Regulation of<i>Staphylococcus aureus</i>Virulence

Jenul, Christian; Horswill, Alexander R.

doi:10.1128/9781683670131.ch41

Cited by 80 publications

(102 citation statements)

References 212 publications

(107 reference statements)

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“…Previous studies described over half a dozen transcription factors with direct or indirect roles in regulation of virulence factor expression in S. aureus 43 . The number of regulators, and their complex network of interactions, make it extremely difficult to understand how these genes are regulated at a genome scale.…”

Section: Ica Reveals Organization Of Virulence Factor Expressionmentioning

confidence: 99%

Revealing 29 sets of independently modulated genes inStaphylococcus aureus, their regulators and role in key physiological responses

Poudel

Tsunemoto

Seif

et al. 2020

Preprint

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The ability of Staphylococcus aureus to infect many different tissue sites is enabled, in part, by its Transcriptional Regulatory Network (TRN) that coordinates its gene expression to respond to different environments. We elucidated the organization and activity of this TRN by applying Independent Component Analysis (ICA) to a compendium of 108 RNAseq expression profiles from two S. aureus clinical strains (TCH1516 and LAC). ICA decomposed the S. aureus transcriptome into 29 independently modulated sets of genes (i-modulons) that revealed (1) high confidence associations between 21 i-modulons and known regulators; (2) an association between an i-modulon and σS, whose regulatory role was previously undefined; (3) the regulatory organization of 65 virulence factors in the form of three i-modulons associated with AgrR, SaeR and Vim-3, (4) the roles of three key transcription factors (codY, Fur and ccpA) in coordinating the metabolic and regulatory networks; and (5) a low dimensional representation, involving the function of few transcription factors, of changes in gene expression between two laboratory media (RPMI, CAMHB) and two physiological media (blood and serum). This representation of the TRN covers 842 genes representing 76% of the variance in gene expression that provides a quantitative reconstruction of transcriptional modules in S. aureus, and a platform enabling its full elucidation. Significance StatementStaphylococcus aureus infections impose an immense burden on the healthcare system. To establish a successful infection in a hostile host environment, S. aureus must coordinate its gene expression to respond to a wide array of challenges. This balancing act is largely orchestrated by the Transcriptional Regulatory Network (TRN). Here, we present a model of 29 independently modulated sets of genes that form the basis for a segment of the TRN in clinical USA300 strains of S. aureus . Using this model, we demonstrate the concerted role of various cellular systems (e.g. metabolism, virulence and stress response) underlying key physiological responses, including response during blood infection. framework to reevaluate the RNA-seq data accelerates discovery by (1) quantitatively formulating TRN organization, (2) simplifying complex changes across hundreds of genes into a few changes in regulator activities, (3) allowing for analysis of interactions among different regulators, (4) connecting transcriptional regulation to metabolism, and (5) defining previously unknown regulons. Main

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Section: Ica Reveals Organization Of Virulence Factor Expressionmentioning

confidence: 99%

Revealing 29 sets of independently modulated genes inStaphylococcus aureus, their regulators and role in key physiological responses

Poudel

Tsunemoto

Seif

et al. 2020

Preprint

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“…S. aureus virulence and biofilm formation is tightly regulated by SarA, Agr and SigB (56). They interact together and are all involved in the production or inhibition of extracellular proteins, regulating biofilm matrix stability.…”

Section: Discussionmentioning

confidence: 99%

“…Biofilm formation in S. aureus is tightly regulated by the quorum sensing (QS) system. S. aureus QS is under the control of the agr operon (55, 56). The agr system initiates the transcription of RNAIII, increasing extracellular proteases production and inhibiting cell adhesion to a surface.…”

Section: Introductionmentioning

confidence: 99%

“…RNAIII is an inhibitor of fnbA and fnbB transcription but fnbA is also under the control of SarA, another global regulator in S. aureus . SarA is under the control of the transcriptional regulator SigB (56, 59). SigB activity is tightly regulated by RsbU, leading to agr (RNAIII) inhibition and decreased extracellular proteases production, favoring FnBPs dependent biofilm formation (60, 61).…”

Section: Introductionmentioning

confidence: 99%

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RpiRc regulates RsbU to modulate eDNA-dependent biofilm formation andin vivovirulence ofStaphylococcus aureusin a mouse model of catheter infection

Fischer

Girard

Laumay

et al. 2019

Preprint

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15Staphylococcus aureus is a major human pathogen. Despite high incidence and morbidity, molecular 16 mechanisms occurring during infection remain largely unknown. Under defined conditions, biofilm 17 formation contributes to the severity of S. aureus related infections. Extracellular DNA (eDNA), a 18 component of biofilm matrix released from apoptotic bacteria, is involved in biofilm structure and 19 stability. In many bacterial biofilms, eDNA originates from cell lysis although eDNA can also be 20 actively secreted or exported by bacterial membrane vesicles. By screening the Nebraska transposon 21 library, we identified rpiRc as a biofilm regulator involved in eDNA regulation. RpiRc is a transcription 22 factor from the pentose phosphate pathway (PPP) whose product is a polysaccharide intercellular 23 adhesin (PIA) precursor. However, rpiRc mutant strain showed neither susceptibility to DispersinB® (a 24 commercially available enzyme disrupting PIA biofilms) nor alteration of ica transcription (the operon 25 regulating PIA production). Decreased biofilm formation was linked to Sln, an extracellular compound 26 degrading eDNA in an autolysis independent pathway. Biofilm susceptibility to antibiotics in wt and 27 mutant strains was tested using a similar protocol as the Calgary biofilm device. Involvement of RpiRc 28 in S. aureus virulence was assessed ex vivo by internalization experiments into HEK293 cells and in 29 vivo in a mouse model of subcutaneous catheter infection. While minimum inhibitory concentrations 30 (MICs) of planktonic cells were not affected in the mutant strain, we observed increased biofilm 31 susceptibility to almost all tested antibiotics, regardless of their mode of action. More importantly, 32 the rpiRc mutant showed reduced virulence in both ex vivo and in vivo experiments related to 33 decreased fnbpA-B transcription and eDNA production. RpiRc is an important regulator involved in 34 eDNA degradation inside the matrix of mature PIA independent biofilms. These results illustrate that 35 RpiRc contributes to increased antibiotic tolerance in mature bacterial biofilm and also to S. aureus 36 cell adhesion and virulence during subcutaneous infection. 37 38 3 39 Author summary 40 Biofilm formation contributes to the severity of Staphylococcus aureus related infections. Biofilm 41 matrix is mainly composed by polysaccharide intercellular adhesion (PIA), proteins and extracellular 42 DNA (eDNA). By screening a mutant library of S. aureus, RpiRc was identified as a new regulator of 43 eDNA dependent biofilm formation. How RpiRc regulates biofilm and its role in S. aureus virulence 44 was studied in four different S. aureus strains. Deletion of RpiRc resulted in a pronounced decreased 45 eDNA dependent biofilm formation, but not PIA dependent biofilm formation. Decreased biofilm 46 formation was not related to increased autolysis, but was linked to extracellular compounds found in 47 the supernatant of mutant biofilms. Sln was identified as one of this compound. RpiRc deletion also 48 decreased...

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“…The ability of S. aureus to rapidly infect host is due to the expression and release of many virulence factors such as cytolysins, hemolysins, leukocidins, coagulases, adhesins, proteases, nucleases, enterotoxins, lipases, exfoliative toxins, and immune-modulatory factors, and cell surface associated proteins including Protein A and fibrinogen-, fibronectin- and collagen-binding proteins(10–15). Although some of the pathways of virulence factor expression and regulation such as sarA , agr , srrAB , saeRS , ArlRS ,(16) in S. aureus as well as the factors acting via one or more of these pathways(17–19) are studied, the understanding of the production and regulation of virulence factors in S. aureus is through a multifaceted network that is still obscure and many genes with unknown functions in S. aureus genome with roles in virulence and pathogenicity remain to be uncovered.…”

Section: Introductionmentioning

confidence: 99%

Uncovering Staphylococcus aureus genes with roles in pathogenicity by silkworm infection model

Paudel

Hamamoto

Panthee

et al. 2019

Preprint

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22The regulatory network of virulence factors production by Staphylococcus aureus, an 23 opportunistic pathogen, is incompletely understood, and the functions of many 24 uncharacterized genes in its genome remain to be uncovered. We screened 380 25 function unassigned genes disrupted mutants of the community-acquired methicillin-26 resistant S. aureus USA300 for pathogenicity using silkworms and identified 11 27 strains with reduced silkworm killing ability. Nine out of the 11 strains displayed 28 reduced virulence in the mouse model as evidenced by reduced colony-forming units 29 in organs of the infected mice. Three of the identified gene-disrupted mutants had 30 reduced hemolytic activity, one among the three also had reduced proteolytic activity 31 and pigment production. These results suggest that silkworm model could identify 32 the genes required for virulence in the mouse model. The newly identified genes 33 involved in virulence in this study facilitates the further understanding of the 34 pathogenicity of S. aureus. 35 36 Importance 37We performed a large scale screening of mutants of Staphylococcus aureus with 38 disruption in function unassigned genes using silkworm infection model and 39identified eleven genes required for full virulence in silkworm. Nine of the eleven 40 genes were involved in virulence in mice and were previously not known to 41 aggravate virulence of S. aureus. The results suggest that silkworm model is suitable 42 for quantitative measurement of virulence, which is shared between silkworms and 43 mammals. 44 45 48 endocarditis, and bacteremia(1). With an increasing rise in the resistance of 49 methicillin-resistant S. aureus (MRSA), the appearance of vancomycin-intermediate 50 S. aureus (VISA)(2, 3), and vancomycin-resistant S. aureus (VRSA)(4-7), S. aureus 51 has become one of the leading causes of morbidity and mortality and has been 52 categorized as a threat among antimicrobial-resistant strains by the World Health 53 Organization(8) and the Centers for Disease Control and Prevention(9). The ability of 54 S. aureus to rapidly infect host is due to the expression and release of many 55 virulence factors such as cytolysins, hemolysins, leukocidins, coagulases, adhesins, 56 proteases, nucleases, enterotoxins, lipases, exfoliative toxins, and immune-57 modulatory factors, and cell surface-associated proteins including Protein A and 58fibrinogen-, fibronectin-and collagen-binding proteins(10-15). Although some of the 59 pathways of virulence factor expression and regulation such as sarA, agr, srrAB, 60 saeRS, ArlRS,(16) in S. aureus as well as the factors acting via one or more of these 61 pathways (17)(18)(19) are studied, the understanding of the production and regulation of 62 virulence factors in S. aureus is through a multifaceted network that is still obscure 63 and many genes with unknown functions in S. aureus genome with roles in virulence 64 and pathogenicity remain to be uncovered. 65 66Since virulence is the degree of pathogenicity of a microorganism that is mostly...

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Regulation ofStaphylococcus aureusVirulence

Cited by 80 publications

References 212 publications

Revealing 29 sets of independently modulated genes inStaphylococcus aureus, their regulators and role in key physiological responses

Revealing 29 sets of independently modulated genes inStaphylococcus aureus, their regulators and role in key physiological responses

RpiRc regulates RsbU to modulate eDNA-dependent biofilm formation andin vivovirulence ofStaphylococcus aureusin a mouse model of catheter infection

Uncovering Staphylococcus aureus genes with roles in pathogenicity by silkworm infection model

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