Cross-Talk between Staphylococcus aureus and Other Staphylococcal Species via the agr Quorum Sensing System

ABSTRACT Methicillin-resistant Staphylococcus aureus (MRSA) infections impact all patient populations both in the community and in health care settings. Despite advances in our knowledge of MRSA virulence, little is known about the regulatory mechanisms of USA100 health care-associated MRSA isolates, which are the second most frequently identified MRSA isolates found in all infections. This work focused on the contribution of the USA100 agr type II quorum-sensing system to virulence and antibiotic resistance. From a MRSA strain collection, we selected 16 representative USA100 isolates, constructed mutants with Δagr mutations, and characterized selected strain pairs for virulence factor expression, murine skin infection, and antibiotic resistance. For each strain pair, hemolysis and extracellular protease expression were significantly greater in the wild-type (WT) strains than in the Δagr mutants. Similarly, mice challenged with the WT strains had larger areas of dermonecrosis and greater weight loss than those challenged with the Δagr mutants, demonstrating that the USA100 agr system regulates virulence. Although USA100 isolates exhibit a high level of antibiotic resistance, the WT and Δagr strain pairs showed no difference in MICs by MIC testing. However, in the presence of a sub-MIC of vancomycin, most of the USA100 Δagr mutants exhibited slower growth than the WT isolates, and a couple of the Δagr mutants also grew more slowly in the presence of a sub-MIC of cefoxitin. Altogether, our findings demonstrate that the USA100 agr system is a critical regulator of virulence, and it may have a contribution to the optimal survival of these MRSA strains in the presence of antibiotics. IMPORTANCE USA100 health care-associated MRSA isolates are highly antibiotic resistant and can cause invasive disease across all patient populations. Even though USA100 strains are some of the most frequently identified causes of infections, little is known about virulence regulation in these isolates. Our study demonstrates that the USA100 agr quorum-sensing system is important for the control of toxin and exoenzyme production and that the agr system has a key role in skin infection. In some USA100 isolates, the agr system is important for growth in the presence of low levels of antibiotics. Altogether, our findings demonstrate that the USA100 agr system is a critical regulator of virulence and that it may make a contribution to the optimal survival of these MRSA strains in the presence of antibiotics.

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Characterizing the Dynamics of the Quorum-Sensing System in Staphylococcus aureus

Journal of Molecular Microbiology and Biotechnology ◽

10.1159/000086704 ◽

2004 ◽

Vol 8 (4) ◽

pp. 232-242 ◽

Cited By ~ 27

Author(s):

Erik Gustafsson ◽

Patric Nilsson ◽

Stefan Karlsson ◽

Staffan Arvidson

Keyword(s):

Staphylococcus Aureus ◽

Quorum Sensing ◽

Sensing System ◽

Quorum Sensing System

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Multifunctional Role And Regulation Of RNAIII Of The Agr Quorum Sensing System In Staphylococcus Aureus

Advances in Microbiology Research ◽

10.24966/amr-694x/100001 ◽

2017 ◽

Vol 1 (1) ◽

pp. 1-4

Author(s):

Ravi Kr Gupta ◽

Keyword(s):

Staphylococcus Aureus ◽

Quorum Sensing ◽

Sensing System ◽

Quorum Sensing System

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Inactivation of traP Has No Effect on the Agr Quorum-Sensing System or Virulence of Staphylococcus aureus

Infection and Immunity ◽

10.1128/iai.00491-07 ◽

2007 ◽

Vol 75 (9) ◽

pp. 4519-4527 ◽

Cited By ~ 28

Author(s):

Lindsey N. Shaw ◽

Ing-Marie Jonsson ◽

Vineet K. Singh ◽

Andrej Tarkowski ◽

George C. Stewart

Keyword(s):

Staphylococcus Aureus ◽

Quorum Sensing ◽

Type Strain ◽

Wild Type Strain ◽

Surface Proteins ◽

Virulence Determinants ◽

Wild Type ◽

Expression Levels ◽

Sensing System ◽

Quorum Sensing System

ABSTRACT The success of Staphylococcus aureus as a pathogen can largely be attributed to the plethora of genetic regulators encoded within its genome that temporally regulate its arsenal of virulence determinants throughout its virulence lifestyle. Arguably the most important of these is the two-component, quorum-sensing system agr. Over the last decade, the controversial presence of a second quorum-sensing system (the TRAP system) has been proposed, and it has been mooted to function as the master regulator of virulence in S. aureus by modulating agr. Mutants defective in TRAP are reported to be devoid of agr expression, lacking in hemolytic activity, essentially deficient in the secretion of virulence determinants, and avirulent in infection models. A number of research groups have questioned the validity of the TRAP findings in recent years; however, a thorough and independent analysis of its role in S. aureus physiology and pathogenesis has not been forthcoming. Therefore, we have undertaken such an analysis of the TRAP locus of S. aureus. We found that a traP mutant was equally hemolytic as the wild-type strain. Furthermore, transcriptional profiling found no alterations in the traP mutant in expression levels of agr or in expression levels of multiple agr-regulated genes (hla, sspA, and spa). Analysis of secreted and surface proteins of the traP mutant revealed no deviation in comparison to the parent. Finally, analysis conducted using a murine model of S. aureus septic arthritis revealed that, in contrast to an agr mutant, the traP mutant was just as virulent as the wild-type strain.

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RNAIII-Independent Target Gene Control by the agr Quorum-Sensing System: Insight into the Evolution of Virulence Regulation in Staphylococcus aureus

Molecular Cell ◽

10.1016/j.molcel.2008.08.005 ◽

2008 ◽

Vol 32 (1) ◽

pp. 150-158 ◽

Cited By ~ 308

Author(s):

Shu Y. Queck ◽

Max Jameson-Lee ◽

Amer E. Villaruz ◽

Thanh-Huy L. Bach ◽

Burhan A. Khan ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Quorum Sensing ◽

Target Gene ◽

Gene Control ◽

Virulence Regulation ◽

Sensing System ◽

Evolution Of Virulence ◽

Quorum Sensing System ◽

Insight Into

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A Nonsense Mutation in agrA Accounts for the Defect in agr Expression and the Avirulence of Staphylococcus aureus 8325-4 traP::kan

Infection and Immunity ◽

10.1128/iai.00679-07 ◽

2007 ◽

Vol 75 (9) ◽

pp. 4534-4540 ◽

Cited By ~ 47

Author(s):

Rajan P. Adhikari ◽

Staffan Arvidson ◽

Richard P. Novick

Keyword(s):

Staphylococcus Aureus ◽

Quorum Sensing ◽

Mutant Strain ◽

Nonsense Mutation ◽

Stop Codon ◽

Response Regulator ◽

Wild Type ◽

Sensing System ◽

Quorum Sensing System ◽

Type Sequence

ABSTRACT TraP is a triply phosphorylated staphylococcal protein that has been hypothesized to be the mediator of a second Staphylococcus aureus quorum-sensing system, “SQS1,” that controls expression of the agr system and therefore is essential for the organism's virulence. This hypothesis was based on the loss of agr expression and virulence by a traP mutant of strain 8325-4 and was supported by full complementation of both phenotypic defects by the cloned traP gene in strain NB8 (Y. Gov, I. Borovok, M. Korem, V. K. Singh, R. K. Jayaswal, B. J. Wilkinson, S. M. Rich, and N. Balaban, J. Biol. Chem. 279:14665-14672, 2004), in which the wild-type traP gene was expressed in trans in the 8325-4 traP mutant. We initiated a study of the mechanism by which TraP activates agr and found that the traP mutant strain used for this and other recently published studies has a second mutation, an adventitious stop codon in the middle of agrA, the agr response regulator. The traP mutation, once separated from the agrA defect by outcrossing, had no effect on agr expression or virulence, indicating that the agrA defect accounts fully for the lack of agr expression and for the loss of virulence attributed to the traP mutation. In addition, DNA sequencing showed that the agrA gene in strain NB8 (Gov et al., J. Biol. Chem., 2004), in contrast to that in the agr-defective 8325-4 traP mutant strain, had the wild-type sequence; further, the traP mutation in that strain, when outcrossed, also had no effect on agr expression.

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