Revisiting the host as a growth medium

Brown, Stacie A.; Palmer, Kelli L.; Whiteley, Marvin

doi:10.1038/nrmicro1955

Cited by 188 publications

(177 citation statements)

References 119 publications

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“…Increasingly, metabolic potential is considered a critical element governing a pathogen's virulence as well as its ability to survive in its host (6,13,16,(40)(41)(42)(43)(44). Here we show that the S. aureus CcpE protein captures changes in citrate levels and transforms them into various cellular responses.…”

Section: Discussionmentioning

confidence: 94%

“…On the other hand, S. aureus produces a wide array of virulence factors to evade host immune defenses and to derive nutrition either parasitically or destructively from the host during infections (6). Indeed, pathogen exploitation of host nutrients is one of the most fundamental aspects of host-pathogen interactions and infectious diseases (11)(12)(13)(14)(15)(16). For example, in vertebrate hosts one of the first lines of defense against S. aureus infection is withholding iron to prevent the growth of S. aureus; therefore S. aureus has evolved highly efficient nutrient-retrieval strategies to counteract this nutritional deprivation (11,17,18).…”

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confidence: 99%

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Metabolic sensor governing bacterial virulence in Staphylococcus aureus

Ding¹,

Liu

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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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.Staphylococcus aureus | metabolism | iron acquisition | virulence gene expression | bacterial virulence

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Section: Discussionmentioning

confidence: 94%

mentioning

confidence: 99%

Metabolic sensor governing bacterial virulence in Staphylococcus aureus

Ding¹,

Liu

Chen³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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show abstract

“…This also suggests an integration of a host cue into the quorum sensing system (either at the level of the small regulatory RNAs or at the level of luxR mRNA). Integration of a host cue into the QS system has also been documented before for Pseudomonas aeruginosa quinolone signalling during growth in sputum of cystic fibrosis patients (Brown et al, 2008) and in Vibrio fischeri during symbiosis with the bobtail squid, where low phosphate has been identified as one of the host cues (Lyell et al, 2010).…”

Section: Harveyi Quorum Sensing During Shrimp Infectionmentioning

confidence: 99%

Monitoring of Vibrio harveyi quorum sensing activity in real time during infection of brine shrimp larvae

Defoirdt

Sorgeloos

2012

The ISME Journal

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Quorum sensing, bacterial cell-to-cell communication, has been linked to the virulence of pathogenic bacteria. Indeed, in vitro experiments have shown that many bacterial pathogens regulate the expression of virulence genes by this cell-to-cell communication process. Moreover, signal molecules have been detected in samples retrieved from infected hosts and quorum sensing disruption has been reported to result in reduced virulence in different host-pathogen systems. However, data on in vivo quorum sensing activity of pathogens during infection of a host are currently lacking. We previously reported that quorum sensing regulates the virulence of Vibrio harveyi in a standardised model system with gnotobiotic brine shrimp (Artemia franciscana) larvae. Here, we monitored quorum sensing activity in Vibrio harveyi during infection of the shrimp, using bioluminescence as a read-out. We found that wild-type Vibrio harveyi shows a strong increase in quorum sensing activity early during infection. In this respect, the bacteria behave remarkably similar in different larvae, despite the fact that only half of them survive the infection. Interestingly, when expressed per bacterial cell, Vibrio harveyi showed around 200-fold higher maximal quorum sensing-regulated bioluminescence when associated with larvae than in the culture water. Finally, the in vivo quorum sensing activity of mutants defective in the production of one of the three signal molecules is consistent with their virulence, with no detectable in vivo quorum sensing activity in AI-2-and CAI-1-deficient mutants. These results indicate that AI-2 and CAI-1 are the dominant signals during infection of brine shrimp.

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“…Wong and R. Kassen unique environment of the CF lung plays an important role in determining the physiological state and evolutionary trajectory of P. aeruginosa during chronic infection. Lungs of CF patients become filled with viscous sputum, and the viscosity, nutritional composition and low aerobicity of CF sputum are important and peculiar features of this microbial habitat (Brown et al, 2008;Hassett et al, 2009;Worlitzsch et al, 2002). In the present context, such features of the CF lung must influence either (or both) the processes of mutation and selection in order to account for differences in drug resistance mechanisms.…”

Section: Parallel Evolution In Quinolone Resistancementioning

confidence: 99%

Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa

Wong

Kassen

2011

Microbiology

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The emergence and spread of antibiotic resistance in pathogens is a major impediment to the control of microbial disease. Here, we review mechanisms of quinolone resistance in Pseudomonas aeruginosa, an important nosocomial pathogen and a major cause of morbidity in cystic fibrosis (CF) patients. In this quantitative literature review, we find that mutations in DNA gyrase A, the primary target of quinolones in Gram-negative bacteria, are the most common resistance mutations identified in clinical samples of all origins, in keeping with previous observations. However, the identities of non-gyrase resistance mutations vary systematically between samples isolated from CF patients and those isolated from acute infections. CF-derived strains tend to harbour mutations in the efflux pump regulator nfxB, while non-CF strains tend to bear mutations in the efflux regulator mexR or in parC, which encodes one of two subunits of DNA topoisomerase IV. We suggest that differences in resistance mechanisms between CF and non-CF strains result either from local adaptation to different sites of infection or from differences in mutational processes between different environments. We further discuss the therapeutic implications of local differentiation in resistance mechanisms to a common antibiotic.

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Revisiting the host as a growth medium

Cited by 188 publications

References 119 publications

Metabolic sensor governing bacterial virulence in Staphylococcus aureus

Metabolic sensor governing bacterial virulence in Staphylococcus aureus

Monitoring of Vibrio harveyi quorum sensing activity in real time during infection of brine shrimp larvae

Parallel evolution and local differentiation in quinolone resistance in Pseudomonas aeruginosa

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