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Human igg increases virulence of streptococcus pyogenes through complement evasion

Ermert, David LU ; Weckel, Antonin; Magda, Michal LU ; Mörgelin, Matthias LU ; Shaughnessy, Jutamas; Rice, Peter A.; Björck, Lars LU ; Ram, Sanjay and Blom, Anna M. LU (2018) In Journal of Immunology 200(10). p.3495-3505
Abstract

Streptococcus pyogenes is an exclusively human pathogen that can provoke mild skin and throat infections but can also cause fatal septicemia. This gram-positive bacterium has developed several strategies to evade the human immune system, enabling S. pyogenes to survive in the host. These strategies include recruiting several human plasma proteins, such as the complement inhibitor, C4b-binding protein (C4BP), and human (hu)-IgG through its Fc region to the bacterial surface to evade immune recognition. We identified a novel virulence mechanism whereby IgG-enhanced binding of C4BP to five of 12 tested S. pyogenes strains expressed diverse M proteins that are important surface-expressed virulence factors. Importantly, all strains that... (More)

Streptococcus pyogenes is an exclusively human pathogen that can provoke mild skin and throat infections but can also cause fatal septicemia. This gram-positive bacterium has developed several strategies to evade the human immune system, enabling S. pyogenes to survive in the host. These strategies include recruiting several human plasma proteins, such as the complement inhibitor, C4b-binding protein (C4BP), and human (hu)-IgG through its Fc region to the bacterial surface to evade immune recognition. We identified a novel virulence mechanism whereby IgG-enhanced binding of C4BP to five of 12 tested S. pyogenes strains expressed diverse M proteins that are important surface-expressed virulence factors. Importantly, all strains that bound C4BP in the absence of IgG bound more C4BP when IgG was present. Further studies with an M1 strain that additionally expressed protein H, also a member of the M protein family, revealed that binding of hu-IgG Fc to protein H increased the affinity of protein H for C4BP. Increased C4BP binding accentuated complement downregulation, resulting in diminished bacterial killing. Accordingly, mortality from S. pyogenes infection in hu-C4BP transgenic mice was increased when hu-IgG or its Fc portion alone was administered concomitantly. Electron microscopy analysis of human tissue samples with necrotizing fasciitis confirmed increased C4BP binding to S. pyogenes when IgG was present. Our findings provide evidence of a paradoxical function of hu-IgG bound through Fc to diverse S. pyogenes isolates that increases their virulence and may counteract the beneficial effects of IgG opsonization.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Immunology
volume
200
issue
10
pages
11 pages
publisher
American Association of Immunologists
external identifiers
  • scopus:85047071113
ISSN
0022-1767
DOI
10.4049/jimmunol.1800090
language
English
LU publication?
yes
id
7984f98a-8f6a-4aea-9e22-b6eb62dbc46a
date added to LUP
2018-05-29 16:01:02
date last changed
2019-08-14 04:17:27
@article{7984f98a-8f6a-4aea-9e22-b6eb62dbc46a,
  abstract     = {<p>Streptococcus pyogenes is an exclusively human pathogen that can provoke mild skin and throat infections but can also cause fatal septicemia. This gram-positive bacterium has developed several strategies to evade the human immune system, enabling S. pyogenes to survive in the host. These strategies include recruiting several human plasma proteins, such as the complement inhibitor, C4b-binding protein (C4BP), and human (hu)-IgG through its Fc region to the bacterial surface to evade immune recognition. We identified a novel virulence mechanism whereby IgG-enhanced binding of C4BP to five of 12 tested S. pyogenes strains expressed diverse M proteins that are important surface-expressed virulence factors. Importantly, all strains that bound C4BP in the absence of IgG bound more C4BP when IgG was present. Further studies with an M1 strain that additionally expressed protein H, also a member of the M protein family, revealed that binding of hu-IgG Fc to protein H increased the affinity of protein H for C4BP. Increased C4BP binding accentuated complement downregulation, resulting in diminished bacterial killing. Accordingly, mortality from S. pyogenes infection in hu-C4BP transgenic mice was increased when hu-IgG or its Fc portion alone was administered concomitantly. Electron microscopy analysis of human tissue samples with necrotizing fasciitis confirmed increased C4BP binding to S. pyogenes when IgG was present. Our findings provide evidence of a paradoxical function of hu-IgG bound through Fc to diverse S. pyogenes isolates that increases their virulence and may counteract the beneficial effects of IgG opsonization.</p>},
  author       = {Ermert, David and Weckel, Antonin and Magda, Michal and Mörgelin, Matthias and Shaughnessy, Jutamas and Rice, Peter A. and Björck, Lars and Ram, Sanjay and Blom, Anna M.},
  issn         = {0022-1767},
  language     = {eng},
  month        = {05},
  number       = {10},
  pages        = {3495--3505},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {Human igg increases virulence of streptococcus pyogenes through complement evasion},
  url          = {http://dx.doi.org/10.4049/jimmunol.1800090},
  volume       = {200},
  year         = {2018},
}