Human polyspecific immunoglobulin attenuates group A streptococcal virulence factor activity and reduces disease severity in a murine necrotizing fasciitis model

Tarnutzer, Andrea; Andreoni, Federica; Keller, Nadia; Zürcher, Claudia; Norrby‐Teglund, Anna; Schüpbach, Reto

doi:10.1016/j.cmi.2018.07.007

Cited by 16 publications

(15 citation statements)

References 30 publications

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“…This is in line with the recent metaanalysis of IVIG-therapy in clindamycin-treated Streptococcal Toxic Shock Syndrome (STSS) in which adjunctive IVIG was associated with a survival benefit [2]. Mechanistic actions of IVIG in this setting include neutralization of GAS superantigens and dampening of inflammation [3][4][5][6][7].…”

Section: Introductionsupporting

confidence: 68%

Correlation Between Immunoglobulin Dose Administered and Plasma Neutralization of Streptococcal Superantigens in Patients With Necrotizing Soft Tissue Infections

Bergsten

Madsen

Bergey

et al. 2020

Clinical Infectious Diseases

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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.

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Section: Introductionsupporting

confidence: 68%

Correlation Between Immunoglobulin Dose Administered and Plasma Neutralization of Streptococcal Superantigens in Patients With Necrotizing Soft Tissue Infections

Bergsten

Madsen

Bergey

et al. 2020

Clinical Infectious Diseases

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“…Since this effect is the result of the extracellular binding between HSA and SLO, from a clinical point of view the demonstration of a neutralizing effect itself rather than the protective effect on different types of adopted cellular models is the most relevant result. In vivo studies clearly demonstrated that the inhibition of SLO activity was significantly associated with a disease severity reduction in necrotizing fasciitis, necrotizing myositis, bacteremia, and soft tissue infection models ( 54 , 55 ). Therefore, we hypothesize that HSA levels could affect streptococcal diseases severity.…”

Section: Discussionmentioning

confidence: 99%

Human Serum Albumin Binds Streptolysin O (SLO) Toxin Produced by Group A Streptococcus and Inhibits Its Cytotoxic and Hemolytic Effects

Vita

Leboffe

et al. 2020

Front. Immunol.

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The pathogenicity of group A Streptococcus (GAS) is mediated by direct bacterial invasivity and toxin-associated damage. Among the extracellular products, the exotoxin streptolysin O (SLO) is produced by almost all GAS strains. SLO is a pore forming toxin (PFT) hemolitically active and extremely toxic in vivo. Recent evidence suggests that human serum albumin (HSA), the most abundant protein in plasma, is a player in the innate immunity “orchestra.” We previously demonstrated that HSA acts as a physiological buffer, partially neutralizing Clostridioides difficile toxins that reach the bloodstream after being produced in the colon. Here, we report the in vitro and ex vivo capability of HSA to neutralize the cytotoxic and hemolytic effects of SLO. HSA binds SLO with high affinity at a non-conventional site located in domain II, which was previously reported to interact also with C. difficile toxins. HSA:SLO recognition protects HEp-2 and A549 cells from cytotoxic effects and cell membrane permeabilization induced by SLO. Moreover, HSA inhibits the SLO-dependent hemolytic effect in red blood cells isolated from healthy human donors. The recognition of SLO by HSA may have a significant protective role in human serum and sustains the emerging hypothesis that HSA is an important constituent of the innate immunity system.

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“…In addition, the actions of IVIG have been demonstrated in vitro and in mice experimental models, including neutralization of circulating superantigens and reduction of the systemic inflammatory response ( 22 , 23 ). A recent study analyzed the effects of IVIG on virulence factor activity in three different ways: in vitro, in vivo in a murine infection model, and ex vivo in patients ( 24 ). In vitro , SLO and Sda1 activities were reduced.…”

Section: Methodsmentioning

confidence: 99%

“…In the murine infection model, mice treated with IVIG had smaller skin lesions and a lower SLO activity. Moreover, serum from patients with iGAS had a reduced SLO and Sda activity after IVIG was administrated compared with before such treatment ( 24 ). In addition, plasma of STSS-patients treated with IVIG was able to neutralize streptococcal superantigens and completely inhibit cytokine production ( 25 ), suggesting a clinical interest of such adjunctive therapy for these patients.…”

Section: Methodsmentioning

confidence: 99%

Invasive Group A Streptococcal Infections: Benefit of Clindamycin, Intravenous Immunoglobulins and Secondary Prophylaxis

et al. 2021

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Introduction: Mortality associated with invasive group A streptococcal infections (iGAS) remains high among adults, with lower mortality in children. The added value of both clindamycin and immunoglobulins in such treatment is still controversial, as is the need for antibiotic secondary prophylaxis. It is unlikely that conclusive randomized clinical studies will ever definitively end these controversies.Materials and Methods: A clinical and experimental literature review was conducted in Pubmed, Cochrane, and lay literature to determine the benefit of adding clindamycin and immunoglobulins to β-lactams in the management of iGAS, as well as the need for secondary prophylaxis measures in close contacts.Results: This review includes two meta-analyses, two randomized controlled trials, four prospective studies, five retrospective studies, and microbiological studies. To reduce mortality and morbidity, it appears useful to add clindamycin to β-lactams in severe clinical presentations, including necrotizing fasciitis or streptococcal toxic shock syndrome, and immunoglobulins for the latter two presentations. The high risk of secondary infection in household contacts justifies the need of taking preventive measures.Conclusions: Both clinical studies and available experimental evidence suggest that adding clindamycin and immunoglobulins as adjunctive therapies in the management of invasive group A streptococcal infections may reduce mortality. Household contacts should be warned about the increased risk of secondary infection, and chemoprophylaxis may be considered in certain situations.

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Human polyspecific immunoglobulin attenuates group A streptococcal virulence factor activity and reduces disease severity in a murine necrotizing fasciitis model

Abstract: The clear reduction in disease severity in IVIG-treated mice and inhibition of virulence factor activity in mouse and human sera suggest that IVIG may be beneficial in invasive group A Streptococcus infections such as NF in addition to streptococcal toxic shock syndrome.

Cited by 16 publications

References 30 publications

Correlation Between Immunoglobulin Dose Administered and Plasma Neutralization of Streptococcal Superantigens in Patients With Necrotizing Soft Tissue Infections

Correlation Between Immunoglobulin Dose Administered and Plasma Neutralization of Streptococcal Superantigens in Patients With Necrotizing Soft Tissue Infections

Human Serum Albumin Binds Streptolysin O (SLO) Toxin Produced by Group A Streptococcus and Inhibits Its Cytotoxic and Hemolytic Effects

Invasive Group A Streptococcal Infections: Benefit of Clindamycin, Intravenous Immunoglobulins and Secondary Prophylaxis

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