Cell Wall-Anchored Nuclease of Streptococcus sanguinis Contributes to Escape from Neutrophil Extracellular Trap-Mediated Bacteriocidal Activity

Morita, Chisato; Sumioka, Ryuichi; Nakata, Masao; Okahashi, Nobuo; Wada, Satoshi; Yamashiro, Takashi; Hayashi, Mikako; Hamada, Shigeyuki; Sumitomo, Tomoko; Kawabata, Shigetada

doi:10.1371/journal.pone.0103125

Cited by 64 publications

(64 citation statements)

References 58 publications

(65 reference statements)

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“…These findings were the opposite of what one would expect based on the literature on NETs, which emphasizes the role of DNA as an antibacterial host defense (23). Nucleases, which destroy NETs, are supposed to help pathogens survive better (24)(25)(26), whereas inhibition of nucleases is supposed to enhance pathogen clearance (27). None of the studies on the role of NETs have been done in the gut, however.…”

Section: Discussionmentioning

confidence: 85%

Biological Activities of Uric Acid in Infection Due to Enteropathogenic and Shiga-Toxigenic Escherichia coli

2016

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In previous work, we identified xanthine oxidase (XO) as an important enzyme in the interaction between the host and enteropathogenic Escherichia coli (EPEC) and Shiga-toxigenic E. coli (STEC). Many of the biological effects of XO were due to the hydrogen peroxide produced by the enzyme. We wondered, however, if uric acid generated by XO also had biological effects in the gastrointestinal tract. Uric acid triggered inflammatory responses in the gut, including increased submucosal edema and release of extracellular DNA from host cells. While uric acid alone was unable to trigger a chloride secretory response in intestinal monolayers, it did potentiate the secretory response to cyclic AMP agonists. Uric acid crystals were formed in vivo in the lumen of the gut in response to EPEC and STEC infections. While trying to visualize uric acid crystals formed during EPEC and STEC infections, we noticed that uric acid crystals became enmeshed in the neutrophilic extracellular traps (NETs) produced from host cells in response to bacteria in cultured cell systems and in the intestine in vivo. Uric acid levels in the gut lumen increased in response to exogenous DNA, and these increases were enhanced by the actions of DNase I. Interestingly, addition of DNase I reduced the numbers of EPEC bacteria recovered after a 20-h infection and protected against EPEC-induced histologic damage. Xanthine oxidase (XO), also known as xanthine oxidoreductase (XOR), has been hailed as an important host defense against enteric pathogens for decades (1, 2). In a recent study, however, we found that XO could have deleterious as well as beneficial effects in the context of infection with Shiga-toxigenic Escherichia coli (STEC) (3). One of the deleterious effects of XO was its ability to induce production of the Shiga toxins (Stx) from STEC bacteria. Low to intermediate amounts of XO activity generated enough H 2 O 2 to induce Stx but not enough to actually kill STEC or enteropathogenic E. coli (EPEC) bacteria, resulting in an "uncanny valley" of worsened disease outcome.In addition to H 2 O 2 , XO also generates uric acid as a product. While uric acid used to be viewed as an inert waste product of purine metabolism, recent advances have highlighted the biological roles of uric acid in inflammation and innate immunity (4, 5). Although monosodium urate (MSU) is the technically more accurate term, we will use "uric acid" here, since the latter term is deeply entrenched in the biomedical literature. In a previous study, we found that uric acid crystals were formed in vivo in response to EPEC and STEC infection in the lumen of the gastrointestinal (GI) tract (6). In the present study, we focused on determining the biological effects of uric acid, as opposed to H 2 O 2 , produced by XO. We investigated the effects of uric acid on inflammatory responses, as well as secretory responses, in intestinal tissues and found that uric acid acted as a potentiator or modulator of proinflammatory or prosecretory agonists and that its crystals became enmeshed in the...

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Section: Discussionmentioning

confidence: 85%

Biological Activities of Uric Acid in Infection Due to Enteropathogenic and Shiga-Toxigenic Escherichia coli

2016

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“…DNase Sda1 is both necessary and sufficient to promote groupA Streptococcus neutrophil resistance (Buchanan et al, 2006). Streptococcus sanguinis produces a wall-anchored nuclease, which contributes to its survival when encountering NETs (Morita et al, 2014). Streptococcus suis DNase SsnA contributes to degradation of NETs and evasion of NET-mediated antimicrobial activity (de Buhr et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

A Nuclease from Streptococcus mutans Facilitates Biofilm Dispersal and Escape from Killing by Neutrophil Extracellular Traps

Liu

Sun

Liu

et al. 2017

Front. Cell. Infect. Microbiol.

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Streptococcus mutans is the primary etiologic agent of dental caries and occasionally infective endocarditis, with the ability to form biofilms and disperse cells into distal sites to exacerbate and spread infection. In this study, we identified a nuclease (DeoC) as a S. mutans biofilm dispersal modulating factor through microarray analysis. In vitro assays revealed a dispersal defect of a deoC deletion mutant, and functional studies with purified protein were indicative of the biofilm dispersal activity of DeoC. Neutrophils are a key host response factor restraining bacterial spreading through the formation of neutrophil extracellular traps (NETs), which consist of a nuclear DNA backbone associated with antimicrobial peptides. Therefore, we hypothesized that the dispersed S. mutans might utilize DeoC to degrade NETs and escape killing by the immune system. It was found that S. mutans induced NET formation upon contact with neutrophils, while the presence of NETs in turn enhanced the deoC expression of S. mutans. Fluorescence microscopy inspection showed that deoC deletion resulted in a decreased NET degradation ability of S. mutans and enhanced susceptibility to neutrophil killing. Data obtained from this study assigned two important roles for DeoC in S. mutans: contributing to the spread of infection through mediating biofilm dispersal, and facilitating the escape of S. mutans from neutrophil killing through NET degradation.

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“…In fact, this might be a common strategy because NET-cleaving nucleases in addition to 5Ј-nucleotidases are also found in other pathogenic bacteria (e.g. in S. sanguinis) (23,38). However, NudP from S. agalactiae is unable to hydrolyze dAMP, and, although this pathogen expresses a NET-cleaving nuclease, production of dAdo from NETs therefore appears unlikely (25,39).…”

Section: Volume 290 • Number 52 • December 25 2015mentioning

confidence: 99%

Streptococcal 5′-Nucleotidase A (S5nA), a Novel Streptococcus pyogenes Virulence Factor That Facilitates Immune Evasion

Zheng¹,

Khemlani²,

Lorenz

et al. 2015

Journal of Biological Chemistry

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Background: 5Ј-Nucleotidases are important virulence factors found in several bacterial pathogens. Results: Streptococcal 5Ј-nucleotidase A (S5nA) generated immunomodulatory molecules adenosine and deoxyadenosine and rescued Lactococcus lactis in a blood killing assay. Conclusion: S5nA is a novel Streptococcus pyogenes virulence factor that facilitates immune evasion from the host. Significance: S5nA might be a target for developing new therapeutics or vaccines.

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Cell Wall-Anchored Nuclease of Streptococcus sanguinis Contributes to Escape from Neutrophil Extracellular Trap-Mediated Bacteriocidal Activity

Cited by 64 publications

References 58 publications

Biological Activities of Uric Acid in Infection Due to Enteropathogenic and Shiga-Toxigenic Escherichia coli

Biological Activities of Uric Acid in Infection Due to Enteropathogenic and Shiga-Toxigenic Escherichia coli

A Nuclease from Streptococcus mutans Facilitates Biofilm Dispersal and Escape from Killing by Neutrophil Extracellular Traps

Streptococcal 5′-Nucleotidase A (S5nA), a Novel Streptococcus pyogenes Virulence Factor That Facilitates Immune Evasion

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