Increased cytotoxicity and streptolysin O activity in group G streptococcal strains causing invasive tissue infections

Siemens, Nikolai; Kittang, Bård Reiakvam; Chakrakodi, Bhavya; Oppegaard, Oddvar; Johansson, Linda; Bruun, Trond; Mylvaganam, Haima; Svensson, Mattias; Skrede, Steinar; Norrby‐Teglund, Anna

doi:10.1038/srep16945

Cited by 28 publications

(21 citation statements)

References 37 publications

(59 reference statements)

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“…Next, we employed a 3D tissue model of human skin that recapitulates key anatomical and functional features of normal skin, including a dermal layer and a stratified epidermis, as well as key structural framework proteins (15). All 3 GAS strains were able to efficiently infect the tissue ( Figure 1C and Supplemental Figure 1B).…”

Section: Resultsmentioning

confidence: 99%

“…3D organotypic skin model. The models were generated using the human N/TERT-1 cells and NHDF dermal fibroblasts following the protocol as previously published (15). The human keratinocyte cells (N/ TERT-1; a gift from J. Rheinwald and the Cell Culture Core of the Harvard Skin Disease Research Centre, Boston, Massachusetts, USA) were maintained in EpiLife medium (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

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Biofilm in group A streptococcal necrotizing soft tissue infections

Siemens¹,

Chakrakodi²,

Shambat³

et al. 2016

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Necrotizing fasciitis caused by group A streptococcus (GAS) is a life-threatening, rapidly progressing infection. At present, biofilm is not recognized as a potential problem in GAS necrotizing soft tissue infections (NSTI), as it is typically linked to chronic infections or associated with foreign devices. Here, we present a case of a previously healthy male presenting with NSTI caused by GAS. The infection persisted over 24 days, and the surgeon documented the presence of a "thick layer biofilm" in the fascia. Subsequent analysis of NSTI patient tissue biopsies prospectively included in a multicenter study revealed multiple areas of biofilm in 32% of the patients studied. Biopsies associated with biofilm formation were characterized by massive bacterial load, a pronounced inflammatory response, and clinical signs of more severe tissue involvement. In vitro infections of a human skin tissue model with GAS NSTI isolates also revealed multilayered fibrous biofilm structures, which were found to be under the control of the global Nra gene regulator. The finding of GAS biofilm formation in NSTIs emphasizes the urgent need for biofilm to be considered as a potential complicating microbiological feature of GAS NSTI and, consequently, emphasizes reconsideration of antibiotic treatment protocols.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Biofilm in group A streptococcal necrotizing soft tissue infections

Siemens¹,

Chakrakodi²,

Shambat³

et al. 2016

JCI Insight

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“…In conclusion, our results uncover new insight into the pathophysiology of GAS and SA-NSTI and provide a new cellular basis for the contribution of S. aureus to pathogenesis of NSTI and other deep-seated infection involving the muscle. It also sustains the potential synergy of GAS and SA in NSTI, a situation that is not uncommon (2, 21). It advocates for future prospective clinical study systematically depicting the anatomical tissue layers of infection according to the micro-organisms.…”

Section: Discussionmentioning

confidence: 65%

Necrotizing Soft Tissue Infections Staphylococcus aureus - but not Streptococcus pyogenes-isolates display high rate of internalization and cytotoxicity toward human myoblasts

Baude

Bastien

Gillet

et al. 2019

Preprint

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Necrotizing Soft Tissue Infections (NSTIs), often reaching the deep fascia and muscle, are mainly caused by group A Streptococcus (GAS) and to a lesser extent by Staphylococcus aureus (SA). Conversely SA is a leading etiologic agent of pyomyositis suggesting that SA could have a specific tropism for the muscle. To assess the pathogenicity of these two bacterial species for muscles cells in comparison to keratinocytes, adhesion and invasion of NSTI-GAS and NSTI-SA were assessed on these cells. Bloodstream infections (BSI) SA isolates and non-invasive coagulase negative Staphylococci (CNS) isolates were used as controls.SA isolates from NSTI and from BSI exhibited stronger internalization into human keratinocytes and myoblasts than CNS or NSTI-GAS. While the median level of SA internalization culminated at 2% in human keratinocytes, it reached over 30% in human myoblasts due to a higher percentage of infected myoblasts (>11%) as compared to keratinocytes (<3%) assessed by transmission electron microscopy. Higher cytotoxicity for myoblasts of NSTI-SA as compared to BSI-SA, was attributed to higher levels of psmα and RNAIII transcripts in NSTI group as compared to hematogenous group. However, the two groups were not discriminated at the genomic level. The cellular basis of high internalization rate in myoblasts was attributed to higher expression of α5β1 integrin in myoblasts as compared to keratinocytes. Major contribution of FnbpAB-integrin α5β1 pathway to internalization was confirmed by isogenic mutants.Our findings suggest the contribution of NSTI-SA severity by its unique propensity to invade and kill myoblasts, a property not shared by NSTI-GAS.ImportanceNecrotizing Soft Tissue Infection (NSTI) is a severe infection caused mainly by group A Streptococcus (GAS) and occasionally by S. aureus (SA); the latter being more often associated with pyomyositis. NSTIs frequently involve the deep fascia and may provoke muscle necrosis. The goal of this study was to determine the tropism and pathogenicity of these two bacterial species for muscle cells. The results revealed a high tropism of SA for myoblasts and myotubes followed by cytotoxicity as opposed to GAS that did not invade these cells. This study uncover a novel mechanism of SA contribution to NSTI with a direct muscle involvement, while in GAS NSTI this is likely indirect, for instance, secondary to vascular occlusion.

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“…Human neutrophils, peripheral blood mononuclear cells (PBMCs), and monocytes were isolated from whole blood or buffy coats from volunteers as previously detailed [27][28][29]. Neutrophil degranulation was determined by measurement of resistin and heparin-binding protein (HBP) in neutrophil (5 × 10 5 cells) super-Group B Streptococcal Pigment 293 J Innate Immun 2020;12:291-303 DOI: 10.1159/000504002 natants collected after 2 h of bacterial (multiplicity of infection 10) or pigment stimulations [30][31][32].…”

Section: In Vitro Cell Assaysmentioning

confidence: 99%

Prothrombotic and Proinflammatory Activities of the β-Hemolytic Group B Streptococcal Pigment

et al. 2019

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A prominent feature of severe streptococcal infections is the profound inflammatory response that contributes to systemic toxicity. In sepsis the dysregulated host response involves both immunological and nonimmunological pathways. Here, we report a fatal case of an immunocompetent healthy female presenting with toxic shock and purpura fulminans caused by group B streptococcus (GBS; serotype III, CC19). The strain (LUMC16) was pigmented and hyperhemolytic. Stimulation of human primary cells with hyperhemolytic LUMC16 and STSS/NF-HH strains and pigment toxin resulted in a release of proinflammatory mediators, including tumor necrosis factor, interleukin (IL)-1β, and IL-6. In addition, LUMC16 induced blood clotting and showed factor XII activity on its surface, which was linked to the presence of the pigment. The expression of pigment was not linked to a mutation within the CovR/S region. In conclusion, our study shows that the hemolytic lipid toxin contributes to the ability of GBS to cause systemic hyperinflammation and interferes with the coagulation system.

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Increased cytotoxicity and streptolysin O activity in group G streptococcal strains causing invasive tissue infections

Cited by 28 publications

References 37 publications

Biofilm in group A streptococcal necrotizing soft tissue infections

Biofilm in group A streptococcal necrotizing soft tissue infections

Necrotizing Soft Tissue Infections Staphylococcus aureus - but not Streptococcus pyogenes-isolates display high rate of internalization and cytotoxicity toward human myoblasts

Prothrombotic and Proinflammatory Activities of the β-Hemolytic Group B Streptococcal Pigment

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