Candida Glabrata Gene Activation During Mucosal Infection

描述（由申请人提供）：真菌感染在发病率、死亡率和医疗费用方面代表着一个重要的健康问题。念珠菌是造成真菌感染的主要原因，其中大部分是白色念珠菌和光念珠菌。这两种病原体都会产生类似的浅表粘膜感染和危及生命的全身感染；然而，与白色念珠菌相比，光滑念珠菌对最重要的三唑类抗真菌药物具有天生的抗性，并且缺乏许多与白色念珠菌入侵宿主组织有关的毒力因子。使这个问题更加复杂的是，一些研究已经证明了光棘球蚴感染的发生率大幅增加。尽管出现了这一现象，但光棘球蚴的生物学在很大程度上尚未被探索，其致病性的基础也不清楚。我们的长期目标是了解C. glabrata在哺乳动物组织中的定植、持续和感染所需的分子机制。在本R21提案中，我们将利用新兴技术研究小鼠念珠菌感染过程中C. glabrata的全球转录谱，并鉴定与感染过程相关的基因。据我们所知，这将是第一个在受感染宿主中识别光斑棘球蚴转录特征的研究。我们推测，光棘球蚴具有一系列毒力相关基因，这些基因在体内定植和入侵宿主组织时被特异性诱导。我们建议：1)鉴定光棘球蚴在体内表达的基因；2)测定光棘球蚴定殖和感染小鼠组织的基因表达谱；3)鉴定出以阶段和/或组织特异性方式特异性诱导的基因亚群；4)确定感染相关基因在光棘球蚴致病性中的作用。筛选宿主诱导的基因代表了一种识别新的毒力因子和确定与病原体相关的全球表达模式的策略。这项研究将为真菌-宿主相互作用的各个方面提供见解，并提高对疾病致病过程的理解。公共卫生相关性：我们的研究结果将通过确定可能针对预防和治疗干预的毒力因素来影响当前的治疗策略。这些知识将加速我们诊断、治疗和控制人类头号真菌病原体的能力。

DESCRIPTION (provided by applicant): Fungal infections represent an important health problem in terms of morbidity, mortality, and health care costs. Candida species are responsible for the largest number of fungal infections, with the majority attributed to Candida albicans and Candida glabrata. Both pathogens produce a similar array of superficial mucosal and life-threatening systemic infections; however, in contrast to C. albicans, C. glabrata is innately resistant to the most important triazole class of antifungals and lacks many of the virulence factors implicated in C. albicans invasion of host tissues. To compound this problem, several studies have documented a substantial increase in the incidence of C. glabrata infections. Despite this emergence, the biology of C. glabrata is largely unexplored and the basis for pathogenicity is unclear. Our long-term goal is to understand the molecular mechanisms required for C. glabrata colonization, persistence, and infection of mammalian tissues. In this R21 proposal, we will use emerging technologies to investigate the global transcript profile of C. glabrata during murine candidiasis and identify genes associated with the infectious process. To our knowledge, this will be the first study to identify the transcriptional signature of C. glabrata within an infected host. We hypothesize that C. glabrata possesses a repertoire of virulence-associated genes that are induced specifically in vivo during colonization and invasion of host tissues. We propose to: 1) identify C. glabrata genes expressed in vivo; 2) determine the gene expression profile of C. glabrata colonizing and infecting murine tissue; 3) identify a subset of genes induced specifically in a stage- and/or tissue-specific manner, and 4) establish a role for infection-associated genes in C. glabrata pathogenicity. Screening for host-induced genes represents a strategy to identify novel virulence factors and define global expression patterns relevant to pathogens. This study will provide insight into the diverse aspects of the fungal-host interaction and an improved understanding of the pathogenic processes contributing to disease. PUBLIC HEALTH RELEVANCE: Our findings will impact current treatment strategies by identifying virulence factors that may be targeted for prophylactic and therapeutic intervention. Such knowledge will accelerate our ability to diagnose, treat, and control the number one fungal pathogen of humans.