NAD<b><sup>+</sup></b>‐glycohydrolase acts as an intracellular toxin to enhance the extracellular survival of group A streptococci

Bricker, Angela L.; Cywes, Colette; Ashbaugh, Cameron D.; Wessels, Michael R.

doi:10.1046/j.1365-2958.2002.02876.x

Cited by 116 publications

(153 citation statements)

References 66 publications

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“…Hence, it is conceivable that apoptosis was enhanced by the presence of extracellular multiplying bacteria. The recent finding that extracellular GAS are also capable of inducing apoptosis by insertion of NAD+-glycohydrolase into the cytoplasm of infected keratinocytes (Bricker et al, 2002), supports such a notion.…”

Section: Hep-2 Cell Damage Is Caused By Programmed Cell Deathmentioning

confidence: 86%

“…Recent studies have revealed that GAS are capable of inducing apoptosis in epithelial cells and in monocyte-like cells. Streptococcal pyrogenic exotoxin B (SpeB), SpeA, streptolysin O and streptolysin S have all been implicated in this process Molinari et al, 2001;Kuo et al, 1999;Bricker et al, 2002). To determine whether HEp-2 cells undergo apoptosis after internalization, we looked for several indicators of apoptosis at various time points.…”

Section: Hep-2 Cell Damage Is Caused By Programmed Cell Deathmentioning

confidence: 99%

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Fate of Streptococcus pyogenes and epithelial cells following internalization

Marouni

Sela

2004

Journal of Medical Microbiology

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The fate of GAS and epithelial cells following internalization was determined in this study. HEp-2 cells harbouring intracellular bacteria were treated with antibiotics to kill extracellular adherent bacteria, washed, and the fate of bacteria and epithelial cells was assessed up to 24 h post-infection. In the absence of antibiotics, massive bacterial growth was apparent in the cell medium, accompanied by extensive cell death, suggesting that intracellular bacteria had multiplied and damaged the monolayer. Addition of the internalization inhibitor, cytochalasin D, either pre-or post-internalization prevented bacterial growth and cell injury; post-internalization treatment with chloramphenicol had the same effect. Analysis of three apoptotic markers in HEp-2 cells -chromatin condensation, DNA laddering and translocation of phosphatidylserine onto the cell-surface membrane -indicated that HEp-2 cells underwent apoptosis. Taken together, the data presented here support a model in which intenalized bacteria can induce their own externalization into the medium by a process that requires both an intact host-cell cytoskeleton and de novo synthesis of bacterial proteins. Concomitantly, intracellular and, apparently, extracellular free bacteria induce apoptosis through their cytotoxic activity, and release essential nutrients required for their growth.

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Section: Hep-2 Cell Damage Is Caused By Programmed Cell Deathmentioning

confidence: 86%

Section: Hep-2 Cell Damage Is Caused By Programmed Cell Deathmentioning

confidence: 99%

Fate of Streptococcus pyogenes and epithelial cells following internalization

Marouni

Sela

2004

Journal of Medical Microbiology

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“…Van Epps and Andersen 28 showed that SLO inhibits neutrophil chemotaxis and mobility. Studies in the recent decade demonstrate SPN and SLO play important roles in circumventing the host immune system via i) inhibiting group A Streptococcus internalization by host cells, 3 ii) promoting apoptosis of macrophages, 29 iii) preventing the bactericidal effects of neutrophils, 7,8 iv) disrupting maturation of the phagosome, and v) promoting intracellular bacterial survival. 5,6,30 Recent advances in S. pyogenes population genomics and pathogenesis further underlined the important roles of SPN and SLO in virulence.…”

Section: Discussionmentioning

confidence: 99%

“…2e4 SLO is a cholesteroldependent cytolysin that forms pores in host cell membranes. SPN and SLO inhibit phagocytosis, 3 inhibit maturation of autophagosomes, 5,6 impair neutrophil oxidative burst, 7 and prevent the killing of S. pyogenes by a variety of host immune cells. 3,5e8 SPN and SLO are interconnected in many ways.…”

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confidence: 99%

Contribution of Secreted NADase and Streptolysin O to the Pathogenesis of Epidemic Serotype M1 Streptococcus pyogenes Infections

Zhu

Olsen

Lee

et al. 2017

The American Journal of Pathology

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Streptococcus pyogenes secretes many toxins that facilitate human colonization, invasion, and dissemination. NADase (SPN) and streptolysin O (SLO) are two toxins that play important roles in pathogenesis. We previously showed that increased production of SPN and SLO in epidemic serotype M1 and M89 S. pyogenes strains is associated with rapid intercontinental spread and enhanced virulence. The biological functions of SPN and SLO have been extensively studied using eukaryotic cell lines, but the relative contribution of each of these two toxins to pathogenesis of epidemic M1 or M89 strains remains unexplored. Herein, using a genetically representative epidemic M1 strain and a panel of isogenic mutant derivative strains, we evaluated the relative contributions of SPN and SLO toxins to virulence in mouse models of necrotizing myositis, bacteremia, and skin and soft tissue infection. We found that isogenic mutants lacking SPN, SLO, and both toxins are equally impaired in ability to cause necrotizing myositis. In addition, mutants lacking either SPN or SLO are significantly attenuated in the bacteremia and soft tissue infection models, and the mutant strain lacking production of both toxins is further attenuated. The mutant strain lacking both SPN and SLO production is severely attenuated in ability to resist killing by human polymorphonuclear leukocytes. We conclude that both SPN and SLO contribute significantly to S. pyogenes pathogenesis in these virulence assays. (Am J Pathol 2017, 187: 605e613; http://dx.doi.org/10.1016/j.ajpath.2016.11.003) Streptococcus pyogenes (alias group A Streptococcus) is a major bacterial pathogen causing human morbidity and mortality globally. Streptococcus pyogenes produces many virulence factors that facilitate transmission, colonization, invasion, and dissemination.1 NADase (SPN) and streptolysin O (SLO) are two potent cytotoxins secreted by S. pyogenes, and multiple roles in virulence have been attributed to each protein. SPN is actively translocated into the host cells, resulting in cell injury and death via depletion of host cell NAD þ . 2e4 SLO is a cholesteroldependent cytolysin that forms pores in host cell membranes. SPN and SLO inhibit phagocytosis, 3 inhibit maturation of autophagosomes, 5,6 impair neutrophil oxidative burst, 7 and prevent the killing of S. pyogenes by a variety of host immune cells. 3,5e8 SPN and SLO are interconnected in many ways. Several lines of evidence suggest that the SPN and SLO proteins interact physically.4,9e11 Moreover, SPN and SLO toxins are functionally related. For example, translocation of SPN into host cells requires SLO.2 In addition, binding of SPN to the host cell membrane promotes SLOmediated pore formation.

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“…The molecular events included phage-mediated virulence gene acquisition, single nucleotide variant accumulation, and horizontal transfer of the 36-kb region encoding the virulence factors Nga and Slo (61)(62)(63)(64)(65)(66)(67)(68)(69)(70)(71)(72)(73), likely mediated by generalized transduction (24). It is now clear from our analysis that a complex multistep (9).…”

Section: Concluding Commentmentioning

confidence: 93%

Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences

Nasser

Beres

Olsen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

233

343

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We sequenced the genomes of 3,615 strains of serotype Emm protein 1 (M1) group A Streptococcus to unravel the nature and timing of molecular events contributing to the emergence, dissemination, and genetic diversification of an unusually virulent clone that now causes epidemic human infections worldwide. We discovered that the contemporary epidemic clone emerged in stepwise fashion from a precursor cell that first contained the phage encoding an extracellular DNase virulence factor (streptococcal DNase D2, SdaD2) and subsequently acquired the phage encoding the SpeA1 variant of the streptococcal pyrogenic exotoxin A superantigen. The SpeA2 toxin variant evolved from SpeA1 by a single-nucleotide change in the M1 progenitor strain before acquisition by horizontal gene transfer of a large chromosomal region encoding secreted toxins NAD + -glycohydrolase and streptolysin O. Acquisition of this 36-kb region in the early 1980s into just one cell containing the phage-encoded sdaD2 and speA2 genes was the final major molecular event preceding the emergence and rapid intercontinental spread of the contemporary epidemic clone. Thus, we resolve a decades-old controversy about the type and sequence of genomic alterations that produced this explosive epidemic. Analysis of comprehensive, population-based contemporary invasive strains from seven countries identified strong patterns of temporal population structure. Compared with a preepidemic reference strain, the contemporary clone is significantly more virulent in nonhuman primate models of pharyngitis and necrotizing fasciitis. A key finding is that the molecular evolutionary events transpiring in just one bacterial cell ultimately have produced millions of human infections worldwide.pathogenesis | phylogeography | mobile genetic element | flesh-eating disease | molecular clock

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NAD⁺‐glycohydrolase acts as an intracellular toxin to enhance the extracellular survival of group A streptococci

Cited by 116 publications

References 66 publications

Fate of Streptococcus pyogenes and epithelial cells following internalization

Fate of Streptococcus pyogenes and epithelial cells following internalization

Contribution of Secreted NADase and Streptolysin O to the Pathogenesis of Epidemic Serotype M1 Streptococcus pyogenes Infections

Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences

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NAD+‐glycohydrolase acts as an intracellular toxin to enhance the extracellular survival of group A streptococci

Cited by 116 publications

References 66 publications

Fate of Streptococcus pyogenes and epithelial cells following internalization

Fate of Streptococcus pyogenes and epithelial cells following internalization

Contribution of Secreted NADase and Streptolysin O to the Pathogenesis of Epidemic Serotype M1 Streptococcus pyogenes Infections

Evolutionary pathway to increased virulence and epidemic group A Streptococcus disease derived from 3,615 genome sequences

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NAD⁺‐glycohydrolase acts as an intracellular toxin to enhance the extracellular survival of group A streptococci