Impacts of
 sarA
 and
 agr
 in
 Staphylococcus aureus
 Strain Newman on Fibronectin-Binding Protein A Gene Expression and Fibronectin Adherence Capacity In Vitro and in Experimental Infective Endocarditis

Xiong, Yan-Qiong; Bayer, Arnold S.; Yeaman, Michael R.; Wamel, Willem van; Manna, A. La; Cheung, Ambrose L.

doi:10.1128/iai.72.3.1832-1836.2004

Cited by 52 publications

(57 citation statements)

References 31 publications

(47 reference statements)

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“…Although there are some contradictory results from different models of infection (7,8,16,35,40,44,48), fibronectin-binding proteins are the main surface-associated proteins that function as adhesins and invasins by assembling the extracellular matrix protein Fn, which bridges to host cell receptors, such as ␣ 5 ␤ 1 -integrin (13,19,54). It has been demonstrated that fibronectinbinding proteins play a critical role in S. aureus infective endocarditis (35,50,60) and osteomyelitis (32,42). The prevalence of FnBPs in clinical isolates also indicates the importance of FnBPs for S. aureus infection (47,48,52).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of a Two-Component Signal Transduction System, SaeRS, Eliminates Adherence and Attenuates Virulence of Staphylococcus aureus

et al. 2006

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Staphylococcus aureus is a major human and animal pathogen. During infection, this organism not only is able to attach to and enter host cells by using its cell surface-associated factors but also exports toxins to induce apoptosis and kill invaded cells. In this study, we identified the regulon of a two-component signal transduction system, SaeRS, and demonstrated that the SaeRS system is required for S. aureus to cause infection both in vitro and in vivo. Using microarray and real-time reverse transcriptase PCR analyses, we found that SaeRS regulates the expression of genes involved in adhesion and invasion (such as those encoding fibronectin-binding proteins and fibrinogen-binding proteins) and genes encoding ␣-, ␤-, and ␥-hemolysins. Surprisingly, we found that SaeRS represses the Agr regulatory system since the mutation of saeS up-regulates agrA expression, which was confirmed by using an agr promoter-reporter fusion system. More importantly, we demonstrated that inactivation of the SaeRS system significantly decreases the bacterium-induced apoptosis and/or death of lung epithelial cells (A549) and attenuates virulence in a murine infection model. Moreover, we found that inactivation of the SaeRS system eliminates staphylococcal adhesion and internalization of lung epithelial cells. We also found that both a novel hypothetical protein (the SA1000 protein) and a bifunctional protein (Efb), which binds to extracellular fibrinogen and complement factor C3, might partially contribute to bacterial adhesion to and invasion of epithelial cells. Our results indicate that activation of the SaeRS system may be required for S. aureus to adhere to and invade epithelial cells.

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Section: Discussionmentioning

confidence: 99%

Inactivation of a Two-Component Signal Transduction System, SaeRS, Eliminates Adherence and Attenuates Virulence of Staphylococcus aureus

et al. 2006

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“…A well-characterized rabbit model of IE (12, 52) was used to study three infection outcomes of S. aureus UAMS-1 (parental strain) versus UAMS-1-glnP::ermB: (i) early bacteremia clearance, (ii) initial vegetation colonization, and (iii) intrinsic virulence. In brief, female New Zealand White rabbits (Irish Farms Products and Services) underwent transcarotid-transaortic valve catheterization (12,52,53). Subsequent infection challenge studies are described below.…”

Section: Methodsmentioning

confidence: 99%

Tricarboxylic Acid Cycle-Dependent Attenuation of Staphylococcus aureus In Vivo Virulence by Selective Inhibition of Amino Acid Transport

et al. 2009

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Staphylococci are the leading causes of endovascular infections worldwide. Commonly, these infections involve the formation of biofilms on the surface of biomaterials. Biofilms are a complex aggregation of bacteria commonly encapsulated by an adhesive exopolysaccharide matrix. In staphylococci, this exopolysaccharide matrix is composed of polysaccharide intercellular adhesin (PIA). PIA is synthesized when the tricarboxylic acid (TCA) cycle is repressed. The inverse correlation between PIA synthesis and TCA cycle activity led us to hypothesize that increasing TCA cycle activity would decrease PIA synthesis and biofilm formation and reduce virulence in a rabbit catheter-induced model of biofilm infection. TCA cycle activity can be induced by preventing staphylococci from exogenously acquiring a TCA cycle-derived amino acid necessary for growth. To determine if TCA cycle induction would decrease PIA synthesis in Staphylococcus aureus, the glutamine permease gene (glnP) was inactivated and TCA cycle activity, PIA accumulation, biofilm forming ability, and virulence in an experimental catheter-induced endovascular biofilm (endocarditis) model were determined. Inactivation of this major glutamine transporter increased TCA cycle activity, transiently decreased PIA synthesis, and significantly reduced in vivo virulence in the endocarditis model in terms of achievable bacterial densities in biofilm-associated cardiac vegetations, kidneys, and spleen. These data confirm the close linkage of TCA cycle activity and virulence factor production and establish that this metabolic linkage can be manipulated to alter infectious outcomes.

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“…In certain infections the central regulator agr is not involved in the activation of virulence factors (17,18,35). For instance in an experimental infective endocarditis model it was shown that fnbA is positively regulated in the absence of agr and sarA (34), suggesting additional regulatory loci in vivo. We could show that the regulator Sae is essential for the transcription of hla during device-related infection in guinea pigs (18).…”

mentioning

confidence: 99%

Role of Staphylococcus aureus Global Regulators sae and σ ^B in Virulence Gene Expression during Device-Related Infection

Goerke

Flückiger²,

Steinhuber³

et al. 2005

Infect Immun

101

112

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The ability of Staphylococcus aureus to adapt to different environments is due to a regulatory network comprising several loci. Here we present a detailed study of the interaction between the two global regulators sae and B of S. aureus and their influence on virulence gene expression in vitro, as well as during devicerelated infection. The expression of sae, asp23, hla, clfA, coa, and fnbA was determined in strain Newman and its isogenic saeS/R and sigB mutants by Northern analysis and LightCycler reverse transcription-PCR. There was no indication of direct cross talk between the two regulators. sae had a dominant effect on target gene expression during device-related infection.B seemed to be less active throughout the infection than under induced conditions in vitro.Staphylococcus aureus causes a variety of local and systemic infections in humans and is one of the most important community-acquired and nosocomial pathogens. Staphylococci are the most frequently implicated etiologic agents in device-related infections, in which the bacteria accumulate locally and often persist until the device is removed. Animal models using tissue cages as devices (37) allow the monitoring of various microbiological and immunological events during the course of infection.The ability of S. aureus to adapt to different environments is probably due to a global regulatory network comprising the loci agr, sar, sigB, rot, arlR/S, svrA, and saeR/S (1, 6-8, 28, 36). Each of these regulators is involved in the control of the expression of virulence factors such as hemolysins (for instance alpha-hemolysin, encoded by hla), protein A, fibronectin-binding proteins (FnBPA and FnBPB, encoded by fnbA and fnbB), or capsular polysaccharide (CP, encoded by the cap operon). Knowledge about the impact of these regulatory circuits on virulence gene expression during infection is still limited. In certain infections the central regulator agr is not involved in the activation of virulence factors (17,18,35). For instance in an experimental infective endocarditis model it was shown that fnbA is positively regulated in the absence of agr and sarA (34), suggesting additional regulatory loci in vivo. We could show that the regulator Sae is essential for the transcription of hla during device-related infection in guinea pigs (18). Recently, the importance of sae was shown in two whole-genome screens for the identification of genes required for full virulence (2, 3). The sae locus consists of four ORFs, two of which (saeR and saeS) show strong sequence homology to response regulators and histidine kinases of bacterial two-component regulators (12). Two additional ORFs, ORF3 and ORF4, located upstream of saeR/S are likely to be important for functionality of the sae operon (29, 31). Four overlapping sae-specific transcripts (T1 to T4) originate from three promoters (P1, P2, and P3): the T1 message (3.1 kb) initiates upstream of ORF4, T2 (2.4 kb) initiates upstream of ORF3, and T3 (2.0 kb) initiates in front of saeR (Fig. 1). T4 (0.7 kb) represents a monocis...

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Impacts of sarA and agr in Staphylococcus aureus Strain Newman on Fibronectin-Binding Protein A Gene Expression and Fibronectin Adherence Capacity In Vitro and in Experimental Infective Endocarditis

Cited by 52 publications

References 31 publications

Inactivation of a Two-Component Signal Transduction System, SaeRS, Eliminates Adherence and Attenuates Virulence of Staphylococcus aureus

Inactivation of a Two-Component Signal Transduction System, SaeRS, Eliminates Adherence and Attenuates Virulence of Staphylococcus aureus

Tricarboxylic Acid Cycle-Dependent Attenuation of Staphylococcus aureus In Vivo Virulence by Selective Inhibition of Amino Acid Transport

Role of Staphylococcus aureus Global Regulators sae and σ ^B in Virulence Gene Expression during Device-Related Infection

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Impacts of sarA and agr in Staphylococcus aureus Strain Newman on Fibronectin-Binding Protein A Gene Expression and Fibronectin Adherence Capacity In Vitro and in Experimental Infective Endocarditis

Cited by 52 publications

References 31 publications

Inactivation of a Two-Component Signal Transduction System, SaeRS, Eliminates Adherence and Attenuates Virulence of Staphylococcus aureus

Inactivation of a Two-Component Signal Transduction System, SaeRS, Eliminates Adherence and Attenuates Virulence of Staphylococcus aureus

Tricarboxylic Acid Cycle-Dependent Attenuation of Staphylococcus aureus In Vivo Virulence by Selective Inhibition of Amino Acid Transport

Role of Staphylococcus aureus Global Regulators sae and σ B in Virulence Gene Expression during Device-Related Infection

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Role of Staphylococcus aureus Global Regulators sae and σ ^B in Virulence Gene Expression during Device-Related Infection