AraC-Type Regulator Rsp Adapts Staphylococcus aureus Gene Expression to Acute Infection

Li, Tianming; He, Lei; Yan, Shijuan; Villaruz, Amer E.; Joo, Hwang-Soo; Liu, Qian; Zhu, Yuanjun; Wang, Yanan; Qin, Juanxiu; Otto, Michael; Li, Min

doi:10.1128/iai.01088-15

Cited by 27 publications

(39 citation statements)

References 47 publications

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“…The attenuated toxicity phenotype was not noted in isolates from skin and soft tissue infection (17), suggesting that such attenuated toxicity and intracellular survival may be particularly important in bloodstream infection, as opposed to other forms of infection, such as skin and soft tissue infection. Our findings that rsp contributed to lethality in pulmonary disease is also supported by a recent study of cutaneous S. aureus disease (54). In both models, toxins have been shown to be key mediators of disease (13,55).…”

Section: Discussionsupporting

confidence: 75%

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Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Das

Lindemann

Young

et al. 2016

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

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Staphylococcus aureus is a major bacterial pathogen, which causes severe blood and tissue infections that frequently emerge by autoinfection with asymptomatically carried nose and skin populations. However, recent studies report that bloodstream isolates differ systematically from those found in the nose and skin, exhibiting reduced toxicity toward leukocytes. In two patients, an attenuated toxicity bloodstream infection evolved from an asymptomatically carried high-toxicity nasal strain by loss-of-function mutations in the gene encoding the transcription factor repressor of surface proteins (rsp). Here, we report that rsp knockout mutants lead to global transcriptional and proteomic reprofiling, and they exhibit the greatest signal in a genome-wide screen for genes influencing S. aureus survival in human cells. This effect is likely to be mediated in part via SSR42, a long-noncoding RNA. We show that rsp controls SSR42 expression, is induced by hydrogen peroxide, and is required for normal cytotoxicity and hemolytic activity. Rsp inactivation in laboratory- and bacteremia-derived mutants attenuates toxin production, but up-regulates other immune subversion proteins and reduces lethality during experimental infection. Crucially, inactivation of rsp preserves bacterial dissemination, because it affects neither formation of deep abscesses in mice nor survival in human blood. Thus, we have identified a spontaneously evolving, attenuated-cytotoxicity, nonhemolytic S. aureus phenotype, controlled by a pleiotropic transcriptional regulator/noncoding RNA virulence regulatory system, capable of causing S. aureus bloodstream infections. Such a phenotype could promote deep infection with limited early clinical manifestations, raising concerns that bacterial evolution within the human body may contribute to severe infection.

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Section: Discussionsupporting

confidence: 75%

“…Some of the Rsp effects are mediated by SSR42, because SSR42-dependent production of the Rsp targets, α-toxin, has been demonstrated (45). Synergy of SSR42-mediated effects with direct effects of Rsp itself, such the recently demonstrated binding of Rsp to the agr promoter, may also occur (54).…”

mentioning

confidence: 99%

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Das

Lindemann

Young

et al. 2016

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

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“…We previously identified repressor of surface proteins (Rsp) as a global regulator of S. aureus hemolysis, cytotoxicity, and virulence and found that Rsp is required for transcription of SSR42, which is located directly upstream of Rsp in an antiparallel orientation (36). Loss of hemolysis has been described for mutants of rsp (36,49,51), and functional Rsp is a requirement for transcription of SSR42 (36). SSR42 is essential for wild-type hemolysis in S. aureus (Fig.…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA SSR42 Controls Staphylococcus aureus Alpha-Toxin Transcription in Response to Environmental Stimuli

et al. 2018

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is a human pathogen causing a variety of diseases by versatile expression of a large set of virulence factors that most prominently features the cytotoxic and hemolytic pore-forming alpha-toxin. Expression of alpha-toxin is regulated by an intricate network of transcription factors. These include two-component systems sensing quorum and environmental signals as well as regulators reacting to the nutritional status of the pathogen. We previously identified the repressor of surface proteins (Rsp) as a virulence regulator. Acute cytotoxicity and hemolysis are strongly decreased in mutants, which are characterized by decreased transcription of toxin genes as well as loss of transcription of a 1,232-nucleotide (nt)-long noncoding RNA (ncRNA), SSR42. Here, we show that SSR42 is the effector of Rsp in transcription regulation of the alpha-toxin gene, SSR42 transcription is enhanced after exposure of to subinhibitory concentrations of oxacillin which thus leads to an SSR42-dependent increase in hemolysis. Aside from Rsp, SSR42 transcription is under the control of additional global regulators, such as CodY, AgrA, CcpE, and σ, but is positioned upstream of the two-component system SaeRS in the regulatory cascade leading to alpha-toxin production. Thus, alpha-toxin expression depends on two long ncRNAs, SSR42 and RNAIII, which control production of the cytolytic toxin on the transcriptional and translational levels, respectively, with SSR42 as an important regulator of SaeRS-dependent toxin production in response to environmental and metabolic signals. is a major cause of life-threatening infections. The bacterium expresses alpha-toxin, a hemolysin and cytotoxin responsible for many of the pathologies of Alpha-toxin production is enhanced by subinhibitory concentrations of antibiotics. Here, we show that this process is dependent on the long noncoding RNA, SSR42. Further, SSR42 itself is regulated by several global regulators, thereby integrating environmental and nutritional signals that modulate hemolysis of the pathogen.

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“…One IS 256 insertion occurred 521-bp upstream of rsp (the gene for the AraC family transcriptional regulator [ 72 ]), suggesting an influence on the regulation system for virulence genes. In order to gain a more precise understanding of the gene expression and potential virulence of Russia ST8-IVc (OC8), further investigations are needed.…”

Section: Discussionmentioning

confidence: 99%

Complete Circular Genome Sequence of Successful ST8/SCCmecIV Community-Associated Methicillin-Resistant Staphylococcus aureus (OC8) in Russia: One-Megabase Genomic Inversion, IS256’s Spread, and Evolution of Russia ST8-IV

et al. 2016

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ST8/SCCmecIV community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has been a common threat, with large USA300 epidemics in the United States. The global geographical structure of ST8/SCCmecIV has not yet been fully elucidated. We herein determined the complete circular genome sequence of ST8/SCCmecIVc strain OC8 from Siberian Russia. We found that 36.0% of the genome was inverted relative to USA300. Two IS256, oppositely oriented, at IS256-enriched hot spots were implicated with the one-megabase genomic inversion (MbIN) and vSaβ split. The behavior of IS256 was flexible: its insertion site (att) sequences on the genome and junction sequences of extrachromosomal circular DNA were all divergent, albeit with fixed sizes. A similar multi-IS256 system was detected, even in prevalent ST239 healthcare-associated MRSA in Russia, suggesting IS256’s strong transmission potential and advantage in evolution. Regarding epidemiology, all ST8/SCCmecIVc strains from European, Siberian, and Far Eastern Russia, examined had MbIN, and geographical expansion accompanied divergent spa types and resistance to fluoroquinolones, chloramphenicol, and often rifampicin. Russia ST8/SCCmecIVc has been associated with life-threatening infections such as pneumonia and sepsis in both community and hospital settings. Regarding virulence, the OC8 genome carried a series of toxin and immune evasion genes, a truncated giant surface protein gene, and IS256 insertion adjacent to a pan-regulatory gene. These results suggest that unique single ST8/spa1(t008)/SCCmecIVc CA-MRSA (clade, Russia ST8-IVc) emerged in Russia, and this was followed by large geographical expansion, with MbIN as an epidemiological marker, and fluoroquinolone resistance, multiple virulence factors, and possibly a multi-IS256 system as selective advantages.

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AraC-Type Regulator Rsp Adapts Staphylococcus aureus Gene Expression to Acute Infection

Cited by 27 publications

References 47 publications

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Natural mutations in a Staphylococcus aureus virulence regulator attenuate cytotoxicity but permit bacteremia and abscess formation

Long Noncoding RNA SSR42 Controls Staphylococcus aureus Alpha-Toxin Transcription in Response to Environmental Stimuli

Complete Circular Genome Sequence of Successful ST8/SCCmecIV Community-Associated Methicillin-Resistant Staphylococcus aureus (OC8) in Russia: One-Megabase Genomic Inversion, IS256’s Spread, and Evolution of Russia ST8-IV

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