The msaABCR Operon Regulates the Response to Oxidative Stress in Staphylococcus aureus

ABSTRACT Staphylococcus aureus has evolved a complex regulatory network that controls a multitude of defense mechanisms against the deleterious effects of oxidative stress stimuli, subsequently leading to the pathogen’s survival and persistence in the hosts. Previously, we characterized the msaABCR operon as a regulator of virulence, antibiotic resistance, and the formation of persister cells in S. aureus. Deletion of the msaABCR operon resulted in the downregulation of several genes involved in resistance against oxidative stress. Notably, those included carotenoid biosynthetic genes and the ohr gene, which is involved in resistance against organic hydroperoxides. These findings led us to hypothesize that the msaABCR operon is involved in resisting oxidative stress generated in the presence of both H2O2 and organic hydroperoxides. Here, we report that a protein product of the msaABCR operon (MsaB) transcriptionally regulates the expression of the crtOPQMN operon and the ohr gene to resist in vitro oxidative stresses. In addition to its direct regulation of the crtOPQMN operon and ohr gene, we also show that MsaB is the transcriptional repressor of sarZ (repressor of ohr). Taken together, these results suggest that the msaABCR operon regulates an oxidative stress defense mechanism, which is required to facilitate persistent and recurrent staphylococcal infections. Moving forward, we plan to investigate the role of msaABCR in the persistence of S. aureus under in vivo conditions. IMPORTANCE This study shows the involvement of the msaABCR operon in resisting oxidative stress by Staphylococcus aureus generated under in vitro and ex vivo conditions. We show that MsaB regulates the expression and production of a carotenoid pigment, staphyloxanthin, which is a potent antioxidant in S. aureus. We also demonstrate that MsaB regulates the ohr gene, which is involved in defending against oxidative stress generated by organic hydroperoxides. This study highlights the importance of msaABCR in the survival of S. aureus in the presence of various environmental stimuli that mainly exert oxidative stress. The findings from this study indicate the possibility that msaABCR is involved in the persistence of staphylococcal infections and therefore could be a potential antimicrobial target to overcome recalcitrant staphylococcal infections.

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Phosphatidylinositol-Specific Phospholipase C Contributes to Survival of Staphylococcus aureus USA300 in Human Blood and Neutrophils

Infection and Immunity ◽

10.1128/iai.01168-13 ◽

2014 ◽

Vol 82 (4) ◽

pp. 1559-1571 ◽

Cited By ~ 28

Author(s):

Mark J. White ◽

Jeffrey M. Boyd ◽

Alexander R. Horswill ◽

William M. Nauseef

Keyword(s):

Oxidative Stress ◽

Staphylococcus Aureus ◽

Phospholipase C ◽

Whole Blood ◽

Dependent Manner ◽

Binding Studies ◽

Content Type ◽

Positive Regulators

ABSTRACTStaphylococcus aureusis an important human pathogen that employs a large repertoire of secreted virulence factors to promote disease pathogenesis. Many strains ofS. aureuspossess aplcgene that encodes a phosphatidylinositol (PI)-specific phospholipase C (PI-PLC) capable of hydrolyzing PI and cleaving glycosyl-PI (GPI)-linked proteins from cell surfaces. Despite being secreted by virulent staphylococci, the contribution of PI-PLC to the capacity ofS. aureusto cause disease remains undefined. Our goal in these studies was to understand PI-PLC in the context ofS. aureusbiology. Among a collection of genetically diverse clinical isolates ofS. aureus, community-associated methicillin-resistantS. aureus(CA-MRSA) USA300 secreted the most PI-PLC. Screening a collection of two-component system (TCS) mutants ofS. aureus, we identified both theagrquorum-sensing system and the SrrAB TCS to be positive regulators ofplcgene expression. Real-time PCR and PI-PLC enzyme assays of the TCS mutants, coupled with SrrA promoter binding studies, demonstrated that SrrAB was the predominant transcriptional activator ofplc. Furthermore,plcregulation was linked to oxidative stress bothin vitroandin vivoin a SrrAB-dependent manner. A Δplcmutant in a CA-MRSA USA300 background exhibited a survival defect in human whole blood and in isolated neutrophils. However, the same mutant strain displayed no survival defect in murine models of infection or murine whole blood. Overall, these data identify potential links between bacterial responses to the host innate immune system and to oxidative stress and suggest how PI-PLC could contribute to the pathogenesis ofS. aureusinfections.

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Novel Synthetic (Poly)Glycerolphosphate-Based Antistaphylococcal Conjugate Vaccine

Infection and Immunity ◽

10.1128/iai.00271-13 ◽

2013 ◽

Vol 81 (7) ◽

pp. 2554-2561 ◽

Cited By ~ 13

Author(s):

Quanyi Chen ◽

Jay Dintaman ◽

Andrew Lees ◽

Goutam Sen ◽

David Schwartz ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Conjugate Vaccine ◽

Animal Studies ◽

Lipoteichoic Acid ◽

Gram Positive ◽

Content Type ◽

Cpg Oligodeoxynucleotides ◽

Staphylococcal Infections

ABSTRACTStaphylococcal infections are a major source of global morbidity and mortality. Currently there exists no antistaphylococcal vaccine in clinical use. Previous animal studies suggested a possible role for purified lipoteichoic acid as a vaccine target for eliciting protective IgG to several Gram-positive pathogens. Since the highly conserved (poly)glycerolphosphate backbone of lipoteichoic acid is a major antigenic target of the humoral immune system during staphylococcal infections, we developed a synthetic method for producing glycerol phosphoramidites to create a covalent 10-mer of (poly)glycerolphosphate for potential use in a conjugate vaccine. We initially demonstrated that intactStaphylococcus aureuselicits murine CD4+T cell-dependent (poly)glycerolphosphate-specific IgM and IgG responsesin vivo. Naive mice immunized with a covalent conjugate of (poly)glycerolphosphate and tetanus toxoid in alum plus CpG-oligodeoxynucleotides produced high secondary titers of serum (poly)glycerolphosphate-specific IgG. Sera from immunized mice enhanced opsonophagocytic killing of liveStaphylococcus aureusin vitro. Mice actively immunized with the (poly)glycerolphosphate conjugate vaccine showed rapid clearance of staphylococcal bacteremiain vivorelative to mice similarly immunized with an irrelevant conjugate vaccine. In contrast to purified, natural lipoteichoic acid, the (poly)glycerolphosphate conjugate vaccine itself exhibited no detectable inflammatory activity. These data suggest that a synthetic (poly)glycerolphosphate-based conjugate vaccine will contribute to active protection against extracellular Gram-positive pathogens expressing this highly conserved backbone structure in their membrane-associated lipoteichoic acid.

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Differential effect of anesthetics on mucociliary clearance in vivo in mice

Scientific Reports ◽

10.1038/s41598-021-84605-y ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Kyle S. Feldman ◽

Eunwon Kim ◽

Michael J. Czachowski ◽

Yijen Wu ◽

Cecilia W. Lo ◽

...

Keyword(s):

Mucociliary Clearance ◽

Defense Mechanism ◽

Ex Vivo ◽

Beat Frequency ◽

Ciliary Beat Frequency ◽

Wild Type ◽

Sulfur Colloid ◽

Ct System

AbstractRespiratory mucociliary clearance (MCC) is a key defense mechanism that functions to entrap and transport inhaled pollutants, particulates, and pathogens away from the lungs. Previous work has identified a number of anesthetics to have cilia depressive effects in vitro. Wild-type C57BL/6 J mice received intra-tracheal installation of 99mTc-Sulfur colloid, and were imaged using a dual-modality SPECT/CT system at 0 and 6 h to measure baseline MCC (n = 8). Mice were challenged for one hour with inhalational 1.5% isoflurane, or intraperitoneal ketamine (100 mg/kg)/xylazine (20 mg/kg), ketamine (0.5 mg/kg)/dexmedetomidine (50 mg/kg), fentanyl (0.2 mg/kg)/1.5% isoflurane, propofol (120 mg/Kg), or fentanyl/midazolam/dexmedetomidine (0.025 mg/kg/2.5 mg/kg/0.25 mg/kg) prior to MCC assessment. The baseline MCC was 6.4%, and was significantly reduced to 3.7% (p = 0.04) and 3.0% (p = 0.01) by ketamine/xylazine and ketamine/dexmedetomidine challenge respectively. Importantly, combinations of drugs containing fentanyl, and propofol in isolation did not significantly depress MCC. Although no change in cilia length or percent ciliation was expected, we tried to correlate ex-vivo tracheal cilia ciliary beat frequency and cilia-generated flow velocities with MCC and found no correlation. Our results indicate that anesthetics containing ketamine (ketamine/xylazine and ketamine/dexmedetomidine) significantly depress MCC, while combinations containing fentanyl (fentanyl/isoflurane, fentanyl/midazolam/dexmedetomidine) and propofol do not. Our method for assessing MCC is reproducible and has utility for studying the effects of other drug combinations.

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Exogenous Alginate Protects Staphylococcus aureus from Killing by Pseudomonas aeruginosa

Journal of Bacteriology ◽

10.1128/jb.00559-19 ◽

2019 ◽

Vol 202 (8) ◽

Cited By ~ 2

Author(s):

Courtney E. Price ◽

Dustin G. Brown ◽

Dominique H. Limoli ◽

Vanessa V. Phelan ◽

George A. O’Toole

Keyword(s):

Staphylococcus Aureus ◽

Pseudomonas Aeruginosa ◽

Physical Space ◽

Late Time ◽

Protective Effects ◽

Content Type ◽

Alginate Production ◽

The Impact

ABSTRACT Cystic fibrosis (CF) patients chronically infected with both Pseudomonas aeruginosa and Staphylococcus aureus have worse health outcomes than patients who are monoinfected with either P. aeruginosa or S. aureus. We showed previously that mucoid strains of P. aeruginosa can coexist with S. aureus in vitro due to the transcriptional downregulation of several toxic exoproducts typically produced by P. aeruginosa, including siderophores, rhamnolipids, and HQNO (2-heptyl-4-hydroxyquinoline N-oxide). Here, we demonstrate that exogenous alginate protects S. aureus from P. aeruginosa in both planktonic and biofilm coculture models under a variety of nutritional conditions. S. aureus protection in the presence of exogenous alginate is due to the transcriptional downregulation of pvdA, a gene required for the production of the iron-scavenging siderophore pyoverdine as well as the downregulation of the PQS (Pseudomonas quinolone signal) (2-heptyl-3,4-dihydroxyquinoline) quorum sensing system. The impact of exogenous alginate is independent of endogenous alginate production. We further demonstrate that coculture of mucoid P. aeruginosa with nonmucoid P. aeruginosa strains can mitigate the killing of S. aureus by the nonmucoid strain of P. aeruginosa, indicating that the mechanism that we describe here may function in vivo in the context of mixed infections. Finally, we investigated a panel of mucoid clinical isolates that retain the ability to kill S. aureus at late time points and show that each strain has a unique expression profile, indicating that mucoid isolates can overcome the S. aureus-protective effects of mucoidy in a strain-specific manner. IMPORTANCE CF patients are chronically infected by polymicrobial communities. The two dominant bacterial pathogens that infect the lungs of CF patients are P. aeruginosa and S. aureus, with ∼30% of patients coinfected by both species. Such coinfected individuals have worse outcomes than monoinfected patients, and both species persist within the same physical space. A variety of host and environmental factors have been demonstrated to promote P. aeruginosa-S. aureus coexistence, despite evidence that P. aeruginosa kills S. aureus when these organisms are cocultured in vitro. Thus, a better understanding of P. aeruginosa-S. aureus interactions, particularly mechanisms by which these microorganisms are able to coexist in proximal physical space, will lead to better-informed treatments for chronic polymicrobial infections.

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Ex VivoMaturation Assay for Testing Antimalarial Sensitivity of Rodent Malaria Parasites

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01292-16 ◽

2016 ◽

Vol 60 (11) ◽

pp. 6859-6866 ◽

Cited By ~ 4

Author(s):

Zi Wei Chang ◽

Benoit Malleret ◽

Bruce Russell ◽

Laurent Rénia ◽

Carla Claser

Keyword(s):

Ex Vivo ◽

Single Step ◽

Parasite Development ◽

Ring Stage ◽

Malaria Parasites ◽

Rodent Malaria ◽

Content Type ◽

Parasite Biology

ABSTRACTEx vivoassay systems provide a powerful approach to studying human malaria parasite biology and to testing antimalarials. For rodent malaria parasites, short-termin vitroculture andex vivoantimalarial susceptibility assays are relatively cumbersome, relying onin vivopassage for synchronization, since ring-stage parasites are an essential starting material. Here, we describe a new approach based on the enrichment of ring-stagePlasmodium berghei,P. yoelii, andP. vinckei vinckeiusing a single-step Percoll gradient. Importantly, we demonstrate that the enriched ring-stage parasites develop synchronously regardless of the parasite strain or species used. Using a flow cytometry assay with Hoechst and ethidium or MitoTracker dye, we show that parasite development is easily and rapidly monitored. Finally, we demonstrate that this approach can be used to screen antimalarial drugs.

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Role of BrnQ1 and BrnQ2 in Branched-Chain Amino Acid Transport and Virulence in Staphylococcus aureus

Infection and Immunity ◽

10.1128/iai.02542-14 ◽

2014 ◽

Vol 83 (3) ◽

pp. 1019-1029 ◽

Cited By ~ 21

Author(s):

Julienne C. Kaiser ◽

Sameha Omer ◽

Jessica R. Sheldon ◽

Ian Welch ◽

David E. Heinrichs

Keyword(s):

Staphylococcus Aureus ◽

Virulence Gene ◽

Defined Medium ◽

Infection Model ◽

Content Type ◽

Virulence Gene Expression ◽

Branched Chain Amino Acid ◽

Branched Chain

The branched-chain amino acids (BCAAs; Ile, Leu, and Val) not only are important nutrients for the growth ofStaphylococcus aureusbut also are corepressors for CodY, which regulates virulence gene expression, implicating BCAAs as an important link between the metabolic state of the cell and virulence. BCAAs are either synthesized intracellularly or acquired from the environment.S. aureusencodes three putative BCAA transporters, designated BrnQ1, BrnQ2, and BrnQ3; their functions have not yet been formally tested. In this study, we mutated all threebrnQparalogs so as to characterize their substrate specificities and their roles in growthin vitroandin vivo. We demonstrated that in the community-associated, methicillin-resistantS. aureus(CA-MRSA) strain USA300, BrnQ1 is involved in uptake of all three BCAAs, BrnQ2 transports Ile, and BrnQ3 does not have a significant role in BCAA transport under the conditions tested. Of the three, only BrnQ1 is essential for USA300 to grow in a chemically defined medium that is limited for Leu or Val. Interestingly, we observed that abrnQ2mutant grew better than USA300 in media limited for Leu and Val, owing to the fact that this mutation leads to overexpression ofbrnQ1. In a murine infection model, thebrnQ1mutant was attenuated, but in contrast,brnQ2mutants had significantly increased virulence compared to that of USA300, a phenotype we suggest is at least partially linked to enhancedin vivoscavenging of Leu and Val through BrnQ1. These data uncover a hitherto-undiscovered connection between nutrient acquisition and virulence in CA-MRSA.

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Heme oxygenase-1 induction by hemin prevents oxidative stress-induced acute cholestasis in the rat

Clinical Science ◽

10.1042/cs20180675 ◽

2019 ◽

Vol 133 (1) ◽

pp. 117-134 ◽

Cited By ~ 7

Author(s):

Pamela L. Martín ◽

Paula Ceccatto ◽

María V. Razori ◽

Daniel E.A. Francés ◽

Sandra M.M. Arriaga ◽

...

Keyword(s):

Oxidative Stress ◽

Heme Oxygenase ◽

Bile Flow ◽

Driving Forces ◽

Membrane Lipids ◽

Ex Vivo ◽

Heme Oxygenase 1 ◽

Canalicular Transporters

Abstract We previously demonstrated in in vitro and ex vivo models that physiological concentrations of unconjugated bilirubin (BR) prevent oxidative stress (OS)-induced hepatocanalicular dysfunction and cholestasis. Here, we aimed to ascertain, in the whole rat, whether a similar cholestatic OS injury can be counteracted by heme oxygenase-1 (HO-1) induction that consequently elevates endogenous BR levels. This was achieved through the administration of hemin, an inducer of HO-1, the rate-limiting step in BR generation. We found that BR peaked between 6 and 8 h after hemin administration. During this time period, HO-1 induction fully prevented the pro-oxidant tert-butylhydroperoxide (tBuOOH)-induced drop in bile flow, and in the biliary excretion of bile salts and glutathione, the two main driving forces of bile flow; this was associated with preservation of the membrane localization of their respective canalicular transporters, bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2), which are otherwise endocytosed by OS. HO-1 induction counteracted the oxidation of intracellular proteins and membrane lipids induced by tBuOOH, and fully prevented the increase in the oxidized-to-total glutathione (GSHt) ratio, a sensitive parameter of hepatocellular OS. Compensatory elevations of the activity of the antioxidant enzymes catalase (CAT) and superoxide dismutase (SOD) were also prevented. We conclude that in vivo HO-1 induction protects the liver from acute oxidative injury, thus preventing consequent cholestasis. This reveals an important role for the induction of HO-1 and the consequently elevated levels of BR in preserving biliary secretory function under OS conditions, thus representing a novel therapeutic tool to limit the cholestatic injury that bears an oxidative background.

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Intestinal IgA Regulates Expression of a Fructan Polysaccharide Utilization Locus in Colonizing Gut Commensal Bacteroides thetaiotaomicron

mBio ◽

10.1128/mbio.02324-19 ◽

2019 ◽

Vol 10 (6) ◽

Cited By ~ 4

Author(s):

Payal Joglekar ◽

Hua Ding ◽

Pablo Canales-Herrerias ◽

Pankaj Jay Pasricha ◽

Justin L. Sonnenburg ◽

...

Keyword(s):

Gut Microbiota ◽

Ex Vivo ◽

Microbial Colonization ◽

Bacteroides Thetaiotaomicron ◽

Content Type ◽

Microbial Utilization ◽

Polysaccharide Utilization Locus ◽

The Impact

ABSTRACT Gut-derived immunoglobulin A (IgA) is the most abundant antibody secreted in the gut that shapes gut microbiota composition and functionality. However, most of the microbial antigens targeted by gut IgA remain unknown, and the functional effects of IgA targeting these antigens are currently understudied. This study provides a framework for identifying and characterizing gut microbiota antigens targeted by gut IgA. We developed a small intestinal ex vivo culture assay to harvest lamina propria IgA from gnotobiotic mice, with the aim of identifying antigenic targets in a model human gut commensal, Bacteroides thetaiotaomicron VPI-5482. Colonization by B. thetaiotaomicron induced a microbe-specific IgA response that was reactive against diverse antigens, including capsular polysaccharides, lipopolysaccharides, and proteins. IgA against microbial protein antigens targeted membrane and secreted proteins with diverse functionalities, including an IgA specific against proteins of the polysaccharide utilization locus (PUL) that are necessary for utilization of fructan, which is an important dietary polysaccharide. Further analyses demonstrated that the presence of dietary fructan increased the production of fructan PUL-specific IgA, which then downregulated the expression of fructan PUL in B. thetaiotaomicron, both in vivo and in vitro. Since the expression of fructan PUL has been associated with the ability of B. thetaiotaomicron to colonize the gut in the presence of dietary fructans, our work suggests a novel role for gut IgA in regulating microbial colonization by modulating their metabolism. IMPORTANCE Given the significant impact that gut microbes have on our health, it is essential to identify key host and environmental factors that shape this diverse community. While many studies have highlighted the impact of diet on gut microbiota, little is known about how the host regulates this critical diet-microbiota interaction. In our present study, we discovered that gut IgA targeted a protein complex involved in the utilization of an important dietary polysaccharide: fructan. While the presence of dietary fructans was previously thought to allow unrestricted growth of fructan-utilizing bacteria, our work shows that gut IgA, by targeting proteins responsible for fructan utilization, provides the host with tools that can restrict the microbial utilization of such polysaccharides, thereby controlling their growth.

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Evaluation of Antibiotics Active against Methicillin-Resistant Staphylococcus aureus Based on Activity in an Established Biofilm

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01251-16 ◽

2016 ◽

Vol 60 (10) ◽

pp. 5688-5694 ◽

Cited By ~ 23

Author(s):

Daniel G. Meeker ◽

Karen E. Beenken ◽

Weston B. Mills ◽

Allister J. Loughran ◽

Horace J. Spencer ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Biofilm Formation ◽

Limit Of Detection ◽

Relative Activity ◽

Methicillin Resistant ◽

Content Type ◽

Comparable Activity ◽

Antibiotic Delivery

ABSTRACTWe usedin vitroandin vivomodels of catheter-associated biofilm formation to compare the relative activity of antibiotics effective against methicillin-resistantStaphylococcus aureus(MRSA) in the specific context of an established biofilm. The results demonstrated that, underin vitroconditions, daptomycin and ceftaroline exhibited comparable activity relative to each other and greater activity than vancomycin, telavancin, oritavancin, dalbavancin, or tigecycline. This was true when assessed using established biofilms formed by the USA300 methicillin-resistant strain LAC and the USA200 methicillin-sensitive strain UAMS-1. Oxacillin exhibited greater activity against UAMS-1 than LAC, as would be expected, since LAC is an MRSA strain. However, the activity of oxacillin was less than that of daptomycin and ceftaroline even against UAMS-1. Among the lipoglycopeptides, telavancin exhibited the greatest overall activity. Specifically, telavancin exhibited greater activity than oritavancin or dalbavancin when tested against biofilms formed by LAC and was the only lipoglycopeptide capable of reducing the number of viable bacteria below the limit of detection. With biofilms formed by UAMS-1, telavancin and dalbavancin exhibited comparable activity relative to each other and greater activity than oritavancin. Importantly, ceftaroline was the only antibiotic that exhibited greater activity than vancomycin when testedin vivoin a murine model of catheter-associated biofilm formation. These results emphasize the need to consider antibiotics other than vancomycin, most notably, ceftaroline, for the treatment of biofilm-associatedS. aureusinfections, including by the matrix-based antibiotic delivery methods often employed for local antibiotic delivery in the treatment of these infections.

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The 5′ NAD Cap of RNAIII Modulates Toxin Production in Staphylococcus aureus Isolates

Journal of Bacteriology ◽

10.1128/jb.00591-19 ◽

2019 ◽

Vol 202 (6) ◽

Cited By ~ 3

Author(s):

Hector Gabriel Morales-Filloy ◽

Yaqing Zhang ◽

Gabriele Nübel ◽

Shilpa Elizabeth George ◽

Natalya Korn ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Secondary Structure ◽

Quorum Sensing ◽

Opportunistic Pathogen ◽

Toxin Production ◽

Dual Function ◽

Content Type ◽

The Stability

ABSTRACT Nicotinamide adenosine dinucleotide (NAD) has been found to be covalently attached to the 5′ ends of specific RNAs in many different organisms, but the physiological consequences of this modification are largely unknown. Here, we report the occurrence of several NAD-RNAs in the opportunistic pathogen Staphylococcus aureus. Most prominently, RNAIII, a central quorum-sensing regulator of this bacterium’s physiology, was found to be 5′ NAD capped in a range from 10 to 35%. NAD incorporation efficiency into RNAIII was found to depend in vivo on the −1 position of the P3 promoter. An increase in RNAIII’s NAD content led to a decreased expression of alpha- and delta-toxins, resulting in reduced cytotoxicity of the modified strains. These effects seem to be caused neither by changes in RNAIII’s secondary structure nor by a different translatability upon NAD attachment, as indicated by unaltered patterns in in vitro chemical probing and toeprinting experiments. Even though we did not observe any effect of this modification on RNAIII’s secondary structure or translatability in vitro, additional unidentified factors might account for the modulation of exotoxins in vivo. Ultimately, the study constitutes a step forward in the discovery of new roles of the NAD molecule in bacteria. IMPORTANCE Numerous organisms, including bacteria, are endowed with a 5′ NAD cap in specific RNAs. While the presence of the 5′ NAD cap modulates the stability of the modified RNA species, a significant biological function and phenotype have not been assigned so far. Here, we show the presence of a 5′ NAD cap in RNAIII from S. aureus, a dual-function regulatory RNA involved in quorum-sensing processes and regulation of virulence factor expression. We also demonstrate that altering the natural NAD modification ratio of RNAIII leads to a decrease in exotoxin production, thereby modulating the bacterium’s virulence. Our work unveils a new layer of regulation of RNAIII and the agr system that might be linked to the redox state of the NAD molecule in the cell.

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