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YjbH contributes to S. aureus skin pathology and immune response through Agr-mediated alpha-toxin regulation

ABSTRACT: Staphylococcus aureus is a global health threat that can cause a multitude of diseases in many different areas of the body and is the leading cause of skin infections. This bacterium can produce a variety of proteins that contribute to virulence and disease progression. These virulence factors include alpha-hemolysin (Hla), which can kill many different cell types in the human body. In this study, we identified a new protein that contributes to Hla production, YjbH. It does so by controlling the activity of the Accessory Gene Regulator (Agr), a major player in the modulation of proteins produced in the bacterium. We demonstrate that without YjbH, S. aureus cultures produce less Hla, and this is corroborated during infection. Accordingly, when YjbH is present, tissue damage is greater during infection than when it is absent. Overall, our study sheds light on the complex regulation involved in virulence factor production by S. aureus and its ability to cause a wide range of diseases.

INSTRUMENT(S): Orbitrap Ascend

ORGANISM(S): Staphylococcus Aureus Subsp. Aureus Usa300 (ncbitaxon:367830)

SUBMITTER: Jeffrey L. Bose

PROVIDER: MSV000094754 | MassIVE | Tue May 14 08:46:00 BST 2024

SECONDARY ACCESSION(S): PXD052262

REPOSITORIES: MassIVE

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YjbH contributes to S. aureus skin pathology and immune response through Agr-mediated alpha-toxin regulation

Project description:Staphylococcus aureus is a global health threat that can cause a multitude of diseases in many different areas of the body and is the leading cause of skin infections. This bacterium can produce a variety of proteins that contribute to virulence and disease progression. These virulence factors include alpha-hemolysin (Hla), which can kill many different cell types in the human body. In this study, we identified a new protein that contributes to Hla production, YjbH. It does so by controlling the activity of the Accessory Gene Regulator (Agr), a major player in the modulation of proteins produced in the bacterium. We demonstrate that without YjbH, S. aureus cultures produce less Hla, and this is corroborated during infection. Accordingly, when YjbH is present, tissue damage is greater during infection than when it is absent. Overall, our study sheds light on the complex regulation involved in virulence factor production by S. aureus and its ability to cause a wide range of diseases.

2024-05-14 | MSV000094753 | MassIVE

Host Response Signature to Staphylococcus aureus alpha-Hemolysin

Project description:Staphylococcus aureus pneumonia causes significant morbidity and mortality. Alpha-hemolysin (Hla), a pore-forming cytotoxin of S. aureus, has been identified through animal models of pneumonia as a critical virulence factor that induces lung injury. In spite of considerable molecular knowledge of how this cytotoxin injures the host, the precise host response to Hla in the context of infection remains poorly understood. We employed whole-genome expression profiling of infected lung to define the host response to wild-type S. aureus compared with an Hla-deficient isogenic mutant in experimental pneumonia. These data provide a complete expression profile at four and at twenty-four hours post-infection, revealing a unique response to the toxin-expressing strain. Gene ontogeny analysis revealed significant differences in the extracellular matrix and cardiomyopathy pathways, both of which govern cellular interactions in the tissue microenvironment. Evaluation of individual transcript responses to Hla-secreting bacteria was notable for upregulation of host cytokine and chemokine genes, including the p19 subunit of interleukin-23. Consistent with this observation, the cellular immune response to infection was characterized by a prominent TH17 response to wild-type staphylococci. These findings define specific host mRNA responses to Hla-producing S. aureus, coupling the pulmonary TH17 response to the presence of this cytotoxin. Expression profiling to define the host response to a single virulence factor proved to be a valuable tool in identifying pathways for further investigation in S. aureus pneumonia. This approach may be broadly applicable to the study of bacterial toxins, defining host pathways that can be targeted to mitigate toxin-induced disease. Animals were treated with PBS, S. aureus wild-type, or S. aureus Hla-deficient isogenic mutant.

2012-05-20 | E-GEOD-38053 | biostudies-arrayexpress

Enhanced Staphylococcus aureus vaccine protection by uncoupling of the alpha-toxin-ADAM10 interaction

Project description:Staphylococcus aureus is the leading global cause of bacterial infection-associated mortality, as vaccine development has been elusive. S. aureus alpha-toxin (Hla) is an essential virulence factor in disease. In children, the anti-Hla neutralizing antibody response is the only known correlate of human protective immunity. We demonstrate that the anti-Hla response is limited in the first 2 years of life, illuminating a vaccine-targetable population. We assessed whether Hla antigenic variants would enhance vaccine-mediated immunity in neonatal mice. We identified a variant (HlaH35L/R66C/E70C, HlaHRE) that elicits a nearly 100-fold increase in the neutralizing anti-Hla antibody response compared to other candidate Hla antigens. HlaHRE immunization durably protects against skin and soft tissue infection, enhancing the T follicular helper response and germinal center B cell response. Protective immunity was also conferred to offspring following maternal immunization with HlaHRE. These findings thereby define a novel path for universal S. aureus vaccine development at the maternal-infant interface.

2024-08-13 | PXD047859 | Pride

Host Response Signature to Staphylococcus aureus alpha-Hemolysin

2012-05-21 | GSE38053 | GEO

Activity of SigB Modulates Virulence Gene Expression in a Murine Staphylococcus aureus Infection Model but Does Not Influence the Host Kidney Gene Expression

Project description:Background. Infections caused by Staphylococcus aureus are associated with significant morbidity and mortality and are an increasing threat not only in hospital settings. The expression of the staphylococcal virulence factor repertoire is known to be affected by the alternative sigma factor B (SigB). However, its impact during infection still is a matter of debate. Methods. Kidney tissue of controls or mice infected with S. aureus HG001 or its isogenic sigB mutant was analyzed by transcriptome profiling to monitor the host response, and additionally expression of selected S. aureus genes was monitored by RT-qPCR. Results. Direct transcript analysis by RT-qPCR revealed significant SigB activity in all mice infected with the wild type strain (WT), but not in its isogenic sigB mutant (p<0.0001). Despite a clear cut difference in the SigB-dependent transcription pattern of virulence genes (clfA, aur, and hla), the host reaction to infection (either WT or sigB mutant) was almost identical. Conclusions. Despite its significant activity in vivo, loss of SigB did not have an effect on the outcome of infection as well as on murine kidney gene expression pattern. Thus, these data support the role of SigB as virulence modulator rather than being a virulence determinant by itself. Murine kidney gene expression pattern of 3 groups were compared: 1) after infection with S. aureus HG001 (wild type); 2) after infection with S. aureus HG001 ΔsigB; 3) sham control (injection of physiological saline solution). The infection was performed twice (2 biological replicates), and the array analysis included 4 or 5 mice (independent samples) per group. In total, the study consisted of 24 arrays.

2011-10-23 | E-GEOD-28540 | biostudies-arrayexpress

The Old Yellow Enzyme OfrA fosters Staphylococcus aureus survival via thiol-dependent redox homeostasis

Project description:Old yellow enzymes (OYEs) are widely found in the bacterial, fungal, and plant kingdoms but absent in humans and have been used as biocatalysts for decades. However, OYEs physiological function in bacterial stress response and infection situations remained enigmatic. In the mode of pathogen, the gram-positive bacterium Staphylococcus aureus adapts to numerous stress conditions during pathogenesis. Here we show that in S. aureus genome, two paralogous genes (ofrA and ofrB) encode for two OYEs. We conducted bioinformatic analysis and found that ofrA is conserved among all publicly available representative staphylococcal genomes and some Firmicutes. Expression of ofrA is induced by electrophilic, oxidative, and hypochlorite stress in S. aureus. Furthermore, ofrA contributes to S. aureus survival against reactive electrophilic, oxygen, and chlorine species (RES, ROS, RCS) via thiol-dependent redox homeostasis. At the host-pathogen interface, ofrA mutation affects S. aureus survival in macrophages and whole human blood and the virulence factor staphyloxanthin production. Overall, our results shed the light onto a novel stress response strategy in the bacterial kingdom especially in the important human pathogen S. aureus.

2022-06-03 | GSE196683 | GEO

Inhibition of Staphylococcus aureus biofilm formation by gurmarin, a plant-derived cyclic peptide

Project description:Staphylococcus aureus is an opportunistic pathogen capable of causing various infections ranging from superficial skin infections to life-threatening severe diseases, including pneumonia and sepsis. This bacterium is attached to biotic and abiotic surfaces and forms biofilms that are resistant to conventional antimicrobial agents and clearance by host defenses. Infections associated with biofilms may result in longer hospitalizations, a need for surgery, and may even result in death. Agents that inhibit the formation of biofilms and virulence without affecting bacterial growth to avoid the development of drug resistance could be useful for therapeutic purposes. In this regard, we identified and isolated a small cyclic peptide, gurmarin, from a plant source that inhibited the formation of S. aureus biofilm without affecting the growth rate of the bacterium. We determined the gene expression of S. aureus biofilm treated with gurmarin and compared it to the untreated control biofilms. Differentially expressed genes were identified and their roles in the inhibition of S. aureus biofilms by gurmarin were analyzed.

2022-09-21 | E-MTAB-12154 | biostudies-arrayexpress

Temperature influences the composition and cytotoxicity of extracellular vesicles in Staphylococcus aureus

Project description:Staphylococcus aureus is a pathogenic bacterium but also a commensal of skin and anterior nares in humans. As S. aureus transits from skins/nares to inside the human body, it experiences changes in temperature. The production and content of S. aureus extracellular vesicles (EV) have been increasingly studied over the past few years and EVs are increasingly being recognized as important to the infectious process. Nonetheless, the impact of temperature variation on S. aureus EVs has not been studied in detail as most reports that investigate EV cargoes and host cell interactions are performed using vesicles produced at 37˚C. Here we report that S. aureus vesicle production is temperature-dependent with greater vesiculation at 40˚C. We demonstrate that the temperature dependent regulation of vesicle production in S. aureus is mediated by the alpha phenol soluble modulin peptides (αPSMs). Through proteomic analysis, we observed increased packaging of virulence factors at 40˚C whereas more total proteins are present in EVs produced at 34˚C. Similar to the protein content, we perform transcriptomic analysis and demonstrate that the RNA cargo is impacted by temperature also. Finally, we demonstrate greater αPSM- and α-toxin mediated erythrocyte lysis with 40˚C EVs but 34˚C EVs are more cytotoxic toward THP-1 cells. Together our study demonstrates that small temperature variations have great impact on EV biogenesis and shape the interaction with host cells.

2021-09-17 | GSE171489 | GEO

Activity of SigB Modulates Virulence Gene Expression in a Murine Staphylococcus aureus Infection Model but Does Not Influence the Host Kidney Gene Expression

2011-10-24 | GSE28540 | GEO

Stress-induced inactivation of the Staphylococcus aureus purine biosynthesis repressor leads to hypervirulence

Project description:Staphylococcus aureus is a significant cause of human infection. Here, we demonstrate that mutations in the transcriptional repressor of purine biosynthesis, purR, enhance the pathogenic potential of S. aureus. Indeed, systemic infection with purR mutants causes accelerated mortality in mice, which is due to aberrant up-regulation of fibronectin binding proteins (FnBPs). Remarkably, purR mutations can arise upon exposure of S. aureus to stress, such as an intact immune system. In humans, naturally occurring anti-FnBP antibodies exist that, while not protective against recurrent S. aureus infection, ostensibly protect against hypervirulent S. aureus infections. Vaccination studies support this notion, where anti-Fnb antibodies in mice protect against purR hypervirulence. These findings provide a novel link between purine metabolism and virulence in S. aureus.

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