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The Staphylococcus aureus response to unsaturated long chain free fatty acids: survival mechanisms and virulence implications.

Kenny JG, Ward D, Josefsson E, Jonsson IM, Hinds J, Rees HH, Lindsay JA, Tarkowski A, Horsburgh MJ - PLoS ONE (2009)

Bottom Line: Similarly, up-regulation of genes involved in capsule formation was recorded as were significant changes in the expression of genes associated with peptidoglycan synthesis and regulation.An adaptive response by S. aureus of reducing cell surface hydrophobicity was also observed.Differences in the prevalence and clinical importance of S. aureus strains might partly be explained by their responses to antimicrobial fatty acids.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom.

ABSTRACT
Staphylococcus aureus is an important human commensal and opportunistic pathogen responsible for a wide range of infections. Long chain unsaturated free fatty acids represent a barrier to colonisation and infection by S. aureus and act as an antimicrobial component of the innate immune system where they are found on epithelial surfaces and in abscesses. Despite many contradictory reports, the precise anti-staphylococcal mode of action of free fatty acids remains undetermined. In this study, transcriptional (microarrays and qRT-PCR) and translational (proteomics) analyses were applied to ascertain the response of S. aureus to a range of free fatty acids. An increase in expression of the sigma(B) and CtsR stress response regulons was observed. This included increased expression of genes associated with staphyloxanthin synthesis, which has been linked to membrane stabilisation. Similarly, up-regulation of genes involved in capsule formation was recorded as were significant changes in the expression of genes associated with peptidoglycan synthesis and regulation. Overall, alterations were recorded predominantly in pathways involved in cellular energetics. In addition, sensitivity to linoleic acid of a range of defined (sigB, arcA, sasF, sarA, agr, crtM) and transposon-derived mutants (vraE, SAR2632) was determined. Taken together, these data indicate a common mode of action for long chain unsaturated fatty acids that involves disruption of the cell membrane, leading to interference with energy production within the bacterial cell. Contrary to data reported for other strains, the clinically important EMRSA-16 strain MRSA252 used in this study showed an increase in expression of the important virulence regulator RNAIII following all of the treatment conditions tested. An adaptive response by S. aureus of reducing cell surface hydrophobicity was also observed. Two fatty acid sensitive mutants created during this study were also shown to diplay altered pathogenesis as assessed by a murine arthritis model. Differences in the prevalence and clinical importance of S. aureus strains might partly be explained by their responses to antimicrobial fatty acids.

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Related in: MedlinePlus

Contribution of vraE and sasF to virulence.A Effect of WT SH1000 (open box) and mutations of vraE (vertical hatched box) and sasF (diagonal hatched box) on percentage change in weight of infected mice. *p<0.05, **p<0.01 by Dunn's test. B Effect of mutations of vraE (closed triangle) and sasF (closed inverted triangle) on cfu of S. aureus SH1000 (closed box) in kidneys of infected mice.
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pone-0004344-g004: Contribution of vraE and sasF to virulence.A Effect of WT SH1000 (open box) and mutations of vraE (vertical hatched box) and sasF (diagonal hatched box) on percentage change in weight of infected mice. *p<0.05, **p<0.01 by Dunn's test. B Effect of mutations of vraE (closed triangle) and sasF (closed inverted triangle) on cfu of S. aureus SH1000 (closed box) in kidneys of infected mice.

Mentions: A murine arthritis model of infection was used to determine a role for the LC-uFFA survival genes sasF and vraE in pathogenesis. This model of infection also reports on systemic inflammation and abscess formation in kidneys and was therefore relevant for in vivo investigation of fatty acid survival mutants. Neither the sasF nor vraE mutations showed a significant reduction in arthritis development of SH1000 in this model (data not shown). However, a significantly reduced weight loss (P<0.05) was observed for both sasF and the vraE mutants for 3 out of 5 weight measurements over the 14 day experiment, when compared to the SH1000 parent strain (Fig. 4A). In contrast, while a reduced bacterial load of both mutant strains was observed in the kidney compared to the wild type this was not found to be significant (pā€Š=ā€Š0.075) (Fig. 4B). Collectively, these data suggest that SasF and VraE might make contributions to the pathogenesis of systemic inflamation, but not to the development of arthritis.


The Staphylococcus aureus response to unsaturated long chain free fatty acids: survival mechanisms and virulence implications.

Kenny JG, Ward D, Josefsson E, Jonsson IM, Hinds J, Rees HH, Lindsay JA, Tarkowski A, Horsburgh MJ - PLoS ONE (2009)

Contribution of vraE and sasF to virulence.A Effect of WT SH1000 (open box) and mutations of vraE (vertical hatched box) and sasF (diagonal hatched box) on percentage change in weight of infected mice. *p<0.05, **p<0.01 by Dunn's test. B Effect of mutations of vraE (closed triangle) and sasF (closed inverted triangle) on cfu of S. aureus SH1000 (closed box) in kidneys of infected mice.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2629846&req=5

pone-0004344-g004: Contribution of vraE and sasF to virulence.A Effect of WT SH1000 (open box) and mutations of vraE (vertical hatched box) and sasF (diagonal hatched box) on percentage change in weight of infected mice. *p<0.05, **p<0.01 by Dunn's test. B Effect of mutations of vraE (closed triangle) and sasF (closed inverted triangle) on cfu of S. aureus SH1000 (closed box) in kidneys of infected mice.
Mentions: A murine arthritis model of infection was used to determine a role for the LC-uFFA survival genes sasF and vraE in pathogenesis. This model of infection also reports on systemic inflammation and abscess formation in kidneys and was therefore relevant for in vivo investigation of fatty acid survival mutants. Neither the sasF nor vraE mutations showed a significant reduction in arthritis development of SH1000 in this model (data not shown). However, a significantly reduced weight loss (P<0.05) was observed for both sasF and the vraE mutants for 3 out of 5 weight measurements over the 14 day experiment, when compared to the SH1000 parent strain (Fig. 4A). In contrast, while a reduced bacterial load of both mutant strains was observed in the kidney compared to the wild type this was not found to be significant (pā€Š=ā€Š0.075) (Fig. 4B). Collectively, these data suggest that SasF and VraE might make contributions to the pathogenesis of systemic inflamation, but not to the development of arthritis.

Bottom Line: Similarly, up-regulation of genes involved in capsule formation was recorded as were significant changes in the expression of genes associated with peptidoglycan synthesis and regulation.An adaptive response by S. aureus of reducing cell surface hydrophobicity was also observed.Differences in the prevalence and clinical importance of S. aureus strains might partly be explained by their responses to antimicrobial fatty acids.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, University of Liverpool, Liverpool, United Kingdom.

ABSTRACT
Staphylococcus aureus is an important human commensal and opportunistic pathogen responsible for a wide range of infections. Long chain unsaturated free fatty acids represent a barrier to colonisation and infection by S. aureus and act as an antimicrobial component of the innate immune system where they are found on epithelial surfaces and in abscesses. Despite many contradictory reports, the precise anti-staphylococcal mode of action of free fatty acids remains undetermined. In this study, transcriptional (microarrays and qRT-PCR) and translational (proteomics) analyses were applied to ascertain the response of S. aureus to a range of free fatty acids. An increase in expression of the sigma(B) and CtsR stress response regulons was observed. This included increased expression of genes associated with staphyloxanthin synthesis, which has been linked to membrane stabilisation. Similarly, up-regulation of genes involved in capsule formation was recorded as were significant changes in the expression of genes associated with peptidoglycan synthesis and regulation. Overall, alterations were recorded predominantly in pathways involved in cellular energetics. In addition, sensitivity to linoleic acid of a range of defined (sigB, arcA, sasF, sarA, agr, crtM) and transposon-derived mutants (vraE, SAR2632) was determined. Taken together, these data indicate a common mode of action for long chain unsaturated fatty acids that involves disruption of the cell membrane, leading to interference with energy production within the bacterial cell. Contrary to data reported for other strains, the clinically important EMRSA-16 strain MRSA252 used in this study showed an increase in expression of the important virulence regulator RNAIII following all of the treatment conditions tested. An adaptive response by S. aureus of reducing cell surface hydrophobicity was also observed. Two fatty acid sensitive mutants created during this study were also shown to diplay altered pathogenesis as assessed by a murine arthritis model. Differences in the prevalence and clinical importance of S. aureus strains might partly be explained by their responses to antimicrobial fatty acids.

Show MeSH
Related in: MedlinePlus