The Candida albicans commensal program

白色念珠菌共生计划

• 批准号: 8282366
• 负责人: SUZANNE M NOBLE
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-02-15 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282366
• 关键词: Accounting; Affect; Area; Behavior; Blood Circulation; Candida; Candida albicans; Cell Surface Proteins; Cells; Collection; Diploidy; Disease; Disseminated candidiasis; Epigenetic Process; Failure; Gastrointestinal tract structure; Gene Deletion; Genes; Genetic Programming; Genetic Screening; Genetic Transcription; Hospitals; Host Defense; Human; Human Microbiome; Infection; Iron; Lead; Leukocytes; Libraries; Life Style; Mediating; Mediator of activation protein; Modality; Modeling; Molecular; Mus; Mycoses; Organism; Pathway interactions; Patients; Phase; Phenotype; Pilot Projects; Play; Prevention; Prevention therapy; Public Health; Research; Role; Screening procedure; Sepsis; Source; Sphingolipids; Symbiosis; Syndrome; Testing; Transcription Coactivator; Virulence; Virulence Factors; Yeasts; activating transcription factor; base; fitness; fungus; gastrointestinal; gastrointestinal infection; genetic resource; improved; in vivo; microbial; mouse model; mutant; novel; pathogen; programs; transcription factor; uptake

DESCRIPTION (provided by applicant): We seek to understand the molecular mechanisms of commensalism in Candida albicans, a normal component of the human microbiome as well as the most common cause of devastating fungal infections. Studies of C. albicans strains recovered from patients with Candida disease syndromes have demonstrated that the vast majority of disseminated infections arise from patients' own commensals (Odds et al., 2006). However, we have scant understanding of the molecular basis of commensalism or the commensal-to-pathogen transition. We recently generated two large collections of more than 750 homozygous gene deletion mutants of this obligate diploid organism (Homann et al., 2009) (Noble et al., 2010). By means of a genetic screen of the mutants in a mouse model of bloodstream infection, we identified multiple novel virulence factors including a fungal-specific sphingolipid (Noble et al., 2010) and a novel transcriptional activator of iron uptake genes (Chen, Pande et al., submitted). We now propose to use the same genetic resource to screen for commensalism factors in a mouse model of gastrointestinal commensalism. To this end, our pilot studies have already revealed a novel opaque- independent role for master regulator of the white-to-opaque phenotypic transition, Wor1, in promoting commensal infections of the gut. We hypothesize that C. albicans possesses distinct genetic programs for commensalism and virulence, and comparison of the results from the commensalism and virulence screens will directly test this hypothesis. The results will significantly enhance an understudied area research and promise to reveal opportunities for prevention and treatment of highly morbid of C. albicans infections. PUBLIC HEALTH RELEVANCE: This project seeks to understand how Candida albicans persists as a commensal organism in the mammalian gastrointestinal tract. This is relevant to public health because the commensal reservoir of this ubiquitous human fungus is the source of disseminated candidiasis, a common and highly morbid infection among hospitalized patients. An improved understanding of the commensal lifestyle and the mechanisms underlying the commensal-to-pathogen switch could lead to novel therapies for prevention as well as treatment of these infections.

描述（由申请人提供）： 我们试图了解白色念珠菌中念珠菌病的分子机制，白色念珠菌是人类微生物组的正常组成部分，也是破坏性真菌感染的最常见原因。研究C。从具有念珠菌病综合征的患者中回收的白色念珠菌菌株已经证明，绝大多数播散性感染来自患者自身的尿道（Odds等人，2006年）。然而，我们对真菌病的分子基础或真菌向病原体的转化缺乏了解。我们最近产生了这种专性二倍体生物体的两个超过750个纯合基因缺失突变体的大集合（Homann等人，2009）（Noble等人，2010年）。通过在血流感染的小鼠模型中遗传筛选突变体，我们鉴定了多种新的毒力因子，包括真菌特异性鞘脂（Noble et al.，2010）和铁摄取基因的新型转录激活因子（Chen，Pande et al.，提交）。我们现在建议使用相同的遗传资源来筛选胃肠炎小鼠模型中的胃肠炎因子。为此，我们的初步研究已经揭示了白色到不透明表型转变的主调节因子Wor1在促进肠道肠道细菌感染中的新的不透明独立作用。我们假设C.白念珠菌具有不同的致病性和毒力遗传程序，比较致病性和毒力筛选的结果将直接检验这一假设。这些结果将大大加强一个未充分研究的领域的研究，并有望揭示预防和治疗高度病态的C。白色念珠菌感染 公共卫生关系： 本项目旨在了解白色念珠菌如何作为一种寄生生物在哺乳动物胃肠道中持续存在。这与公共卫生有关，因为这种普遍存在的人类真菌的真菌库是播散性念珠菌病的来源，这是住院患者中常见的高度病态感染。对肠道生活方式和肠道向病原体转换的机制的进一步了解可能会导致预防和治疗这些感染的新疗法。