Roles of acetate metabolism in the virulence of Candida albicans

描述（由申请人提供）：酵母菌白色念珠菌是人类最重要的真菌病原体，几乎可以感染任何身体部位，突出了显着的适应性，使其能够在广泛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的严重缺陷。这里概述的项目来自对C.白念珠菌被巨噬细胞吞噬，巨噬细胞是一种关键的抗真菌细胞类型，其中大量的代谢重组伴随着一个充分研究的形态发生程序。我们专注于代谢的变化，这是集中在关键中间乙酰辅酶A，并已表明，在几个基因的突变重要的生产，消费或运输这种化合物降低毒力的小鼠模型播散性念珠菌病。这些研究表明，C。白色念珠菌在感染期间寻找并使用非优选的碳源。与其独特的生态位作为哺乳动物的哺乳动物，管理同化这些化合物所必需的代谢途径的监管网络是显着不同的，但非致病性的，酵母酿酒酵母。此外，我们有证据表明，这些代谢变化也直接影响了传统上被认为对毒力更重要的过程，如细菌形成和pH调节。特别地，我们发现C.白色念珠菌可以主动改变细胞外pH值到一个戏剧性的程度（高达3个单位），并假设这发生在哺乳动物吞噬溶酶体作为一种保护措施。我们在这里提出的研究，以了解乙酰辅酶A的稳态，因为它涉及到毒力，pH调节，和形态发生和大纲实验，以破译如何C。白色念珠菌已经适应了替代碳利用的调节以满足其体内需要。概述：在美国，真菌感染每年导致1万人死亡（而且还在上升），使得进一步的研究导向最终的药物开发势在必行。该提案使用了一个分离的免疫系统-真菌模型系统，使用白色念珠菌，最重要的真菌病原体，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.