Streptococcus pyogenes induces epithelial inflammatory responses through NF-κB/MAPK signaling pathways

Tsai, Pei Jane; Chen, Ying Huei; Hsueh, Chieh Hsing; Hsieh, Hsiao Chun; Liu, Ya Hui; Wu, Jiunn Jong; Tsou, Chih Cheng

doi:10.1016/j.micinf.2006.01.002

Cited by 27 publications

(50 citation statements)

References 30 publications

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“…Furthermore, the anti-inflammatory effect of KS may occur through inhibition of the NF-B signaling pathway (24). Based on previous findings (30,41,42), GAS can induce NF-B activation in various cells. The inhibitory effect of KS on GASinduced NF-B activation requires further clarification.…”

Section: Fig 7 Ks Reduces Liver Damage Of Gas-infected Mice Mouse Blmentioning

confidence: 89%

Kallistatin Modulates Immune Cells and Confers Anti-Inflammatory Response To Protect Mice from Group A Streptococcal Infection

Tsai

Luo

et al. 2013

Antimicrob Agents Chemother

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i Group A streptococcus (GAS) infection may cause severe life-threatening diseases, including necrotizing fasciitis and streptococcal toxic shock syndrome. Despite the availability of effective antimicrobial agents, there has been a worldwide increase in the incidence of invasive GAS infection. Kallistatin (KS), originally found to be a tissue kallikrein-binding protein, has recently been shown to possess anti-inflammatory properties. However, its efficacy in microbial infection has not been explored. In this study, we transiently expressed the human KS gene by hydrodynamic injection and investigated its anti-inflammatory and protective effects in mice via air pouch inoculation of GAS. The results showed that KS significantly increased the survival rate of GAS-infected mice. KS treatment reduced local skin damage and bacterial counts compared with those in mice infected with GAS and treated with a control plasmid or saline. While there was a decrease in immune cell infiltration of the local infection site, cell viability and antimicrobial factors such as reactive oxygen species actually increased after KS treatment. The efficiency of intracellular bacterial killing in neutrophils was directly enhanced by KS administration. Several inflammatory cytokines, including tumor necrosis factor alpha, interleukin 1␤, and interleukin 6, in local infection sites were reduced by KS. In addition, KS treatment reduced vessel leakage, bacteremia, and liver damage after local infection. Therefore, our study demonstrates that KS provides protection in GAS-infected mice by enhancing bacterial clearance, as well as reducing inflammatory responses and organ damage.

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Section: Fig 7 Ks Reduces Liver Damage Of Gas-infected Mice Mouse Blmentioning

confidence: 89%

Kallistatin Modulates Immune Cells and Confers Anti-Inflammatory Response To Protect Mice from Group A Streptococcal Infection

Tsai

Luo

et al. 2013

Antimicrob Agents Chemother

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“…Our array data showed an increase in the level of phosphorylated IB kinase (IKK␣), increased RelB (an NF-B subunit), and increased levels of several NF-B gene targets, including IB␣ (inhibitory protein of NF-B), COX2 (prostaglandin pathway), several superoxide dismutases (involved in dealing with oxidative stress), heat shock protein 90 (chaperone involved in stress responses), and STAT3 (regulating cell death and cytokine signaling) (see Table S1, S2, and S3 in the supplemental material). Activation of NF-B signaling has previously been associated with GAS infection, but the virulence factors involved in its activation have not been fully characterized (38)(39)(40). To confirm that SLS influences the activation of this inflammatory pathway in epithelial cells, we used immunofluorescence microscopy to visualize localization of the NF-B p65 subunit during GAS infection of keratinocytes.…”

Section: Streptolysin S Induces Alterations In Keratinocyte Survival mentioning

confidence: 99%

Streptolysin S Promotes Programmed Cell Death and Enhances Inflammatory Signaling in Epithelial Keratinocytes during Group A Streptococcus Infection

et al. 2015

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Streptococcus pyogenes, or group A Streptococcus (GAS), is a pathogen that causes a multitude of human diseases from pharyngitis to severe infections such as toxic shock syndrome and necrotizing fasciitis. One of the primary virulence factors produced by GAS is the peptide toxin streptolysin S (SLS). In addition to its well-recognized role as a cytolysin, recent evidence has indicated that SLS may influence host cell signaling pathways at sublytic concentrations during infection. We employed an antibody arraybased approach to comprehensively identify global host cell changes in human epithelial keratinocytes in response to the SLS toxin. We identified key SLS-dependent host responses, including the initiation of specific programmed cell death and inflammatory cascades with concomitant downregulation of Akt-mediated cytoprotection. Significant signaling responses identified by our array analysis were confirmed using biochemical and protein identification methods. To further demonstrate that the observed SLS-dependent host signaling changes were mediated primarily by the secreted toxin, we designed a Transwell infection system in which direct bacterial attachment to host cells was prevented, while secreted factors were allowed access to host cells. The results using this approach were consistent with our direct infection studies and reveal that SLS is a bacterial toxin that does not require bacterial attachment to host cells for activity. In light of these findings, we propose that the production of SLS by GAS during skin infection promotes invasive outcomes by triggering programmed cell death and inflammatory cascades in host cells to breach the keratinocyte barrier for dissemination into deeper tissues. Streptococcus pyogenes, also known as group A Streptococcus (GAS), is a common colonizer of the skin and mucosal surfaces of humans (1-3). GAS is typically innocuous in these locations or else leads to fairly minor and generally self-limiting infections of the skin or respiratory tract, such as impetigo or pharyngitis (1-3). In cases where an initial infection is left untreated, GAS may cause one of several severe postinfection (p.i.) sequelae, including rheumatic fever or glomerulonephritis (1-3). Furthermore, in rare cases, this exclusively human pathogen breaches the epithelial barrier and invades deeper tissues and blood, resulting in outcomes such as necrotizing fasciitis and Streptococcus toxic shock (1-3). The World Health Organization (WHO) estimates that GAS is responsible for about 18 million cases of severe postinfection sequelae and 700,000 cases of invasive disease each year (2, 4). Combined, GAS infections lead to approximately 500,000 deaths annually (2, 4).The success of GAS in causing both mild and severe infections is due largely to the myriad of secreted and surface-bound virulence factors expressed by this pathogen. One of the most potent virulence factors produced by GAS is streptolysin S (SLS), a small, ribosomally produced peptide whose mature product is predicted to be 2.7 kDa in size (5-8...

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“…9 Freed NF-κB can translocate into the nucleus, leading to the transcriptional activation of NF-κB-dependent genes, 10 such as chemokines and cytokines genes. 11 Previous studies have demonstrated that NF-κB in eukaryocyte could be activated by diverse bacteria, such as Porphyromonas gingivalis, 12 Streptococcus pyogenes, 13,14 or Mycobacterium bovis Bacillus Calmette-Guerin (BCG).…”

Section: Introductionmentioning

confidence: 99%

Staphylococcus aureus regulates secretion of interleukin-6 and monocyte chemoattractant protein-1 through activation of nuclear factor kappaB signaling pathway in human osteoblasts

Ning¹,

Zhang²,

Guo³

et al. 2011

Braz J Infect Dis

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Objective: Activation of nuclear factor kappaB by diverse bacteria regulates the secretion of chemokines and cytokines. Staphylococcus aureus (S. aureus)-infected osteoblasts can significantly increase the secretion of interleukin-6 and monocyte chemoattractant protein-1. The aim of this study was to investigate whether S. aureus can activate nuclear factor kappaB in human osteoblasts, and whether the activation of nuclear factor kappaB by S. aureus regulates the secretion of interleukin-6 and monocyte chemoattractant protein-1. Methods: Immunoblot and electrophoretic mobility shift assay were used to detect the degradation of IκBa and activation of nuclear factor kappaB in human osteoblasts in response to S. aureus, respectively. Enzyme-linked immunosorbent assay was used to measure the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants. Lastly, carbobenzoxyl-l-leucinyl-l-leucinyl-l-leucinal, an inhibitor of the nuclear factor kappaB, was used to determine if activation of nuclear factor kappaB by S. aureus in human osteoblasts regulates the secretions of interleukin-6 and monocyte chemoattractant protein-1. Results: Our results for the first time demonstrated that S. aureus can induce the degradation of IκBa and activation of nuclear factor kappaB in human osteoblasts in a time and dose-dependent manner. In addition, inhibition of nuclear factor kappaB by carbobenzoxyl-l-leucinyl-l-leucinyl-l-leucinal suppressed the secretion of interleukin-6 and monocyte chemoattractant protein-1 in the supernatants of S. aureus-infected human osteoblasts in a dose-dependent manner. Conclusions: These findings suggest that S. aureus can activate nuclear factor kappaB in human osteoblasts, and subsequently regulate the secretion of interleukin-6 and monocyte chemoattractant protein-1. The nuclear factor kappaB transcription factor regulates a number of genes involved in a wide variety of biological processes. Further study of the effects of nuclear factor kappaB activation on S. aureus-infected human osteoblast may provide us new insights into discovery of the immune mechanisms in osteomyelitis.

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Streptococcus pyogenes induces epithelial inflammatory responses through NF-κB/MAPK signaling pathways

Cited by 27 publications

References 30 publications

Kallistatin Modulates Immune Cells and Confers Anti-Inflammatory Response To Protect Mice from Group A Streptococcal Infection

Kallistatin Modulates Immune Cells and Confers Anti-Inflammatory Response To Protect Mice from Group A Streptococcal Infection

Streptolysin S Promotes Programmed Cell Death and Enhances Inflammatory Signaling in Epithelial Keratinocytes during Group A Streptococcus Infection

Staphylococcus aureus regulates secretion of interleukin-6 and monocyte chemoattractant protein-1 through activation of nuclear factor kappaB signaling pathway in human osteoblasts

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