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是一个重要的健康问题。真菌感染数量最多的是假丝酵母菌，其中大部分是白色念珠菌和光滑念珠菌。这两种病原体都会产生一系列类似的浅表粘膜感染和危及生命的全身感染；然而，与白念珠菌不同的是，光滑念珠菌对最重要的三唑类抗真菌药物具有天生的耐药性，并且缺乏许多与白念珠菌入侵宿主组织有关的毒力因子。使这一问题复杂化的是，几项研究证明光滑毛囊线虫感染的发病率大幅增加。尽管出现了这种情况，但光滑毛囊线虫的生物学特性仍未得到很大程度的研究，致病性的基础也不清楚。我们的长期目标是了解光滑毛囊线虫在哺乳动物组织中的定植、持久性和感染所需的分子机制。在这份R21提案中，我们将使用新兴技术来研究小鼠念珠菌感染期间光滑念珠菌的全球转录谱，并识别与感染过程相关的基因。据我们所知，这将是第一次在受感染的宿主中鉴定光滑隐翅虫转录特征的研究。我们推测，光肩星天牛拥有一系列毒力相关基因，这些基因是在寄主组织的定植和入侵过程中在体内特异性诱导的。我们建议：1)鉴定在体内表达的光滑线虫基因；2)确定光面线虫定植和感染小鼠组织的基因表达谱；3)确定阶段和/或组织特异性诱导的基因子集；4)建立感染相关基因在光面线虫致病中的作用。筛选宿主诱导的基因代表了一种识别新的毒力因子和定义与病原体相关的全球表达模式的策略。这项研究将提供对真菌-宿主相互作用的不同方面的洞察，并更好地理解导致疾病的致病过程。公共卫生相关性：我们的发现将通过确定可能作为预防和治疗干预目标的毒力因素来影响当前的治疗战略。这些知识将加快我们诊断、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.