The Candida albicans commensal program

描述（由申请人提供）：我们试图了解白色念珠菌共生的分子机制，白色念珠菌是人类微生物群的正常组成部分，也是破坏性真菌感染的最常见原因。对念珠菌病综合征患者恢复的白色念珠菌菌株的研究表明，绝大多数播散性感染来自患者自身的共生菌（Odds et al., 2006）。然而，我们对共栖的分子基础或共栖到病原体的转变知之甚少。我们最近收集了750多个专性二倍体有机体的纯合基因缺失突变体（Homann等，2009）（Noble等，2010）。通过在小鼠血液感染模型中对突变体进行遗传筛选，我们发现了多种新的毒力因子，包括真菌特异性鞘脂（Noble et al., 2010）和一种新的铁摄取基因转录激活因子（Chen, Pande et al.，提交）。我们现在建议使用相同的遗传资源在小鼠胃肠道共生模型中筛选共生因子。为此，我们的试点研究已经揭示了白色到不透明表型转变的主调节因子Wor1在促进肠道共生感染中的一种新的不透明独立作用。我们假设白色念珠菌在共栖性和毒力方面具有不同的遗传程序，比较共栖性和毒力筛选的结果将直接验证这一假设。该结果将显著加强一个研究不足的领域的研究，并有望揭示预防和治疗高度病态的白色念珠菌感染的机会。

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.