Candida Glabrata Gene Activation During Mucosal Infection

描述（由申请人提供）：真菌感染在发病率、死亡率和医疗保健费用方面代表了一个重要的健康问题。念珠菌属是最大数量的真菌感染的原因，其中大多数归因于白色念珠菌和光滑念珠菌。这两种病原体产生一系列类似的浅表粘膜和危及生命的全身感染; albicans、假丝酵母C. glabrata对最重要的三唑类抗真菌剂具有天然抗性，并且缺乏与C.白色念珠菌侵入宿主组织。为了使这个问题复杂化，一些研究已经证明了C. glabrata感染尽管出现了这种情况，但C. glabrata在很大程度上未被探索，致病性的基础尚不清楚。我们的长期目标是了解C。glabrata定植，持久性和感染的哺乳动物组织。在这个R21计划中，我们将使用新兴技术来研究C. glabrata在鼠念珠菌病和鉴定与感染过程相关的基因。据我们所知，这将是第一个确定C。在受感染的宿主内光滑。我们假设C. glabrata具有在宿主组织的定殖和侵入期间在体内特异性诱导的毒力相关基因库。我们建议：1）确定C。glabrata基因在体内的表达情况; 2）确定C. glabrata定殖并感染鼠组织; 3）鉴定以阶段特异性和/或组织特异性方式特异性诱导的基因子集，和4）建立C.光果菌致病性筛选宿主诱导的基因是鉴定新的毒力因子和确定与病原体相关的全局表达模式的一种策略。这项研究将深入了解真菌-宿主相互作用的各个方面，并加深对导致疾病的致病过程的理解。公共卫生相关性：我们的研究结果将影响目前的治疗策略，确定毒力因子，可能有针对性的预防和治疗干预。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.