Identifying Host and Pathogen Factors That Control Growth in Microsporidia

 描述(申请人提供)：微孢子虫包括一门类似真菌的专性细胞内病原体，感染从无脊椎动物到人类的各种宿主。在免疫功能低下的人类中，微孢子虫可以导致致命的消耗性腹泻。微孢子虫潜伏感染是一种常见现象，高达56%的免疫能力人群没有症状地感染并短暂地脱落孢子。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，即阿苯达唑，这种药物对引起微孢子虫病的主要原因比内氏肠孢子虫无效。确定微孢子虫致病的分子机制对于了解这些病原体如何致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已经导致了极端的基因丢失和基因组紧凑，包括失去了负责控制其他真菌的增殖和产孢量的保守信号成分。此外，微孢子虫这种专性的细胞内生活方式严重阻碍了这些生物的繁殖和研究能力，也是对这些病原体了解如此之少的主要原因。然而，模式线虫秀丽线虫的自然病原体--帕氏线虫的发现，为在整个动物模型中理解微孢子虫致病的分子机制提供了一个容易处理的系统。我推测，微孢子虫和宿主细胞信号通路都调节微孢子虫的增殖和向孢子的分化。我将利用诺氏线虫/线虫感染系统来 确定控制微孢子虫增殖和产孢量的寄主信号。然后，我将对拟青霉孢子形成的候选发育调控因子进行分析，以确定它们的阶段特异性表达，并鉴定这些转录因子的直接靶标。最终，这些研究将阐明微孢子虫致病的关键宿主因素， 微孢子虫中的发育调节基因；对形成感染性孢子很重要的基因。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宿主细胞出口的基因，形成特殊的孢子结构，包括那些负责入侵宿主细胞的基因。微孢子虫增殖和分化为孢子所需的宿主基因是对抗这些无处不在的病原体的新策略的关键目标。

 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.