Roles of acetate metabolism in the virulence of Candida albicans

描述(申请人提供)：酵母白色念珠菌是人类最重要的真菌病原体，可以感染几乎任何身体部位，突出了非凡的适应性，使其能够在完全不同的条件下茁壮成长。死亡率高于可比的细菌感染，部分原因是诊断和治疗方案严重不足。这里概述的项目源于对白色念珠菌对巨噬细胞吞噬反应的全面基因组分析，巨噬细胞是一种关键的抗真菌细胞类型，在这种分析中，大规模的代谢重组伴随着一个经过充分研究的形态发生程序。我们重点研究了以关键中间体乙酰辅酶A为中心的代谢变化，并表明在这种化合物的生产、消费或运输过程中，几个重要基因的突变降低了播散性念珠菌病小鼠的毒力。总而言之，这些研究表明，白色念珠菌在感染期间发现并使用非首选碳源。与其作为哺乳动物共生生物的独特生态位相一致，控制同化此类化合物所需代谢途径的调控网络与相关但非致病的酿酒酵母中的调控网络显著不同。此外，我们有证据表明，这些代谢变化也直接影响传统上被认为对毒力更关键的过程，如丝状化和pH调节。特别是，我们发现白色念珠菌可以积极地改变细胞外pH到戏剧性的程度(高达3个单位)，并假设这发生在哺乳动物吞噬酶体内作为一种保护措施。我们建议进行研究，以了解乙酰辅酶A动态平衡与毒力、pH调节和形态发生的关系，并概述实验以破译白色念珠菌如何适应替代碳利用的调节，以满足其体内需求。总结：在美国，真菌感染每年导致1万人死亡(而且还在上升)，这使得针对最终药物开发的进一步研究势在必行。这项建议使用分离的免疫系统-真菌模型系统，使用最重要的真菌病原体白色念珠菌来研究基本的细胞代谢，其中的变化被认为是感染过程的关键组成部分。

DESCRIPTION (provided by applicant): The yeast Candida albicans is the most important fungal pathogen of humans and can infect virtually any body site, highlighting a remarkable adaptability that allows it to thrive in widely disparate conditions. Mortality is higher than in comparable bacterial infections, partly due to serious deficiencies in diagnostic and treatment options. The projects outlined here derive from a comprehensive genomic analysis of the response of C. albicans to phagocytosis by macrophages, a key antifungal cell type, in which a massive metabolic reorganization accompanies a well-studied morphogenetic program. We have focused on the metabolic changes, which are centered on the key intermediate acetyl-CoA and have shown that mutations in several genes important in the production, consumption or transport of this compound reduce virulence in a mouse model of disseminated candidiasis. Together these studies have shown that C. albicans finds and uses non-preferred carbon sources during infection. Consistent with its unique ecological niche as a mammalian commensal, the regulatory networks that govern the metabolic pathways necessary to assimilate such compounds are significantly different than those in the related, but non-pathogenic, yeast Saccharomyces cerevisiae. Further, we have evidence that these metabolic changes also directly affect processes conventionally thought to be more central to virulence, such as filamentation and pH regulation. In particular, we find that C. albicans can actively change extracellular pH to a dramatic degree (up to 3 units) and hypothesize that that this occurs within the mammalian phagolysosome as a protective measure. We propose here studies to understand acetyl-CoA homeostasis as it relates to virulence, pH modulation, and morphogenesis and outline experiments to decipher how C. albicans has adapted the regulation of alternative carbon utilization to meet its in vivo needs. Lay Summary: Fungal infections kill -10,000 people (and rising) per year in the U.S., making further studies directed towards eventual drug development imperative. This proposal uses an isolated immune system- fungal model system using Candida albicans, the most important fungal pathogen, to study basic cellular metabolism, changes in which are suggested to be a key component of the infection process.