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: 8415560
• 负责人: Emily R Troemel
• 金额: $ 35.94万
• 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/8415560
• 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.

描述（由申请人提供）：本项目的主要目标是了解微孢子虫如何引起疾病。微孢子虫是真核细胞内的病原体，可以感染多种宿主，但知之甚少。这些病原体可导致人类严重感染，特别是艾滋病患者。了解微孢子虫的致病特性与NIH的使命相关，因为它有望帮助减轻人类疾病的负担。关于微孢子虫和它们的宿主肠细胞之间的分子相互作用知之甚少，尽管一些观察表明它们之间存在密切的动态。我们的长期目标是更好地了解微孢子虫利用宿主肠道细胞的策略，以及宿主控制这些感染的策略。本研究的目的是探讨线虫C. elegans及其天然微孢子虫病原N. parisii。N. parisii感染C. elegans肠细胞，这是透明的，有利于直接成像的感染。C.线虫肠细胞与哺乳动物肠细胞有许多共同的特征，例如指状微绒毛，其锚定在称为终网的细胞骨架结构中。有趣的是，N。parisii可以专门操纵终端网络，可能是作为退出策略的一部分。这个建议的中心假设是，在宿主和病原体之间存在特定的分子相互作用，使得N。parisii直接靶向宿主细胞成分，并允许C. elegans来调节对感染的抵抗力。我们将追求两个具体目标来解决这个假设：1）确定N使用的机制。parisii重组和修改C. elegans肠细胞;和2）确定调节对N. Parisii感染。为了实现第一个目标，我们将使用N.在表达荧光标记的细胞骨架和亚细胞标记的C.线虫肠这些研究将辅之以对感染后果的生理和生化分析。在第二个目标下，我们将结合使用遗传和基因组技术来确定哪些途径对于控制N.帕氏杆菌感染。该方法是创新的，因为它利用了自然宿主/病原体模型，提供了遗传，分子和成像工具，以更好地了解微孢子虫及其宿主之间的分子相互作用。这项研究意义重大，因为它有望为微孢子虫与人类宿主之间的分子相互作用提供见解。