Regulation of Toxin-Antitoxin System savRS in Staphylococcus aureus Virulence and Host Key Signaling pathway
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ABSTRACT:
ORGANISM(S): Mus Musculus
SUBMITTER: 
Baolin Sun
PROVIDER: PXD059235 | iProX | Wed Dec 25 00:00:00 GMT 2024
REPOSITORIES: iProX
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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
Project description:While a plethora of small regulatory RNAs (sRNAs) have been identified in the human pathogen Staphylococcus aureus, the physiological function of most of them remains unknown. We report the characterization of SprY, a sRNA from S. aureus expressed from a pathogenicity island. RNAIII, a major regulator of S. aureus virulence, was discovered as a potential SprY target by an MS2-affinity purification assay. In silico interaction studies suggest a RNA-RNA pairing between the SprY 5’end and the 13rd stem-loop of RNAIII. Overproduction of SprY leads to a 1.5-fold reduction of RNAIII amount. By affecting the rnaIII expression, SprY affects the amount of RNAIII known targets. Indeed, SprY downregulates hla mRNA translation, but also upregulates other secreted factors such as Ecb and Rot. Furthermore, SprY decreases the hemolytic activity and virulence of S. aureus. Our results lead to propose that SprY is involved in S. aureus virulence through a post-transcriptional regulation of RNAIII.
2021-02-10 | GSE166499 | GEO
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.
2012-05-21 | GSE38053 | GEO
Project description:Hospital-acquired pneumonia caused by Staphylococcus aureus is associated with patient morbidity and mortality, in spite of adequate antibiotic therapy. Therefore, there is a need for novel treatment concepts that go beyond antibiotics. The pore-forming heptameric toxin α-hemolysin (Hla) is a major pathogenicity factor of S. aureus and a clinically validated target. Using Hla-dependent phenotypic cellular assays, we discovered quinoxalinediones (QDS) as highly potent Hla inhibitors. QDS reverted the hallmarks of Hla pathogenicity by conferring protection against Hla-induced Ca2+ influx, cytotoxicity, hemolysis, and by maintaining monolayer integrity of lung epithelial cells. The cellular effects were exerted in the nM range across all major Hla subtypes and shown in relevant cell types, including lung epithelial and endothelial cells, and primary human immune cells. QDS prevented the formation of functional pores by interacting with Hla monomers. Structural data by NMR and chemoproteomics showed monomer binding near the phospholipid binding site of the protein, a functional site required for membrane integration. The analog H052 was active in mouse models of S. aureus lung infections in pre-emptive and therapeutic settings, as a monotherapy and in combination with subtherapeutic doses of linezolid. The QDS provide first evidence that of large bacterial toxins can be effectively inhibited by drug-like small molecules. The virulence-attenuating drug candidate may now be developed as a monotherapy in a pre-emptive intervention setting.
2025-03-05 | PXD050156 | Pride
Project description:To maintain cellular homeostasis under the stresses, bacteria always initiate various responses. The transcriptomic profiles of S. aureus treated with longistylin A were assessed by RNA-sequencing. A total of 2585 genes were identified. KEGG analysis enriched differentially expressed genes (DEGs) in different physiological processes. Two-component system and bacterial infection metabolisms, the most significant enrichment pathways, were downregulated by longistry A. The SaeRS two-component system is essential for the hemolytic activity and virulence in S. aureus. SarT is a repressor of alpha-hemolysin (Hla) in S. aureus. Transcriptome data shows that the expression of genes encoding gama-hemolysin components and SaeRS two-component system were inhibited under the treatment of LGA, while the expression of SarT is increased. The Type VII secretory system (T7SS) is responsible for the secretion of virulence factors. Longistry A dramatically upregulated the expression of T7SS related genes, such as essB and esaC. LGA did not affect intracellular Hla accumulation. The downregulation of hemolysin-related genes and upregulation of T7SS related genes may be due to the feedback regulation of inhibited hemolysin secretion caused by longistry A treatment. Overall, longistry A inhibited hemolysin secretion by targeting cell membrane phospholipids, thereby inhibited SaeRS-dependent hemolysin expression and activated Type VII secretory system.
2025-01-09 | GSE286163 | GEO
Project description:Pandemic and endemic strains of Vibrio cholerae arise from toxigenic conversion by the CTXφ bacteriophage, a process by which CTXφ infects non-toxigenic strains of V. cholerae. CTXφ encodes the cholera toxin, an enterotoxin responsible for the watery diarrhea associated with cholera infections. Despite the critical role of CTXφ during infections, signals that affect CTXφ-driven toxigenic conversion or expression of the CTXφ-encoded cholera toxin remain poorly characterized, particularly in the context of the gut mucosa. Here, we identify mucin polymers as potent regulators of CTXφ-driven pathogenicity in V. cholerae. Our results indicate that mucin-associated O-glycans block toxigenic conversion by CTXφ and suppress the expression of CTXφ-related virulence factors, including the toxin co-regulated pilus and cholera toxin, by interfering with the TcpP/ToxR/ToxT virulence pathway. By synthesizing individual mucin glycan structures de novo, we identify the Core 2 motif as the critical structure governing this virulence attenuation. Overall, our results highlight a novel mechanism by which mucins and their associated O-glycan structures affect CTXφ-mediated evolution and pathogenicity of V. cholerae, underscoring the potential regulatory power housed within mucus.
2022-12-01 | GSE213598 | GEO
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
Project description:Staphylococcus aureus can infect a wide range of animals and pose as a serious threat to public health by transferring via animals or animal-derived food stuff. Even more importantly, multiple drug resistance development in the bacteria has resulted in therapeutic failure of a number of antibiotics. Therefore by realizing the need of time, this study was designed to investigate the underlying mechanisms of virulence and resistance in S. aureus. After screening through in vivo and in vitro virulence assays and susceptibility test, a highly virulent and multidrug resistant MRSA strain was selected for differential analysis by RNA-seq technology and gene expression results were verified by RT-qPCR. Up-regulation of crucial regulators like sarA and KdpDE seemed to play role in decreased expression of many exotoxin genes while enhanced the adhesion and cell wall protein expression, leading to strong biofilm production in the presence of inactivated agr system. In addition to resistance genes like blaZ, ermC and femA, up-regulation of vraS and multidrug ABC transporter genes contributed to the multidrug resistance in MRSA. Fluoroquinolone resistance was attributed to mutational changes in gyrA and parC genes. Our findings suggested that many virulence and resistance determinants in S. aureus are controlled by complex network of various regulators, and sarA is the most important of those as it adds to pathogenicity of the bacteria and ensures its survival in diverse environment. Further investigations are required to unveil these mechanisms in S. aureus. Four samples were analysed including 2 MRSA1679a test strain and 2 reference strain ATCC1 samples with two replicates of each.
2016-03-02 | E-GEOD-78764 | biostudies-arrayexpress
Project description:Responsiveness of cells to alpha-toxin (Hla) from Staphylococcus aureus appears to occur in a cell-type dependent manner. Here, we compare two human bronchial epithelial cell lines, i.e. Hla-susceptible 16HBE14o- and Hla-resistant S9 cells, by a quantitative multi-omics strategy for a better understanding of Hla-induced cellular programs. Phosphoproteomics revealed a substantial impact on phosphorylation-dependent signaling in both cell models and highlights alterations in signaling pathways associated with cell-cell and cell-matrix contacts as well as the actin cytoskeleton as key features of early rHla-induced effects. Along comparable changes in down-stream activity of major protein kinases significant differences between both models were found upon rHla-treatment including activation of EGFR and MAPK1/3 signaling in S9 and repression in 16HBE14o- cells. System-wide transcript and protein expression profiling indicate induction of an immediate early response in either model. In addition, EGFR and MAPK1/3-mediated changes in gene expression suggest cellular recovery and survival in S9 cells but cell death in 16HBE14o- cells. Strikingly, inhibition of the EGFR sensitized S9 cells to Hla indicating that the cellular capacity of activation of the EGFR is a major protective determinant against Hla-mediated cytotoxic effects. Design includes two different human bronchial epithelial cell lines, one control treatment (mock treatment for 2 hours) and one condition (2 alpha toxin treatment for 2 hours). Experiments for both cell line were replicated twice (biological replication).
2015-03-31 | E-GEOD-65018 | biostudies-arrayexpress
Project description:Staphylococcus aureus is a significant Gram-positive human pathogenic bacterium that can give rise to skin and soft tissue infections and may also result in lethal diseases such as sepsis, pneumonia, endocarditis, osteomyelitis, etc. The cell wall of Staphylococcus aureus is a crucial immunogenic substance and participates in physiological processes like antibiotic resistance and virulence. The previous studies in the laboratory have indicated that the deletion of LCPB can upregulate the virulence of Staphylococcus aureus. However, the specific mechanisms by which LCPB regulates the virulence system of Staphylococcus aureus and its interaction with the host remain unclear. To explore the specific signal pathways by which lcpb regulates the interaction between Staphylococcus aureus and the host, we conducted proteomic experiments. This research discovered that both the knockout of LCPB and the application of WTA synthesis inhibitors can prevent the synthesis of the main component of the cell wall, wall teichoic acid (WTA), and upregulate the expression of excreted virulence factors such as HlgA, LukAB, and hla in Staphylococcus aureus. Subsequently, it was found that the central virulence regulation system agr of Staphylococcus aureus can respond to the reduction of WTA content, and the activation of agr is dependent on the expression of the two-component signal system saeRS.
2024-12-25 | PXD059233 |