳杆菌感染很重要。该方法具有创新性，因为它利用了一种天然的宿主/病原体模型，该模型提供遗传，分子和成像工具来更好地了解微孢子虫及其宿主之间的分子相互作用。拟议的研究之所以重要，是因为预计它将对微孢子虫与其人类宿主之间的分子相互作用提供见解。 公共卫生相关性：微孢子虫造成多种感染，包括艾滋病患者的严重肠道感染。然而，对宿主细胞的分子机制以及宿主对这些感染的先天免疫反应的理解很少。该提案采用天然线虫宿主模型来用于肠中的微孢子虫发病机理，该模型具有潜在的适用性，可用于理解人类肠中微孢子虫感染的发病机理。