期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2014
卷号：111
期号：46
页码：E4981-E4990
DOI：10.1073/pnas.1411077111
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceStaphylococcus aureus is one of the most successful and adaptable human pathogens and is a major cause of hospital-acquired infections. Here we provide insight into how S. aureus uses the catabolite control protein E (CcpE) to sense its intracellular metabolic status and to regulate its virulence-associated properties. We define a key circuit of the virulence regulatory network of S. aureus and emphasize that metabolic status may be a critical element governing the virulence of this pathogen. Understanding the role of metabolites in virulence factor expression ultimately may contribute to the development of novel strategies to combat this dreaded infectious disease. An effective metabolism is essential to all living organisms, including the important human pathogen Staphylococcus aureus. To establish successful infection, S. aureus must scavenge nutrients and coordinate its metabolism for proliferation. Meanwhile, it also must produce an array of virulence factors to interfere with host defenses. However, the ways in which S. aureus ties its metabolic state to its virulence regulation remain largely unknown. Here we show that citrate, the first intermediate of the tricarboxylic acid (TCA) cycle, binds to and activates the catabolite control protein E (CcpE) of S. aureus. Using structural and site-directed mutagenesis studies, we demonstrate that two arginine residues (Arg145 and Arg256) within the putative inducer-binding cavity of CcpE are important for its allosteric activation by citrate. Microarray analysis reveals that CcpE tunes the expression of 126 genes that comprise about 4.7% of the S. aureus genome. Intriguingly, although CcpE is a major positive regulator of the TCA-cycle activity, its regulon consists predominantly of genes involved in the pathogenesis of S. aureus. Moreover, inactivation of CcpE results in increased staphyloxanthin production, improved ability to acquire iron, increased resistance to whole-blood-mediated killing, and enhanced bacterial virulence in a mouse model of systemic infection. This study reveals CcpE as an important metabolic sensor that allows S. aureus to sense and adjust its metabolic state and subsequently to coordinate the expression of virulence factors and bacterial virulence.
