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


Tarnutzer, Andrea A; Andreoni, Federica F; Keller, Nadia N; Zürcher, Claudia C; Norrby-Teglund, Anna A; Schuepbach, Reto Ra; Zinkernagel, Annelies As (2019). Human polyspecific immunoglobulin attenuates group A streptococcal virulence factor activity and reduces disease severity in a murine necrotizing fasciitis model. Clinical Microbiology and Infection, 25(4):512.e7-512.e13.

Abstract

OBJECTIVES Streptococcus pyogenes causes life-threatening invasive infections including necrotizing fasciitis (NF). Current treatment guidelines recommend the use of a cell-wall active antibiotic combined with a protein synthesis inhibitor and surgical debridement in NF patients. Adjunctive therapy with intravenous immunoglobulin (IVIG) has been proposed for superantigen-associated streptococcal toxic shock syndrome. So far, benefits of IVIG treatment remain unclear and prospective clinical studies are scarce. Thus, we aimed to assess the effects of IVIG on virulence factor activity in vitro, ex vivo in patients and in vivo in a NF mouse model. METHODS We investigated the effect of IVIG on the activity of the virulence factors streptolysin O (SLO), streptodornase 1 (Sda1), S. pyogenes cell envelope protease (SpyCEP) and streptococcal pyrogenic exotoxin B (SpeB) in vitro and ex vivo in patients' sera. Additionally, we assessed the influence of IVIG on the clinical outcome in a murine NF model. RESULTS In vitro, IVIG inhibited various streptococcal virulence factors. Further, IVIG treatment of GAS-infected mice led to a reduced skin lesion size (median day 3 [interquartile range] intraperitoneal: 12mm [9-14.5] vs 4mm [0.8-10.5], subcutaneous: 10.3mm [6.9-18.6] vs 0.5mm [0.1-6.8]) and lower SLO activity. After treatment with IVIG, patient's sera showed an elevated titre of specific SLO (7/9) and Sda1 (5/9) antibodies, reducing SLO and Sda1 activity. CONCLUSIONS The clear reduction in disease severity in IVIG-treated mice and inhibition of virulence factor activity in mouse and human serum suggest that IVIG may be beneficial in invasive GAS infections such as NF in addition to STSS.

Abstract

OBJECTIVES Streptococcus pyogenes causes life-threatening invasive infections including necrotizing fasciitis (NF). Current treatment guidelines recommend the use of a cell-wall active antibiotic combined with a protein synthesis inhibitor and surgical debridement in NF patients. Adjunctive therapy with intravenous immunoglobulin (IVIG) has been proposed for superantigen-associated streptococcal toxic shock syndrome. So far, benefits of IVIG treatment remain unclear and prospective clinical studies are scarce. Thus, we aimed to assess the effects of IVIG on virulence factor activity in vitro, ex vivo in patients and in vivo in a NF mouse model. METHODS We investigated the effect of IVIG on the activity of the virulence factors streptolysin O (SLO), streptodornase 1 (Sda1), S. pyogenes cell envelope protease (SpyCEP) and streptococcal pyrogenic exotoxin B (SpeB) in vitro and ex vivo in patients' sera. Additionally, we assessed the influence of IVIG on the clinical outcome in a murine NF model. RESULTS In vitro, IVIG inhibited various streptococcal virulence factors. Further, IVIG treatment of GAS-infected mice led to a reduced skin lesion size (median day 3 [interquartile range] intraperitoneal: 12mm [9-14.5] vs 4mm [0.8-10.5], subcutaneous: 10.3mm [6.9-18.6] vs 0.5mm [0.1-6.8]) and lower SLO activity. After treatment with IVIG, patient's sera showed an elevated titre of specific SLO (7/9) and Sda1 (5/9) antibodies, reducing SLO and Sda1 activity. CONCLUSIONS The clear reduction in disease severity in IVIG-treated mice and inhibition of virulence factor activity in mouse and human serum suggest that IVIG may be beneficial in invasive GAS infections such as NF in addition to STSS.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Infectious Diseases
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 April 2019
Deposited On:13 Sep 2018 11:37
Last Modified:24 Sep 2019 23:36
Publisher:Elsevier
ISSN:1198-743X
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.cmi.2018.07.007
PubMed ID:30025835

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