In vivo-induction of Candida albicans morphogenesis

白色念珠菌形态发生的体内诱导

• 批准号: 7924038
• 负责人: Caroline Westwater
• 金额: $ 18.33万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7924038
• 关键词: Animals; Antifungal Agents; Blood; Candida albicans; Candidiasis; Cells; Data; Data Set; Defect; Development; Diagnosis; Emerging Technologies; Environment; Epithelial; Epithelial Cells; Epithelium; Exhibits; Filament; Gene Expression; Gene Proteins; Genes; Genetic Programming; Goals; Growth; Human; Hyphae; Immunocompromised Host; In Vitro; Infection; Knock-out; Knowledge; Laboratories; Modeling; Molecular Target; Morbidity - disease rate; Morphogenesis; Morphology; Mucous Membrane; Mutation; Pathway interactions; Pattern; Process; Proteins; Regulation; Regulatory Pathway; Signal Transduction; Site; Stimulus; Surface; Technology; Testing; Therapeutic Intervention; Time; Tissues; Transcript; Transcription factor genes; Validation; Virulence Factors; Yeasts; base; fungus; in vivo; insight; mortality; mutant; pathogen; programs; promoter; prophylactic; public health relevance; response; tissue culture; transcription factor; treatment strategy

DESCRIPTION (provided by applicant): Candida albicans is the major fungal pathogen of humans, and is a significant cause of morbidity and mortality especially in immunocompromised hosts. Unlike most pathogens, C. albicans is capable of infecting virtually every anatomical site within the body and has no known reservoir outside of warm-blooded animals. The ability to reversibly switch between the unicellular (yeast) and filamentous form contributes significantly to the invasion and pathogenic process. Thus, there is a great impetus to understand the signals and regulatory pathways that govern the yeast-filament-yeast switch. The majority of studies examining this process, however, have been performed in vitro using conditions that attempt to mimic host-like stimuli. Recent studies in our laboratory have shown that `hyphal defective' mutants `locked' in the yeast mode of growth in vitro are capable of forming filaments during invasion of mucosal tissue in vivo. Additional data suggests that morphogenesis is triggered by host-derived signals at specific tissue sites. Furthermore, these signals activate a morphogenetic pathway that is silent in vitro. Based on these observations, we HYPOTHESIZE that C. albicans possesses a host environment-sensing mechanism that stimulates filamentous growth in response to in vivo mucosal cell contact. In this R21 proposal, we will use emerging technologies to investigate the global transcript profile of C. albicans cells infecting mucosal tissue in vivo and identify genes associated with host-induced morphogenesis. We propose to: 1) identify C. albicans genes expressed during the in vivo host-pathogen interaction; 2) identify a subset of C. albicans genes expressed specifically during mucosal-induced morphogenesis; 3) validate global expression datasets, and 4) assess the ability of knockout strains to undergo morphogenesis in vitro and in vivo. To our knowledge, this proposal will be the first to: 1) identify the transcriptional signature of C. albicans cells at the in vivo mucosal surface, and 2) elucidate new molecular targets and pathways that are independent of the major in vitro morphological regulators. These studies will generate significant insight into understanding the host-fungal pathogen interaction and allow the development of new antifungal strategies targeting the morphogenetic- and invasive-processes. 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 should accelerate our ability to diagnose, treat, and control the number one fungal pathogen of humans.

描述(申请人提供)：白色念珠菌是人类的主要真菌病原体，是发病率和死亡率的重要原因，特别是在免疫功能低下的宿主中。与大多数病原体不同，白色念珠菌能够感染人体内的几乎每个解剖部位，并且在温血动物之外没有已知的宿主。可逆地在单细胞(酵母)和丝状形态之间切换的能力在入侵和致病过程中起着重要作用。因此，有很大的动力来理解控制酵母-丝状-酵母开关的信号和调控途径。然而，大多数检验这一过程的研究都是在体外进行的，使用的条件是试图模仿宿主样刺激。我们实验室最近的研究表明，‘菌丝缺陷’突变体在体外以酵母菌的生长模式‘锁定’，能够在体内入侵粘膜组织时形成细丝。更多的数据表明，形态发生是由特定组织部位的宿主信号触发的。此外，这些信号激活了一条在体外是沉默的形态发生途径。基于这些观察，我们假设白色念珠菌具有宿主环境感知机制，刺激丝状细胞生长，以响应体内粘膜细胞的接触。在这个R21提案中，我们将使用新兴技术来研究体内感染黏膜组织的白色念珠菌细胞的全球转录谱，并识别与宿主诱导的形态发生相关的基因。我们建议：1)鉴定在体内宿主和病原体相互作用过程中表达的白色念珠菌基因；2)鉴定在黏膜诱导的形态发生过程中特异表达的白色念珠菌基因的子集；3)验证整体表达数据集；4)评估敲除菌株在体外和体内进行形态发生的能力。据我们所知，这一建议将是第一次：1)鉴定体内白念珠菌细胞在粘膜表面的转录特征；2)阐明新的分子靶点和途径，这些分子靶点和途径不依赖于主要的体外形态调控因子。这些研究将对理解宿主-真菌病原体的相互作用产生重要的洞察力，并使针对形态发生和侵袭过程的新的抗真菌策略的开发成为可能。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策略。这些知识应该会加速我们诊断、治疗和控制人类头号真菌病原体的能力。