scholarly journals Staphylococcus aureus Fur Regulates the Expression of Virulence Factors That Contribute to the Pathogenesis of Pneumonia

2010 ◽  
Vol 78 (4) ◽  
pp. 1618-1628 ◽  
Author(s):  
Victor J. Torres ◽  
Ahmed S. Attia ◽  
William J. Mason ◽  
M. Indriati Hood ◽  
Brian D. Corbin ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Iron Status ◽  
Mechanistic Explanation ◽  
Ferric Uptake Regulator ◽  
Pathogenic Microorganisms ◽  
Iron Availability ◽  
The Impact ◽  
Reciprocal Expression ◽  
Host Tissues

ABSTRACT The tremendous success of Staphylococcus aureus as a pathogen is due to the controlled expression of a diverse array of virulence factors. The effects of host environments on the expression of virulence factors and the mechanisms by which S. aureus adapts to colonize distinct host tissues are largely unknown. Vertebrates have evolved to sequester nutrient iron from invading bacteria, and iron availability is a signal that alerts pathogenic microorganisms when they enter the hostile host environment. Consistent with this, we report here that S. aureus senses alterations in the iron status via the ferric uptake regulator (Fur) and alters the abundance of a large number of virulence factors. These Fur-mediated changes protect S. aureus against killing by neutrophils, and Fur is required for full staphylococcal virulence in a murine model of infection. A potential mechanistic explanation for the impact of Fur on virulence is provided by the observation that Fur coordinates the reciprocal expression of cytolysins and a subset of immunomodulatory proteins. More specifically, S. aureus lacking fur exhibits decreased expression of immunomodulatory proteins and increased expression of cytolysins. These findings reveal that Fur is involved in initiating a regulatory program that organizes the expression of virulence factors during the pathogenesis of S. aureus pneumonia.

scholarly journals Mapping the Global Network of Extracellular Protease Regulation in Staphylococcus aureus

2019 ◽  
Author(s):  
Brittney D. Gimza ◽  
Maria I. Larias ◽  
Bridget G. Budny ◽  
Lindsey N. Shaw
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Global Network ◽  
Protease Production ◽  
Secondary Circuit ◽  
Pathogenic Potential ◽  
Regulatory Circuit ◽  
Primary Network ◽  
The Impact ◽  
Protease Expression

AbstractA primary function of the extracellular proteases of Staphylococcus aureus is to control the progression of infection by selectively modulating the stability of virulence factors. Consequently, a regulatory network exists to titrate protease abundance/activity, to influence accumulation, or lack thereof, of individual virulence factors. Herein, we comprehensively map this system, exploring regulation of the four protease loci by known and novel factors. In so doing, we determine that seven major elements (SarS, SarR, Rot, MgrA, CodY, SaeR, and SarA) form the primary network of control, with the latter three being the most powerful. We note that expression of aureolysin is largely repressed by these factors, whilst the spl operon is subject to the strongest upregulation of any protease loci, particularly by SarR and SaeR. Furthermore, when exploring scpA expression, we find it to be profoundly influenced in opposing fashions by SarA (repressor) and SarR (activator). We also present the screening of >100 regulator mutants of S. aureus, identifying 7 additional factors (ArgR2, AtlR, MntR, Rex, XdrA, Rbf, and SarU) that form a secondary circuit of protease control. Primarily these elements serve as activators, although we reveal XdrA as a new repressor of protease expression. With the exception or ArgR2, each of the new effectors appear to work through the primary network of regulation to influence protease production. Collectively, we present a comprehensive regulatory circuit that emphasizes the complexity of protease regulation and suggest that its existence speaks to the importance of these enzymes to S. aureus physiology and pathogenic potential.ImportanceThe complex regulatory role of the proteases necessitates very tight coordination and control of their expression. Whilst this process has been well studied, a major oversight has been the consideration of proteases as a single entity, rather than 10 enzymes produced from four different promoters. As such, in this study we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in Staphylococcus aureus.

scholarly journals Staphylococcus aureus Arsenal To Conquer the Lower Respiratory Tract

mSphere ◽  
2021 ◽  
Vol 6 (3) ◽  
Author(s):  
Mariane Pivard ◽  
Karen Moreau ◽  
François Vandenesch
Keyword(s):  
Staphylococcus Aureus ◽  
Respiratory Tract ◽  
Virulence Factors ◽  
Lower Respiratory Tract ◽  
Defense Mechanisms ◽  
Future Research ◽  
Epithelial Barrier ◽  
Content Type ◽  
Wide Range ◽  
The Impact

ABSTRACT Staphylococcus aureus is both a commensal and a pathogenic bacterium for humans. Its ability to induce severe infections is based on a wide range of virulence factors. S. aureus community-acquired pneumonia (SA-CAP) is rare and severe, and the contribution of certain virulence factors in this disease has been recognized over the past 2 decades. First, the factors involved in metabolism adaptation are crucial for S. aureus survival in the lower respiratory tract, and toxins and enzymes are required for it to cross the pulmonary epithelial barrier. S. aureus subsequently faces host defense mechanisms, including the epithelial barrier, but most importantly the immune system. Here, again, S. aureus uses myriad virulence factors to successfully escape from the host’s defenses and takes advantage of them. The impact of S. aureus virulence, combined with the collateral damage caused by an overwhelming immune response, leads to severe tissue damage and adverse clinical outcomes. In this review, we summarize step by step all of the S. aureus factors implicated in CAP and described to date, and we provide an outlook for future research.

scholarly journals Mapping the Global Network of Extracellular Protease Regulation in Staphylococcus aureus

mSphere ◽  
2019 ◽  
Vol 4 (5) ◽  
Author(s):  
Brittney D. Gimza ◽  
Maria I. Larias ◽  
Bridget G. Budny ◽  
Lindsey N. Shaw
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Global Network ◽  
Protease Production ◽  
Pathogenic Potential ◽  
Content Type ◽  
Regulatory Circuit ◽  
Primary Network ◽  
The Impact ◽  
Protease Expression

ABSTRACT A primary function of the extracellular proteases of Staphylococcus aureus is to control the progression of infection by selectively modulating the stability of virulence factors. Consequently, a regulatory network exists to titrate protease abundance/activity to influence the accumulation, or lack thereof, of individual virulence factors. Herein, we comprehensively map this system, exploring the regulation of the four protease loci by known and novel factors. In so doing, we determined that seven major elements (SarS, SarR, Rot, MgrA, CodY, SaeR, and SarA) form the primary network of control, with the latter three being the most powerful. We note that expression of aureolysin is largely repressed by these factors, while the spl operon is subject to the strongest upregulation of any protease loci, particularly by SarR and SaeR. Furthermore, when exploring scpA expression, we find it to be profoundly influenced in opposing fashions by SarA (repressor) and SarR (activator). We also present the screening of >100 regulator mutants of S. aureus, identifying 7 additional factors (ArgR2, AtlR, MntR, Rex, XdrA, Rbf, and SarU) that form a secondary circuit of protease control. Primarily, these elements serve as activators, although we reveal XdrA as a new repressor of protease expression. With the exception or ArgR2, each of the new effectors appears to work through the primary network of regulation to influence protease production. Collectively, we present a comprehensive regulatory circuit that emphasizes the complexity of protease regulation and suggest that its existence speaks to the importance of these enzymes to S. aureus physiology and pathogenic potential. IMPORTANCE The complex regulatory role of the proteases necessitates very tight coordination and control of their expression. While this process has been well studied, a major oversight has been the consideration of proteases as a single entity rather than as 10 enzymes produced from four different promoters. As such, in this study, we comprehensively characterized the regulation of each protease promoter, discovering vast differences in the way each protease operon is controlled. Additionally, we broaden the picture of protease regulation using a global screen to identify novel loci controlling protease activity, uncovering a cadre of new effectors of protease expression. The impact of these elements on the activity of proteases and known regulators was characterized by producing a comprehensive regulatory circuit that emphasizes the complexity of protease regulation in Staphylococcus aureus.

scholarly journals Validation of stable reference genes in Staphylococcus aureus to study gene expression under photodynamic treatment: a case study of SEB virulence factor analysis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Patrycja Ogonowska ◽  
Joanna Nakonieczna
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Virulence Factor ◽  
Reference Genes ◽  
Red Light ◽  
Green Light ◽  
Bacterial Cells ◽  
Photodynamic Treatment ◽  
Study Gene Expression ◽  
The Impact

Abstract Staphylococcal enterotoxin B (SEB), encoded by the seb gene, is a virulence factor produced by Staphylococcus aureus that is involved mainly in food poisoning and is known to act as an aggravating factor in patients with atopic dermatitis. Research results in animal infection models support the concept that superantigens, including SEB contribute to sepsis and skin and soft tissue infections. In contrast to antibiotics, antimicrobial photodynamic inactivation (aPDI) is a promising method to combat both bacterial cells and virulence factors. The main aims of this research were to (1) select the most stable reference genes under sublethal aPDI treatments and (2) evaluate the impact of aPDI on seb. Two aPDI combinations were applied under sublethal conditions: rose bengal (RB) and green light (λmax = 515 nm) and new methylene blue (NMB) and red light (λmax = 632 nm). The stability of ten candidate reference genes (16S rRNA, fabD, ftsZ, gmk, gyrB, proC, pyk, rho, rpoB and tpiA) was evaluated upon aPDI using four software packages—BestKeeper, geNorm, NormFinder and RefFinder. Statistical analyses ranked ftsZ and gmk (RB + green light) and ftsZ, proC, and fabD (NMB + red light) as the most stable reference genes upon photodynamic treatment. Our studies showed downregulation of seb under both aPDI conditions, suggesting that aPDI could decrease the level of virulence factors.

scholarly journals Antibiotic susceptibility of human-associated Staphylococcus aureus and its relation to agr typing, virulence genes, and biofilm formation

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Safoura Derakhshan ◽  
Masoumeh Navidinia ◽  
Fakhri Haghi
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Antibiotic Susceptibility ◽  
Biofilm Formation ◽  
Virulence Genes ◽  
Production Capacity ◽  
Diffusion Method ◽  
Accessory Gene ◽  
Disk Diffusion Method ◽  
The Impact

Abstract Background and objective Carriage of virulence factors confers some evolutionary benefit to bacteria, which favors the resistant strains. We aimed to analyze whether antibiotic susceptibility of Staphylococcus aureus strains is affected by agr typing, biofilm formation ability, and virulence profiles. Methods A total of 123 S. aureus clinical isolates were subjected to antimicrobial susceptibility testing by disk diffusion method, biofilm formation by microtiter plate method, as well as polymerase chain reaction screening to identify virulence genes and the accessory gene regulator (agr) types I-IV. A P value < 0.05 was considered significant. Results The most prevalent virulence gene was staphyloxanthin crtN, followed by hemolysin genes, capsular cap8H, toxic shock toxin tst, and enterotoxin sea, respectively. Resistant isolates were more commonly found in the agr-negative group than in the agr-positive group. Isolates of agr type III were more virulent than agr I isolates. Strong biofilm producers showed more antibiotic susceptibility and carried more virulence genes than non-strong biofilm producers. Associations were found between the presence of virulence genes and susceptibility to antibiotics. Carriage of the virulence genes and agr was higher in the inpatients; while, resistance and strong biofilms were more prevalent in the outpatients. Conclusion These findings indicated the presence of several virulence factors, biofilm production capacity, agr types and resistance to antibiotics in clinical S. aureus isolates. Considering the importance of S. aureus for human medicine, an understanding of virulence and resistance relationships would help to reduce the impact of S. aureus infections.

scholarly journals The Increased Accumulation of Staphylococcus aureus Virulence Factors Is Maximized in a purR Mutant by the Increased Production of SarA and Decreased Production of Extracellular Proteases

2021 ◽  
Vol 89 (4) ◽  
Author(s):  
Duah Alkam ◽  
Piroon Jenjaroenpun ◽  
Aura M. Ramirez ◽  
Karen E. Beenken ◽  
Horace J. Spencer ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Binding Proteins ◽  
Protease Production ◽  
Alpha Toxin ◽  
Extracellular Proteases ◽  
Content Type ◽  
Enhanced Production ◽  
Fibronectin Binding ◽  
The Impact

ABSTRACT Mutation of purR was previously shown to enhance the virulence of Staphylococcus aureus in a murine sepsis model, and this cannot be fully explained by increased expression of genes within the purine biosynthesis pathway. Rather, the increased production of specific S. aureus virulence factors, including alpha toxin and the fibronectin-binding proteins, was shown to play an important role. Mutation of purR was also shown previously to result in increased abundance of SarA. Here, we demonstrate by transposon sequencing that mutation of purR in the USA300 strain LAC increases fitness in a biofilm while mutation of sarA has the opposite effect. Therefore, we assessed the impact of sarA on reported purR-associated phenotypes by characterizing isogenic purR, sarA, and sarA/purR mutants. The results confirmed that mutation of purR results in increased abundance of alpha toxin, protein A, the fibronectin-binding proteins, and SarA, decreased production of extracellular proteases, an increased capacity to form a biofilm, and increased virulence in an osteomyelitis model. Mutation of sarA had the opposite effects on all of these phenotypes and, other than bacterial burdens in the bone, all of the phenotypes of sarA/purR mutants were comparable to those of sarA mutants. Limiting the production of extracellular proteases reversed all of the phenotypes of sarA mutants and most of those of sarA/purR mutants. We conclude that a critical component defining the virulence of a purR mutant is the enhanced production of SarA, which limits protease production to an extent that promotes the accumulation of critical S. aureus virulence factors.

scholarly journals Identification and characterization of msa (SA1233), a gene involved in expression of SarA and several virulence factors in Staphylococcus aureus

Microbiology ◽  
2006 ◽  
Vol 152 (9) ◽  
pp. 2559-2572 ◽  
Author(s):  
Karthik Sambanthamoorthy ◽  
Mark S. Smeltzer ◽  
Mohamed O. Elasri
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Protein A ◽  
Laboratory Strain ◽  
Reporter System ◽  
Accessory Gene ◽  
Accessory Gene Regulator ◽  
Genes Encoding ◽  
Membrane Spanning ◽  
The Impact

The staphylococcal accessory regulator (sarA) plays a central role in the regulation of virulence in Staphylococcus aureus. To date, studies involving sarA have focused on its activity as a global regulator that modulates transcription of a wide variety of genes (>100) and its role in virulence. However, there is also evidence to suggest the existence of accessory elements that modulate SarA production and/or function. A reporter system was developed to identify such elements, and a new gene, msa (SA1233), mutation of which results in reduced expression of SarA, was identified and characterized. Additionally, it was shown that mutation of msa resulted in altered transcription of the accessory gene regulator (agr) and the genes encoding several virulence factors including alpha toxin (hla) and protein A (spa). However, the impact of mutating msa was different in the laboratory strain RN6390 and the clinical isolate UAMS-1. For instance, mutation of msa caused a decrease in spa and hla transcription in RN6390 but had a different effect in UAMS-1. The strain-dependent effects of the msa mutation were similar to those observed previously, which suggests that msa may modulate the production of specific virulence factors through its impact on sarA. Interestingly, sequence analysis of Msa suggests that it is a putative membrane protein with three membrane-spanning regions, indicating that Msa might interact with the environment. The findings show that msa is involved in the expression of SarA and several virulence factors.

scholarly journals IscR Regulates Synthesis of Colonization Factor Antigen I Fimbriae in Response to Iron Starvation in Enterotoxigenic Escherichia coli

2015 ◽  
Vol 197 (18) ◽  
pp. 2896-2907 ◽  
Author(s):  
Sara Haines ◽  
Nadège Arnaud-Barbe ◽  
David Poncet ◽  
Sylvie Reverchon ◽  
Julien Wawrzyniak ◽  
...  
Keyword(s):  
Gene Expression ◽  
Escherichia Coli ◽  
Virulence Factors ◽  
Promoter Region ◽  
Promoter Activity ◽  
Enterotoxigenic Escherichia Coli ◽  
Iron Availability ◽  
Iron Starvation ◽  
Content Type ◽  
The Impact

ABSTRACTIron availability functions as an environmental cue for enteropathogenic bacteria, signaling arrival within the human host. As enterotoxigenicEscherichia coli(ETEC) is a major cause of human diarrhea, the effect of iron on ETEC virulence factors was evaluated here. ETEC pathogenicity is directly linked to production of fimbrial colonization factors and secretion of heat-labile enterotoxin (LT) and/or heat-stable enterotoxin (ST). Efficient colonization of the small intestine further requires at least the flagellin binding adhesin EtpA. Under iron starvation, production of the CFA/I fimbriae was increased in the ETEC H10407 prototype strain. In contrast, LT secretion was inhibited. Furthermore, under iron starvation, gene expression of thecfa(CFA/I) andetp(EtpBAC) operons was induced, whereas transcription of toxin genes was either unchanged or repressed. Transcriptional reporter fusion experiments focusing on thecfaoperon further showed that iron starvation stimulatedcfaApromoter activity in ETEC, indicating that the impact of iron on CFA/I production was mediated by transcriptional regulation. Evaluation ofcfaApromoter activity in heterologousE. colisingle mutant knockout strains identified IscR as the regulator responsible for inducingcfafimbrial gene expression in response to iron starvation, and this was confirmed in an ETEC ΔiscRstrain. The global iron response regulator, Fur, was not implicated. IscR binding sites were identifiedin silicowithin thecfaApromoter and fixation confirmed by DNase I footprinting, indicating that IscR directly binds the promoter region to induce CFA/I.IMPORTANCEPathogenic enterobacteria modulate expression of virulence genes in response to iron availability. Although the Fur transcription factor represents the global regulator of iron homeostasis inEscherichia coli, we show that several ETEC virulence factors are modulated by iron, with expression of the major fimbriae under the control of the iron-sulfur cluster regulator, IscR. Furthermore, we demonstrate that the apo form of IscR, lacking an Fe-S cluster, is able to directly fix the corresponding promoter region. These results provide further evidence implicating IscR in bacterial virulence and suggest that IscR may represent a more general regulator mediating the iron response in enteropathogens.

scholarly journals The δ Subunit of RNA Polymerase Guides Promoter Selectivity and Virulence in Staphylococcus aureus

2014 ◽  
Vol 82 (4) ◽  
pp. 1424-1435 ◽  
Author(s):  
Andy Weiss ◽  
J. Antonio Ibarra ◽  
Jessica Paoletti ◽  
Ronan K. Carroll ◽  
Lindsey N. Shaw
Keyword(s):  
Staphylococcus Aureus ◽  
Rna Polymerase ◽  
Virulence Factors ◽  
Alpha Toxin ◽  
Rna Seq ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Secreted Proteases ◽  
The Impact ◽  
Panton Valentine Leukocidin

ABSTRACTIn Gram-positive bacteria, and particularly theFirmicutes, the DNA-dependent RNA polymerase (RNAP) complex contains an additional subunit, termed the δ factor, or RpoE. This enigmatic protein has been studied for more than 30 years for various organisms, but its function is still not well understood. In this study, we investigated its role in the major human pathogenStaphylococcus aureus. We showed conservation of important structural regions of RpoE inS. aureusand other species and demonstrated binding to core RNAP that is mediated by the β and/or β′ subunits. To identify the impact of the δ subunit on transcription, we performed transcriptome sequencing (RNA-seq) analysis and observed 191 differentially expressed genes in therpoEmutant. Ontological analysis revealed, quite strikingly, that many of the downregulated genes were known virulence factors, while several mobile genetic elements (SaPI5 and prophage ϕSA3usa) were strongly upregulated. Phenotypically, therpoEmutant had decreased accumulation and/or activity of a number of key virulence factors, including alpha toxin, secreted proteases, and Panton-Valentine leukocidin (PVL). We further observed significantly decreased survival of the mutant in whole human blood, increased phagocytosis by human leukocytes, and impaired virulence in a murine model of infection. Collectively, our results demonstrate that the δ subunit of RNAP is a critical component of theS. aureustranscription machinery and plays an important role during infection.

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