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YjbH regulates virulence genes expression and oxidative stress resistance in Staphylococcus aureus.

ABSTRACT: We previously reported that disruption of the yjbI gene reduced virulence of Staphylococcus aureus. In this study, we found virulence in both silkworms and mice was restored by introducing the yjbH gene but not the yjbI gene to both yjbI and yjbH genes-disrupted mutants, suggesting that yjbH, the gene downstream to the yjbI gene in a two-gene operon-yjbIH, is responsible for this phenomenon. We further observed a decrease in various surface-associated proteins and changes in cell envelope glycostructures in the mutants. RNA-seq analysis revealed that disruption of the yjbI and the yjbH genes resulted in differential expression of a broad range of genes, notably, significant downregulation of genes involved in virulence and oxidative stress. Administration of N-acetyl-L-cysteine, a free-radical scavenger, restored the virulence in both the mutants. Our findings suggested that YjbH plays a role in staphylococcal pathogenicity by regulating virulence gene expression, affecting the bacterial surface structure, and conferring resistance to oxidative stress in a host.

SUBMITTER: Paudel A

PROVIDER: S-EPMC7849776 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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YjbH regulates virulence genes expression and oxidative stress resistance in Staphylococcus aureus.

Paudel Atmika A Panthee Suresh S Hamamoto Hiroshi H Grunert Tom T Sekimizu Kazuhisa K

Virulence 20211201 1

We previously reported that disruption of the yjbI gene reduced virulence of Staphylococcus aureus. In this study, we found virulence in both silkworms and mice was restored by introducing the yjbH gene but not the yjbI gene to both yjbI and yjbH genes-disrupted mutants, suggesting that yjbH, the gene downstream to the yjbI gene in a two-gene operon-yjbIH, is responsible for this phenomenon. We further observed a decrease in various ...[more]

PMID: 33487122

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Project description:Staphylococcus aureus is a human pathogen that has developed several approaches to evade the immune system, including a strategy to resist oxidative killing by phagocytes. This resistance is mediated by production of superoxide dismutase (SOD) enzymes which use manganese as a cofactor. S. aureus encodes two manganese ion transporters, MntABC and MntH, and a possible Nramp family manganese transporter, exemplified by S. aureus N315 SA1432. Their relative contributions to manganese transport have not been well defined in clinically relevant isolates. For this purpose, insertional inactivation mutations were introduced into mntC, mntH, and SA1432 individually and in combination. mntC was necessary for full resistance to methyl viologen, a compound that generates intracellular free radicals. In contrast, strains with an intact mntH gene had a minimal increase in resistance that was revealed only in mntC strains, and no change was observed upon mutation of SA1432 in strains lacking both mntC and mntH Similarly, MntC alone was required for high cellular SOD activity. In addition, mntC strains were attenuated in a murine sepsis model. To further link these observations to manganese transport, an S. aureus MntC protein lacking manganese binding activity was designed, expressed, and purified. While circular dichroism experiments demonstrated that the secondary and tertiary structures of this protein were unaltered, a defect in manganese binding was confirmed by isothermal titration calorimetry. Unlike complementation with wild-type mntC, introduction of the manganese-binding defective allele into the chromosome of an mntC strain did not restore resistance to oxidative stress or virulence. Collectively, these results underscore the importance of MntC-dependent manganese transport in S. aureus oxidative stress resistance and virulence.IMPORTANCE Work outlined in this report demonstrated that MntC-dependent manganese transport is required for S. aureus virulence. These study results support the model that MntC-specific antibodies elicited by a vaccine have the potential to disrupt S. aureus manganese transport and thus abrogate to its virulence.

Project description:Manganese (Mn) is an essential micronutrient critical for the pathogenesis of Staphylococcus aureus, a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic; therefore, maintenance of intracellular Mn homeostasis is required for survival. Here we describe a Mn exporter in S. aureus, MntE, which is a member of the cation diffusion facilitator (CDF) protein family and conserved among Gram-positive pathogens. Upregulation of mntE transcription in response to excess Mn is dependent on the presence of MntR, a transcriptional repressor of the mntABC Mn uptake system. Inactivation of mntE or mntR leads to reduced growth in media supplemented with Mn, demonstrating MntE is required for detoxification of excess Mn. Inactivation of mntE results in elevated levels of intracellular Mn, but reduced intracellular iron (Fe) levels, supporting the hypothesis that MntE functions as a Mn efflux pump and Mn efflux influences Fe homeostasis. Strains inactivated for mntE are more sensitive to the oxidants NaOCl and paraquat, indicating Mn homeostasis is critical for resisting oxidative stress. Furthermore, mntE and mntR are required for full virulence of S. aureus during infection, suggesting S. aureus experiences Mn toxicity in vivo Combined, these data support a model in which MntR controls Mn homeostasis by balancing transcriptional repression of mntABC and induction of mntE, both of which are critical for S. aureus pathogenesis. Thus, Mn efflux contributes to bacterial survival and virulence during infection, establishing MntE as a potential antimicrobial target and expanding our understanding of Mn homeostasis.IMPORTANCE Manganese (Mn) is generally viewed as a critical nutrient that is beneficial to pathogenic bacteria due to its function as an enzymatic cofactor and its capability of acting as an antioxidant; yet paradoxically, high concentrations of this transition metal can be toxic. In this work, we demonstrate Staphylococcus aureus utilizes the cation diffusion facilitator (CDF) family protein MntE to alleviate Mn toxicity through efflux of excess Mn. Inactivation of mntE leads to a significant reduction in S. aureus resistance to oxidative stress and S. aureus-mediated mortality within a mouse model of systemic infection. These results highlight the importance of MntE-mediated Mn detoxification in intracellular Mn homeostasis, resistance to oxidative stress, and S. aureus virulence. Therefore, this establishes MntE as a potential target for development of anti-S. aureus therapeutics.

Project description:BackgroundStaphylococcus aureus causes many human infections, including wound infections, and its pathogenicity is mainly influenced by several virulence factors.AimThis study aimed to detect virulence genes (hla, sea, icaA, and fnbA) in S. aureus isolated from different wound infections among Egyptian patients admitted to Minia University Hospital. This study also aimed to investigate the prevalence of these genes in methicillin-resistant S. aureus (MRSA), methicillin-susceptible S. aureus (MSSA), and vancomycin-resistant S. aureus isolates and the resistance and sensitivity to different antibiotic classes.MethodsA cross-sectional study was carried out from November 2019 to September 2021. Standard biochemical and microbiological tests revealed 59 S. aureus isolates. The Kirby-Bauer disc diffusion method was used to determine antibiotic susceptibility. DNA was extracted using a DNA extraction kit, and polymerase chain reaction was used to amplify all genes.ResultsA total of 59 S. aureus isolates were detected from 51 wound samples. MRSA isolates accounted for 91.5%, whereas MSSA isolates accounted for 8.5%. The multidrug resistance (MDR) percentage in S. aureus isolates was 54.2%. S. aureus showed high sensitivity pattern against vancomycin, linezolid, and chloramphenicol. However, a high resistance pattern was observed against oxacillin and piperacillin. sea was the most predominant gene (72.9%), followed by icaA (49.2%), hla (37.3%), and fnbA (13.6%). sea was the commonest virulence gene among MRSA isolates (72.2%), and a significant difference in the distribution of icaA was found. However, sea and icaA were the commonest genes among MSSA isolates (79.9%). The highest distribution of sea was found among ciprofloxacin-resistant isolates (95.2%).ConclusionThe incidence of infections caused by MDR S. aureus significantly increased with MRSA prevalence. sea is the most predominant virulence factor among antibiotic-resistant strains with a significant correlation to piperacillin, gentamicin, and levofloxacin.

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YjbH regulates virulence genes expression and oxidative stress resistance in Staphylococcus aureus.

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YjbH regulates virulence genes expression and oxidative stress resistance in <i>Staphylococcus aureus</i>.

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