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: 8908443
• 负责人: Michael R. Botts
• 金额: $ 2.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2015-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8908443
• 关键词: Affect; Albendazole; Animal Model; Animals; Binding; Binding Sites; Caenorhabditis elegans; Cells; Complex; Crohn' s disease; DNA Binding; Development; Diarrhea; Disease; Enterocytozoon bieneusi; Fungal Spores; Genes; Genome; Goals; Growth; Health; Human; Immune; Immunocompromised Host; Infection; Integration Host Factors; Intestines; Invaded; Invertebrates; Life Style; Light; Mediating; Mentors; Microsporidia; Microsporidiosis; Modeling; Molecular; Nematoda; Organism; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Population; Positioning Attribute; Process; Production; Proliferating; Proteins; Reproduction spores; Research; Resources; Signal Pathway; Signal Transduction; Staging; Structure; System; Therapeutic; Therapeutic Intervention; Time; TimeLine; Tissues; cell type; combat; fungus; genetic approach; insight; latent infection; novel; novel strategies; novel therapeutics; pathogen; public health relevance; tool; transcription factor; wasting

 DESCRIPTION (provided by applicant): Microsporidia comprise a phylum of fungal-like obligate intracellular pathogens that infect hosts ranging from invertebrates to humans. In immunocompromised humans, microsporidia can cause fatal wasting diarrhea. Latent infection by microsporidia is a common phenomenon, with up to 56% of the immune- competent population asymptomatically infected and transiently shedding spores. The full impact of these pathogens on human health is unknown. There is 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 obligat 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 a tractable system for understanding the molecular mechanisms of microsporidian pathogenesis in a whole animal model. I hypothesize that both microsporidian and host cell signaling pathways regulate microsporidia 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 proliferation and spore production. Then, I will analyze candidate developmental regulators of N. parisii sporulation to determine their stage-specific expression, and characterize the direct targets of these transcription factors. Ultimately, these studies will shed light on host factors critical for microsporidian pathogenesis, and developmentally regulated genes in microsporidia; genes important for the formation of infectious spores. Genes expressed during microsporidian differentiation are likely to include many genes responsible for coordinating egress from host cells, forming specialized spore- structures, including those responsible for invading host cells. Host genes that are required for microsporidian proliferation and differentiation into spores are key targets for novel strategies t combat these ubiquitous pathogens.

 描述（由申请人提供）：微孢子虫包括真菌样专性细胞内病原体门，其感染从无脊椎动物到人类的宿主。对于免疫功能低下的人类，微孢子虫可导致致命的消耗性腹泻。微孢子虫的潜伏感染是一种常见现象，高达56%的免疫活性群体无症状感染并短暂脱落孢子。这些病原体对人类健康的全面影响尚不清楚。目前严重缺乏治疗微孢子虫病的有效药物。只有一种药物被批准用于治疗人类，阿苯达唑，这是无效的微孢子虫病的主要原因，比氏肠细胞虫。确定微孢子虫致病的分子机制对于理解这些病原体如何引起疾病和开发新的治疗干预策略至关重要。 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和基因组压缩，包括负责控制其他真菌增殖和孢子形成的保守信号组分的丢失。此外，微孢子虫的这种强制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，并且是对这些病原体理解不足的主要原因。然而，杀线虫Parisii的发现，模式线虫秀丽隐杆线虫的天然病原体，提供了一个易于处理的系统，在整个动物模型中理解微孢子虫发病的分子机制。 我推测微孢子虫和宿主细胞的信号通路都调节微孢子虫增殖和分化成孢子。我将利用N。parisii C.线虫感染系统， 识别控制微孢子虫增殖和孢子产生的宿主信号。然后，我将分析候选的发育调节N。Parisii孢子形成，以确定它们的阶段特异性表达，并表征这些转录因子的直接靶标。最终，这些研究将揭示微孢子虫致病的关键宿主因素， 微孢子虫发育调控基因;感染性孢子形成的重要基因。在微孢子虫分化过程中表达的基因可能包括许多负责协调从宿主细胞中排出的基因，形成专门的孢子结构，包括负责入侵宿主细胞的那些。微孢子虫增殖和分化为孢子所需的宿主基因是对抗这些普遍存在的病原体的新策略的关键目标。