<scp>N</scp>uclease <scp>A</scp> (<scp>Gbs</scp>0661), an extracellular nuclease of <i><scp>S</scp>treptococcus agalactiae</i>, attacks the neutrophil extracellular traps and is needed for full virulence

Derré-Bobillot, Aurélie; Cortes-Perez, Naima G.; Yamamoto, Yuji; Kharrat, Pascale; Couvé, Elizabeth; Cunha, Violette Da; Decker, Patrice; Boissier, Marie‐Christophe; Escartin, Frédéric; Cesselin, Bénédicte; Langella, Philippe; Bermúdez‐Humarán, Luis G.; Gaudu, Philippe

doi:10.1111/mmi.12295

Cited by 93 publications

(76 citation statements)

References 58 publications

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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: Discussioncontrasting

confidence: 54%

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: Discussioncontrasting

confidence: 54%

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

2016

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“…Another streptococcal nuclease, nucA, was found to be secreted by group B Streptococcus (GBS) and demonstrated to be capable of degrading NETs (29). As in the previous examples, the nucleasedeficient mutant was associated with higher bacterial clearance and lower mortality.…”

Section: Group B Streptococcus: Net Degradation and Inhibitionmentioning

confidence: 49%

Evasion of Neutrophil Extracellular Traps by Respiratory Pathogens

Storisteanu¹,

Pocock²,

Cowburn

et al. 2017

Am J Respir Cell Mol Biol

101

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The release of neutrophil extracellular traps (NETs) is a major immune mechanism intended to capture pathogens. These histoneand protease-coated DNA structures are released by neutrophils in response to a variety of stimuli, including respiratory pathogens, and have been identified in the airways of patients with respiratory infection, cystic fibrosis, acute lung injury, primary graft dysfunction, and chronic obstructive pulmonary disease. NET production has been demonstrated in the lungs of mice infected with Staphylococcus aureus, Klebsiella pneumoniae, and Aspergillus fumigatus. Since the discovery of NETs over a decade ago, evidence that "NET evasion" might act as an immune protection strategy among respiratory pathogens, including group A Streptococcus, Bordetella pertussis, and Haemophilus influenzae, has been growing, with the majority of these studies being published in the past 2 years. Evasion strategies fall into three main categories: inhibition of NET release by down-regulating host inflammatory responses; degradation of NETs using pathogen-derived DNases; and resistance to the microbicidal components of NETs, which involves a variety of mechanisms, including encapsulation. Hence, the evasion of NETs appears to be a widespread strategy to allow pathogen proliferation and dissemination, and is currently a topic of intense research interest. This article outlines the evidence supporting the three main strategies of NET evasion-inhibition, degradation, and resistance-with particular reference to common respiratory pathogens.

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“…Species of Streptococcus, Staphylococcus, Vibrio, and Leishmania express nucleases that aid in escape from NETs, to promote pathogen survival and spread [24][25][26][27][28]. We now add N. gonorrhoeae to this list, with 3 pieces of evidence to show that N. gonorrhoeae Nuc can degrade NETs.…”

Section: Discussionmentioning

confidence: 99%

A Thermonuclease ofNeisseria gonorrhoeaeEnhances Bacterial Escape From Killing by Neutrophil Extracellular Traps

et al. 2015

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Acute gonorrhea is characterized by neutrophilic inflammation that is insufficient to clear Neisseria gonorrhoeae. Activated neutrophils release extracellular traps (NETs), which are composed of chromatin and decorated with antimicrobial proteins. The N. gonorrhoeae NG0969 open reading frame contains a gene (nuc) that encodes a putatively secreted thermonuclease (Nuc) that contributes to biofilm remodeling. Here, we report that Nuc degrades NETs to help N. gonorrhoeae resist killing by neutrophils. Primary human neutrophils released NETs after exposure to N. gonorrhoeae, but NET integrity declined over time with Nuc-containing bacteria. Recombinant Nuc and conditioned medium from Nuc-containing N. gonorrhoeae degraded human neutrophil DNA and NETs. NETs were found to have antimicrobial activity against N. gonorrhoeae, and Nuc expression enhanced N. gonorrhoeae survival in the presence of neutrophils that released NETs. We propose that Nuc enables N. gonorrhoeae to escape trapping and killing by NETs during symptomatic infection, highlighting Nuc as a multifunctional virulence factor for N. gonorrhoeae.

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Nuclease A (Gbs0661), an extracellular nuclease of Streptococcus agalactiae, attacks the neutrophil extracellular traps and is needed for full virulence

Cited by 93 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

Evasion of Neutrophil Extracellular Traps by Respiratory Pathogens

A Thermonuclease ofNeisseria gonorrhoeaeEnhances Bacterial Escape From Killing by Neutrophil Extracellular Traps

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