Dual modes of membrane binding direct pore formation by <scp>S</scp>treptolysin <scp>O</scp>

Mozola, Cara C.; Caparon, Michael G.

doi:10.1111/mmi.13085

Cited by 23 publications

(47 citation statements)

References 41 publications

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“…12 Furthermore, the NADase activity of SPN augments the cytotoxicity and the hemolytic activity of SLO. 4 These findings suggest the virulence function of SPN is (at least partially) dependent on SLO, and vice versa.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 99%

“…2 In addition, binding of SPN to the host cell membrane promotes SLOmediated pore formation. 12 Furthermore, the NADase activity of SPN augments the cytotoxic and hemolytic activity of SLO.…”

mentioning

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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“…Streptolysin O pore formation occurs in stages, including cholesterol-dependent binding of monomeric forms to the cell membrane, followed by oligomerization, which results in the development of pores . In addition to cholesterol, the membrane-binding domain of SLO also implicates a glycan (galactose) receptor involvement in binding and pore formation (Mozola and Caparon, 2015;Shewell et al, 2014). These pores result in disruption of the integrity of host cell membranes and induce apoptosis (Timmeret al, 2009).…”

Section: Toxinmentioning

confidence: 99%

Review on Major Virulence Factors of Pathogenic Streptococcus Species

Seid¹,

Demeke²

2018

International Journal of Research Studies in Microbiology and B

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Streptococcus species possesses a wide variety of virulence factors and can cause severe invasive infections. Accordingly, the field of bacterial pathogenesis has rapidly expanded with a greater understanding of pathogenesis at the molecular level over the last decades. The ability of bacteria to cause disease is described in terms of the number of infecting bacteria, the route of entry into the body, the effects of host defense mechanisms, and intrinsic characteristics of the bacteria called virulence factors. One essential prokaryotic cell function is the transport of proteins from the cytoplasm into other compartments of the cell, the environment, and/or other bacteria or eukaryotic cells a process known as protein secretion.Secreted proteins can play many roles in promoting bacterial virulence, from enhancing attachment to eukaryotic cells, to scavenging resources in an environmental niche, to directly intoxicating target cells and disrupting their functions. Virulence factors encoded on pathogenic islands represent the entire spectrum of bacterial virulence factors, from adhesins ,toxins, secretion systems, invasins, modulins, effectors, proteases, lipases, and enterotoxins, superantigens, iron uptake systems, immunoglobulin A proteases, capsule synthesis, host defense avoidance mechanisms.

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“…Since SLO and SLS are known to be released into the culture medium (27,28), we anticipated that the high level of biofilm formation observed in Fig. 4C could, in part, be caused by the secreted SLO and SLS present in the filtered CM.…”

Section: Er Stress-induced Host-associated Factor(s) Contributes To Gmentioning

confidence: 99%

Streptolysin-induced endoplasmic reticulum stress promotes group A streptococcalin vivobiofilm formation and necrotizing fasciitis

Vajjala

Biswas

Chong

et al. 2017

Preprint

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Group A Streptococcus (GAS) is a human pathogen that causes infections ranging from mild to fulminant and life-threatening. Biofilms have been implicated in acute GAS soft-tissue infections such as necrotizing fasciitis (NF). However, most in vitro models used to study GAS biofilms have been designed to mimic chronic infections and insufficiently recapitulate in vivo conditions and the hostpathogen interactions that might influence biofilm formation. Here we establish and characterize an in vitro model of GAS biofilm development on mammalian cells that simulates microcolony formation observed in a murine model of human NF. We show that on mammalian cells, GAS forms dense aggregates that display hallmark biofilm characteristics including a three-dimensional architecture and enhanced tolerance to antibiotics. In contrast to abiotic-grown biofilms, host-associated biofilms require the expression of secreted GAS streptolysins O and S (SLO, SLS) resulting in the release of a host-associated biofilm promoting-factor(s). Supernatants from GAS-infected mammalian cells or from cells treated with endoplasmic reticulum (ER) stressors restore biofilm formation to an SLO and SLS null mutant that is otherwise attenuated in biofilm formation on cells, together suggesting a role for streptolysin-induced ER stress in this process. In an in vivo mouse model, the streptolysin-null mutant is attenuated in both microcolony formation and bacterial spread, but pre-treatment of softtissue with an ER-stressor restores the ability of the mutant to form wild type like microcolonies that disseminate throughout the soft tissue. Taken together, we have identified a new role of streptolysindriven ER stress in GAS biofilm formation and NF disease progression. Significance StatementAlthough it is well-accepted that bacterial biofilms are associated with many chronic infections, little is known about the mechanisms by which group A Streptococcus (GAS) biofilms contribute to acute soft tissue-invasive diseases like necrotizing fasciitis (NF). In this study, we establish a physiologically relevant in vitro model to study GAS biofilm formation on mammalian cells and validate our findings in a mouse model that mimics human NF. This study demonstrates a novel role of GAS streptolysin-mediated ER stress in the development and spread of GAS biofilms in acute softnot peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/183012 doi: bioRxiv preprint first posted online Aug. 31, 2017; 3 tissue infections. We also show that biofilm formation depends on the release of a host-associated factor that promotes microcolony formation and GAS dissemination in vivo.

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Dual modes of membrane binding direct pore formation by Streptolysin O

Cited by 23 publications

References 41 publications

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

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

Review on Major Virulence Factors of Pathogenic Streptococcus Species

Streptolysin-induced endoplasmic reticulum stress promotes group A streptococcalin vivobiofilm formation and necrotizing fasciitis

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