The Stringent Response of Staphylococcus aureus and Its Impact on Survival after Phagocytosis through the Induction of Intracellular PSMs Expression

Geiger, Tobias; François, Patrice; Liebeke, Manuel; Fraunholz, Martin; Goerke, Christiane; Krismer, Bernhard; Schrenzel, Jacques; Lalk, Michael; Wolz, Christiane

doi:10.1371/journal.ppat.1003016

Cited by 197 publications

(262 citation statements)

References 67 publications

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“…This observation is consistent with a report by Kobayashi et al describing the escape of different USA300 strains from PMNs, where the investigators concluded that escape from PMNs by S. aureus was independent of toxins when evaluated 6 h postinfection (42). In light of this new role for LukAB, which may be shared with other staphylococcal factors such as delta hemolysin and beta hemolysin (48) and PSMs (38,43), vaccine strategies that aim to promote phagocyte-mediated killing of S. aureus through opsonization may prove to be ineffective. Our data show that opsonization does cause PMN-mediated killing of USA300, but factors such as LukAB allow the early escape and propagation of surviving bacteria.…”

Section: Discussionsupporting

confidence: 92%

“…Similar results were obtained when PMN lysis was monitored with lactate dehydrogenase (LDH) (data not shown). This observation is most dramatic at 1 h postsynchronization, although as the infection proceeds, membrane damage occurs regardless of whether or not the strains have lukAB, consistent with the production of additional cytolytic factors (9,10,38,43).…”

Section: Figmentioning

confidence: 69%

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Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils

et al. 2013

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bMethicillin-resistant Staphylococcus aureus (MRSA) strains of the pulsed-field type USA300 are primarily responsible for the current community-associated epidemic of MRSA infections in the United States. The success of USA300 is partly attributed to the ability of the pathogen to avoid destruction by human neutrophils (polymorphonuclear leukocytes [PMNs]), which are crucial to the host immune response to S. aureus infection. In this work, we investigated the contribution of bicomponent poreforming toxins to the ability of USA300 to withstand attack from primary human PMNs. We demonstrate that in vitro growth conditions influence the expression, production, and availability of leukotoxins by USA300, which in turn impact the cytotoxic potential of this clone toward PMNs. Interestingly, we also found that upon exposure to PMNs, USA300 preferentially activates the promoter of the lukAB operon, which encodes the recently identified leukocidin AB (LukAB). LukAB elaborated by extracellular S. aureus forms pores in the plasma membrane of PMNs, leading to PMN lysis, highlighting a contribution of LukAB to USA300 virulence. We now show that LukAB also facilitates the escape of bacteria engulfed within PMNs, in turn enabling the replication and outgrowth of S. aureus. Together, these results suggest that upon encountering PMNs S. aureus induces the production of LukAB, which serves as an extra-and intracellular weapon to protect the bacterium from destruction by human PMNs.

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Section: Discussionsupporting

confidence: 92%

Section: Figmentioning

confidence: 69%

Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils

et al. 2013

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“…CodY senses the branched-chain amino acid pool and the intracellular GTP concentration and is activated by the binding of these cofactors (24)(25)(26). Previously, we showed that the stringent response imposed by amino acid limitation deactivates the CodY repressor in S. aureus (8,23). Here, this interaction can be observed just by the expression of any of the (p)ppGpp synthases without changes in the availability of branched-chain amino acids.…”

Section: Resultsmentioning

confidence: 88%

“…4). These genes represent some of the hallmark genes that are typically influenced by the RSH-mediated stringent response and are repressed upon amino acid deprivation (8,23). brnQ1, which codes for a branched-chain amino acid transporter, showed transcriptional induction once a (p)ppGpp synthase was present.…”

Section: Resultsmentioning

confidence: 99%

Two Small (p)ppGpp Synthases in Staphylococcus aureus Mediate Tolerance against Cell Envelope Stress Conditions

et al. 2014

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The stringent response is a conserved global regulatory mechanism that is related to the synthesis of (p)ppGpp nucleotides. Gram-positive bacteria, such as Staphylococcus aureus, possess three (p)ppGpp synthases: the bifunctional RSH (RelA/SpoT homolog) protein, which consists of a (p)ppGpp synthase and a (p)ppGpp hydrolase domain, and two truncated (p)ppGpp synthases, designated RelP and RelQ. Here, we characterized these two small (p)ppGpp synthases. Biochemical analyses of purified proteins and in vivo studies revealed a stronger synthetic activity for RelP than for RelQ. However, both enzymes prefer GDP over GTP as the pyrophosphate recipient to synthesize ppGpp. Each of the enzymes was shown to be responsible for the essentiality of the (p)ppGpp hydrolase domain of the RSH protein. The staphylococcal RSH-hydrolase is an efficient enzyme that prevents the toxic accumulation of (p)ppGpp. Expression of (p)ppGpp synthases in a hydrolase-negative background leads not only to growth arrest but also to cell death. Transcriptional analyses showed that relP and relQ are strongly induced upon vancomycin and ampicillin treatments. Accordingly, mutants lacking relP and relQ showed a significantly reduced survival rate upon treatments with cell wall-active antibiotics. Thus, RelP and RelQ are active (p)ppGpp synthases in S. aureus that are induced under cell envelope stress to mediate tolerance against these conditions.

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“…The genome of S. aureus also encodes two other monofunctional synthetases, RelP and RelQ, and transcription of these genes increases when cells are exposed to cell wall-targeting antimicrobials (20,21). Recent work on S. aureus has shown that the ability to switch on the stringent response is essential for its virulence and is required for the organism to cause chronic infections (22)(23)(24)(25).…”

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confidence: 99%

ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria

Corrigan

Bellows

Wood

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

185

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The stringent response is a survival mechanism used by bacteria to deal with stress. It is coordinated by the nucleotides guanosine tetraphosphate and pentaphosphate [(p)ppGpp], which interact with target proteins to promote bacterial survival. Although this response has been well characterized in proteobacteria, very little is known about the effectors of this signaling system in Grampositive species. Here, we report on the identification of seven target proteins for the stringent response nucleotides in the Grampositive bacterium Staphylococcus aureus. We demonstrate that the GTP synthesis enzymes HprT and Gmk bind with a high affinity, leading to an inhibition of GTP production. In addition, we identified five putative GTPases-RsgA, RbgA, Era, HflX, and ObgE-as (p)ppGpp target proteins. We show that RsgA, RbgA, Era, and HflX are functional GTPases and that their activity is promoted in the presence of ribosomes but strongly inhibited by the stringent response nucleotides. By characterizing the function of RsgA in vivo, we ascertain that this protein is involved in ribosome assembly, with an rsgA deletion strain, or a strain inactivated for GTPase activity, displaying decreased growth, a decrease in the amount of mature 70S ribosomes, and an increased level of tolerance to antimicrobials. We additionally demonstrate that the interaction of ppGpp with cellular GTPases is not unique to the staphylococci, as homologs from Bacillus subtilis and Enterococcus faecalis retain this ability. Taken together, this study reveals ribosome inactivation as a previously unidentified mechanism through which the stringent response functions in Gram-positive bacteria.ribosome | stringent response | tolerance | ppGpp | Staphylococcus aureus

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The Stringent Response of Staphylococcus aureus and Its Impact on Survival after Phagocytosis through the Induction of Intracellular PSMs Expression

Cited by 197 publications

References 67 publications

Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils

Staphylococcus aureus Elaborates Leukocidin AB To Mediate Escape from within Human Neutrophils

Two Small (p)ppGpp Synthases in Staphylococcus aureus Mediate Tolerance against Cell Envelope Stress Conditions

ppGpp negatively impacts ribosome assembly affecting growth and antimicrobial tolerance in Gram-positive bacteria

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