Impact of the functional status of <scp>saeRS</scp> on in vivo phenotypes of <scp>S</scp>taphylococcus aureus <scp>sarA</scp> mutants

Beenken, Karen E.; Mrak, Lara N.; Zielińska, Agnieszka; Atwood, Danielle N.; Loughran, Allister J.; Griffin, Linda M.; Matthews, Kathleen A.; Anthony, Allison; Spencer, Horace J.; Skinner, Robert A.; Post, Ginell R.; Lee, Chia Y.; Smeltzer, Mark S.

doi:10.1111/mmi.12629

Cited by 28 publications

(53 citation statements)

References 53 publications

(111 reference statements)

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“…To date, the single most promising target that we have identified is the staphylococcal accessory regulator A (sarA), mutation of which limits S. aureus biofilm formation to a degree that can be correlated with increased antibiotic susceptibility and improved therapeutic outcomes in relevant animal models (18-23). We also confirmed that the increased production of extracellular proteases plays an important role in defining the biofilm-deficient phenotype of sarA mutants (14,16,17,23,24). Moreover, we demonstrated that sarA mutants exhibit reduced virulence in a murine bacteremia model and that this can also be correlated with the increased production of extracellular proteases owing to the decreased accumulation of specific virulence factors, including alpha toxin and phenol-soluble modulins (23,25).…”

supporting

confidence: 65%

“…The protease-deficient derivative of LAC was unable to produce any extracellular protease other than the proteases encoded by the spl operon; the use of this protease-deficient strain was necessitated by the fact that the spl mutation is defined by resistance to erythromycin (14,16,19,23,25). However, previous studies confirmed that biofilm formation is comparable in LAC sarA mutants unable to produce any extracellular protease and those that retain the capacity to produce only the spl-encoded proteases (17,24).…”

Section: Methodsmentioning

confidence: 77%

“…On the basis of this, much of our research effort has focused on identifying factors that contribute to S. aureus biofilm formation (13)(14)(15)(16)(17). To date, the single most promising target that we have identified is the staphylococcal accessory regulator A (sarA), mutation of which limits S. aureus biofilm formation to a degree that can be correlated with increased antibiotic susceptibility and improved therapeutic outcomes in relevant animal models (18)(19)(20)(21)(22)(23).…”

mentioning

confidence: 99%

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XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

et al. 2016

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We demonstrate that mutation of xerC, which reportedly encodes a homologue of an Escherichia coli recombinase, limits biofilm formation in the methicillin-resistant Staphylococcus aureus strain LAC and the methicillin-sensitive strain UAMS-1. This was not due to the decreased production of the polysaccharide intracellular adhesin (PIA) in either strain because the amount of PIA was increased in a UAMS-1 xerC mutant and undetectable in both LAC and its isogenic xerC mutant. Mutation of xerC also resulted in the increased production of extracellular proteases and nucleases in both LAC and UAMS-1, and limiting the production of either class of enzymes increased biofilm formation in the isogenic xerC mutants. More importantly, the limited capacity to form a biofilm was correlated with increased antibiotic susceptibility in both strains in the context of an established biofilm in vivo. Mutation of xerC also attenuated virulence in a murine bacteremia model, as assessed on the basis of the bacterial loads in internal organs and overall lethality. It also resulted in the decreased accumulation of alpha toxin and the increased accumulation of protein A. These findings suggest that xerC may impact the functional status of agr. This was confirmed by demonstrating the reduced accumulation of RNAIII and AgrA in LAC and UAMS-1 xerC mutants. However, this cannot account for the biofilmdeficient phenotype of xerC mutants because mutation of agr did not limit biofilm formation in either strain. These results demonstrate that xerC contributes to biofilm-associated infections and acute bacteremia and that this is likely due to agr-independent and -dependent pathways, respectively. Staphylococcus aureus is a ubiquitous human pathogen capable of causing a wide variety of infections. These range from acute infections like bacteremia to chronic biofilm-associated infections. It is generally assumed that severe, acute infections are defined by the production of extracellular toxins, but a recent report demonstrated a negative correlation between toxicity for mammalian cells and invasive disease among human isolates (1). Although expression of the accessory gene regulator (agr), which is a primary determinant of toxin production (2), is negatively correlated with biofilm formation (3, 4), no correlation between toxicity and biofilm formation was observed in the current study. In fact, the only correlation was that decreased toxicity was associated with increased fitness, as assessed on the basis of survival in human serum (1).Nevertheless, it is clear that S. aureus has the capacity to cause diverse forms of infection. In the case of acute infections, the primary therapeutic concern is acquired resistance and the decreasing availability of effective antibiotics (5). In the case of biofilmassociated infections, a critical concern is the biofilm itself, which confers a therapeutically relevant level of intrinsic resistance to both host defenses and conventional antibiotics (6-9). There are multiple reasons for this, including the limited...

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supporting

confidence: 65%

Section: Methodsmentioning

confidence: 77%

mentioning

confidence: 99%

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XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

et al. 2016

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“…Considering the protective roles of the SaeRS TCS described above, it is not surprising that the SaeRS TCS is required for disease progression in several animal models of infection including silkworm and nematode killing [130,131], murine survival and skin infection [132], infective endocarditis [4], necrotizing pneumonia and skin infection [133], osteomyelitis [74], and sepsis [134]. The SaeRS TCS was even needed for staphylococcal gastrointestinal dissemination and transmission following bacteremia [135].…”

Section: The Role Of Sae In the Virulence Of S Aureusmentioning

confidence: 99%

The SaeRS Two‐Component System of Staphylococcus aureus

Liu

Yeo

Bae

2016

Genes

173

195

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In the Gram-positive pathogenic bacterium Staphylococcus aureus, the SaeRS two-component system (TCS) plays a major role in controlling the production of over 20 virulence factors including hemolysins, leukocidins, superantigens, surface proteins, and proteases. The SaeRS TCS is composed of the sensor histidine kinase SaeS, response regulator SaeR, and two auxiliary proteins SaeP and SaeQ. Since its discovery in 1994, the sae locus has been studied extensively, and its contributions to staphylococcal virulence and pathogenesis have been well documented and understood; however, the molecular mechanism by which the SaeRS TCS receives and processes cognate signals is not. In this article, therefore, we review the literature focusing on the signaling mechanism and its interaction with other global regulators.

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“…111 The resulting changes in the profile of secreted virulence factors may lead to a reduced impact on tissue degradation or cell cytotoxicity. 40,112,113 Alternatively, it is possible that antibiotics initially reduce the bacterial burden, allowing bone healing to be initiated before the infection reactivates.…”

Section: What Is the Mechanism Of The Observed Pro-osteogenic Responsmentioning

confidence: 99%

Impact of Bacterial Infections on Osteogenesis: Evidence From In Vivo Studies

Croes

Wal

Charles

2019

Journal Orthopaedic Research

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The clinical impact of bacterial infections on bone regeneration has been incompletely quantified and documented. As a result, controversy exists about the optimal treatment strategy to maximize healing of a contaminated defect. Animal models are extremely useful in this respect, as they can elucidate how a bacterial burden influences quantitative healing of various types of defects relative to non‐infected controls. Moreover, they may demonstrate how antibacterial treatment and/or bone grafting techniques facilitate the osteogenic response in the harsh environment of a bacterial infection. Finally, it a well‐known contradiction that osteomyelitis is characterized by uncontrolled bone remodeling and bone loss, but at the same time, it can be associated with excessive new bone apposition. Animal studies can provide a better understanding of how osteolytic and osteogenic responses are related to each other during infection. This review discusses the in vivo impact of bacterial infection on osteogenesis by addressing the following questions (i) How does osteomyelitis affect the radiographic bone appearance? (ii) What is the influence of bacterial infection on histological bone healing? (iii) How do bacterial infections affect quantitative bone healing? (iv) What is the effect of antibacterial treatment on the healing outcome during infection? (v) What is the efficacy of osteoinductive proteins in infected bones? (vi) What is the balance between the osteoclastic and osteoblastic response during bacterial infections? (vii) What is the mechanism of the observed pro‐osteogenic response as observed in osteomyelitis? © 2019 The Authors. Journal of Orthopaedic Research© published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 37:2067–2076, 2019

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Impact of the functional status of saeRS on in vivo phenotypes of Staphylococcus aureus sarA mutants

Cited by 28 publications

References 53 publications

XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

XerC Contributes to Diverse Forms of Staphylococcus aureus Infection via agr -Dependent and agr -Independent Pathways

The SaeRS Two‐Component System of Staphylococcus aureus

Impact of Bacterial Infections on Osteogenesis: Evidence From In Vivo Studies

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