Genetic Architecture of Group A Streptococcal Necrotizing Soft Tissue Infections in the Mouse

Abstract Analyses of plasma collected pre- and postadministration of intravenous immunoglobulin (IVIG) from patients with group A Streptococcus necrotizing soft tissue infections demonstrated a negative correlation between IVIG dose and toxin-triggered T-cell proliferation (r = −.67, P < .0001). One 25-g IVIG dose was sufficient to yield plasma-neutralizing activity against streptococcal superantigens. Clinical Trials Registration. NCT 01790698 and NCT02111161.

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The Role of Streptococcal and Staphylococcal Exotoxins and Proteases in Human Necrotizing Soft Tissue Infections

Toxins ◽

10.3390/toxins11060332 ◽

2019 ◽

Vol 11 (6) ◽

pp. 332 ◽

Cited By ~ 5

Author(s):

Patience Shumba ◽

Srikanth Mairpady Shambat ◽

Nikolai Siemens

Keyword(s):

Soft Tissue ◽

Current Knowledge ◽

Special Focus ◽

Soft Tissue Infections ◽

Gram Positive Bacteria ◽

Necrotizing Soft Tissue Infections ◽

Group A ◽

Clinical Conditions ◽

Major Pathogens

Necrotizing soft tissue infections (NSTIs) are critical clinical conditions characterized by extensive necrosis of any layer of the soft tissue and systemic toxicity. Group A streptococci (GAS) and Staphylococcus aureus are two major pathogens associated with monomicrobial NSTIs. In the tissue environment, both Gram-positive bacteria secrete a variety of molecules, including pore-forming exotoxins, superantigens, and proteases with cytolytic and immunomodulatory functions. The present review summarizes the current knowledge about streptococcal and staphylococcal toxins in NSTIs with a special focus on their contribution to disease progression, tissue pathology, and immune evasion strategies.

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

10.1101/530493 ◽

2019 ◽

Author(s):

Jessica Baude ◽

Sylvère Bastien ◽

Yves Gillet ◽

Pascal Leblanc ◽

Andreas Itzek ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Soft Tissue ◽

Bacterial Species ◽

Human Keratinocytes ◽

High Rate ◽

Deep Fascia ◽

Soft Tissue Infections ◽

Muscle Involvement ◽

Necrotizing Soft Tissue Infections ◽

Group A

AbstractNecrotizing 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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Host Genetic Variations and Sex Differences Potentiate Predisposition, Severity, and Outcomes of Group A Streptococcus-Mediated Necrotizing Soft Tissue Infections

Infection and Immunity ◽

10.1128/iai.01191-15 ◽

2015 ◽

Vol 84 (2) ◽

pp. 416-424 ◽

Cited By ~ 4

Author(s):

Karthickeyan Chella Krishnan ◽

Santhosh Mukundan ◽

Jeyashree Alagarsamy ◽

Donna Laturnus ◽

Malak Kotb

Keyword(s):

Sex Differences ◽

Soft Tissue ◽

Dominant Role ◽

Genetic Variations ◽

Mouse Strains ◽

Soft Tissue Infections ◽

Content Type ◽

Necrotizing Soft Tissue Infections ◽

Group A ◽

Host Genetic

Host genetic variations play an important role in several pathogenic diseases, and we previously provided strong evidence that these genetic variations contribute significantly to differences in susceptibility and clinical outcomes of invasive group AStreptococcus(GAS) patients, including sepsis and necrotizing soft tissue infections (NSTIs). The goal of the present study was to investigate how genetic variations and sex differences among four commonly used mouse strains contribute to variation in severity, manifestations, and outcomes of NSTIs. DBA/2J mice were more susceptible to NSTIs than C57BL/6J, BALB/c, and CD-1 mice, as exhibited by significantly greater bacteremia, excessive dissemination to the spleen, and significantly higher mortality. Differences in the sex of the mice also contributed to differences in disease severity and outcomes: DBA/2J female mice were relatively resistant compared to their male counterparts. However, DBA/2J mice exhibited minimal weight loss and developed smaller lesions than did the aforementioned strains. Moreover, at 48 h after infection, compared with C57BL/6J mice, DBA/2J mice had increased bacteremia, excessive dissemination to the spleen, and excessive concentrations of inflammatory cytokines and chemokines. These results indicate that variations in the host genetic context as well as sex play a dominant role in determining the severity of and susceptibility to GAS NSTIs.

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