Identifying Host and Pathogen Factors That Control Growth in Microsporidia

识别控制微孢子虫生长的宿主和病原体因素

• 批准号: 9109895
• 负责人: Michael R. Botts
• 金额: $ 2.71万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109895
• 关键词: Affect; Albendazole; Animal Model; Animals; Binding; Binding Sites; Biological Assay; C. elegans genome; Caenorhabditis elegans; Cell Survival; Cells; ChIP-seq; Defect; Dependence; Development; Diarrhea; Disease; Enterocytozoon bieneusi; Fungal Spores; Genes; Genome; Goals; Growth; Health; Human; Immune; Infection; Integration Host Factors; Invaded; Invertebrates; Life Style; Light; Mediating; Microsporidia; Microsporidiosis; Modeling; Molecular; Nematoda; Organism; Pathogenesis; Pharmaceutical Preparations; Phenotype; Population; Positioning Attribute; Production; Proteins; RNA Interference; Reproduction spores; Research; Resistance; Signal Pathway; Signal Transduction; Staging; Staining method; Stains; Structure; System; Therapeutic Intervention; Time; Tissues; cell type; fungus; genetic approach; insight; latent infection; novel therapeutics; pathogen; prevent; single molecule; therapeutic target; tool; transcription factor; wasting

Research Summary Microsporidia are a phylum of obligate intracellular pathogens within the fungal kingdom that infect hosts ranging from invertebrates to humans. In humans, microsporidia cause potentially fatal wasting diarrhea. Latent infection by microsporidia is a common phenomenon, with up to 11% of the immune-competent population asymptomatically infected and transiently shedding spores. The full impact of these pathogens on human health is unknown. There is also a critical lack of effective drugs to treat microsporidiosis. Only one drug is approved for treating humans, albendazole, which is ineffective against the leading cause of microsporidiosis, Enterocytozoon bieneusi. Determining the molecular mechanisms of microsporidian pathogenesis is critical for understanding how these pathogens cause disease and for developing new strategies for therapeutic intervention. Adaptation of microsporidia to this intracellular parasitic lifestyle has resulted in extreme gene loss and genome compaction, including the loss of conserved signaling components responsible for controlling proliferation and sporulation in other fungi. In addition, this obligate intracellular lifestyle of microsporidia has severely hampered the ability to propagate and study these organisms and is the primary reason for such a poor understanding of these pathogens. However, the discovery of Nematocida parisii, a natural pathogen of the model nematode Caenorhabditis elegans, provides for the first time a tractable system for understanding the molecular mechanisms of microsporidian pathogenesis in a whole animal model. I hypothesize that microsporidia co-opts host cell signaling pathways to gauge host cell conditions and control proliferation and differentiation into spores. I will take advantage of the N. parisii/C. elegans infection system to identify the host signals that control microsporidian spore production. I will use an RNAi screen to identify host genes that contribute to the production of N. parisii spores. Then I will analyze candidate developmental regulators of N. parisii sporulation to determine their stage-specific expression. Lastly, I will determine the host factor dependence of these N. parisii transcription factor networks. Ultimately, these studies will shed light on developmentally regulated genes in microsporidia; genes important for the formation of specialized infectious spores. Many of these developmentally regulated genes will likely contribute to host cell egress and host cell invasion machinery, which are attractive therapeutic targets to prevent and limit disease caused by microsporidia.

研究综述 微孢子虫是真菌界内专性胞内病原体的一门， 宿主包括无脊椎动物和人类。在人类中，微孢子虫会导致潜在的致命性消耗性腹泻。 微孢子虫潜伏感染是一种常见现象，高达11%的免疫活性 群体无症状感染和短暂脱落孢子。这些病原体的全部影响 人类健康是未知的。也严重缺乏治疗微孢子虫病的有效药物。只有一 阿苯达唑是一种被批准用于治疗人类疾病的药物，它对引起糖尿病的主要原因无效。 微孢子虫病，比氏肠胞虫病。确定微孢子虫的分子机制 致病机理对于理解这些病原体如何引起疾病和开发新的 治疗干预的策略。 微孢子虫对这种细胞内寄生生活方式的适应导致了极端的基因丢失， 基因组压缩，包括保守的信号成分的损失，负责控制 在其他真菌中的增殖和孢子形成。此外，微孢子虫的这种专性细胞内生活方式， 严重阻碍了繁殖和研究这些生物体的能力，这是造成这种情况的主要原因。 对这些病原体的认识不足。然而，杀线虫（Nematocida parisii）的发现， 模式线虫秀丽隐杆线虫，首次提供了一个易于理解的系统， 微孢子虫致病的分子机制。 我假设微孢子虫选择宿主细胞的信号通路来测量宿主细胞的状况， 控制增殖和分化成孢子。我将利用N。parisii C.线虫感染 系统来识别控制微孢子虫孢子产生的宿主信号。我会用RNAi筛选 确定有助于产生N的宿主基因。巴氏孢子然后我会分析候选人 N. Parisii孢子形成以确定它们的阶段特异性表达。最后，我将 确定这些N的宿主因子依赖性。Parisii转录因子网络。最终，这些研究 将揭示微孢子虫发育调控基因;基因的形成， 专门的传染性孢子许多这些发育调控基因可能有助于宿主细胞 出口和宿主细胞入侵机制，它们是预防和限制疾病的有吸引力的治疗靶点 由微孢子虫引起的