Skip to main content

Lund University Publications

LUND UNIVERSITY LIBRARIES

C4b-Binding Protein and Factor H Attenuate NLRP3 Inflammasome-Mediated Signalling Response during Group A Streptococci Infection in Human Cells

Bettoni, Serena LU orcid ; Dziedzic, Mateusz LU ; Bierschenk, Damien LU ; Chrobak, Maja LU ; Magda, Michal LU orcid ; Laabei, Maisem LU ; King, Ben C. LU orcid ; Riesbeck, Kristian LU orcid and Blom, Anna M. LU orcid (2024) In Journal of Innate Immunity 16(1). p.554-572
Abstract

Introduction: Streptococcus pyogenes (group A streptococcus; GAS) is a pathogen causing over half a million deaths annually worldwide. Human immune cells respond to GAS infection by activating the NLRP3 inflammasome leading to the release of pro-inflammatory cytokines that control infection. We investigated the role of C4b-binding protein (C4BP) and factor H (FH) in the inflammasome response to GAS, as they are recruited by GAS to prevent complement deposition and limit phagocytosis. Methods: The inflammasome response was investigated using primary human cells and the strain GAS-AP1. Cytokine responses were evaluated by ELISA. C4BP internalisation was investigated using confocal microscopy. Activation of the NLRP3 inflammasome... (More)

Introduction: Streptococcus pyogenes (group A streptococcus; GAS) is a pathogen causing over half a million deaths annually worldwide. Human immune cells respond to GAS infection by activating the NLRP3 inflammasome leading to the release of pro-inflammatory cytokines that control infection. We investigated the role of C4b-binding protein (C4BP) and factor H (FH) in the inflammasome response to GAS, as they are recruited by GAS to prevent complement deposition and limit phagocytosis. Methods: The inflammasome response was investigated using primary human cells and the strain GAS-AP1. Cytokine responses were evaluated by ELISA. C4BP internalisation was investigated using confocal microscopy. Activation of the NLRP3 inflammasome components was assessed by Western blotting. Results: Interleukin-1β (IL-1β) release, induced by GASAP1, was inhibited by FH which interferes with priming of human cells. In contrast, C4BP restricted the IL-1β response without affecting cell priming. C4BP was engulfed by cells together with bacteria and excluded from low-pH vesicles but localised within the cytosol and near the ASC speck inflammasome complex. C4BP did not inhibit either the inflammasome complex assembly or caspase-1 activation. However, C4BP limited the cleavage of gasdermin D N-terminal fragments by interfering with caspase-1 enzymatic activity. Conclusion: Given that the amount of IL-1β modulates the severity of GAS infection, our results provide new insights into the effect of FH and internalised C4BP to control GAS sensing by inflammasomes.

(Less)
Please use this url to cite or link to this publication:
author
; ; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
C4b-binding protein, Factor H, Interleukin-1β, NLRP3, Streptococcus pyogenes
in
Journal of Innate Immunity
volume
16
issue
1
pages
19 pages
publisher
Karger
external identifiers
  • scopus:85212713839
  • pmid:39496236
ISSN
1662-811X
DOI
10.1159/000542434
language
English
LU publication?
yes
id
c2ff75bd-1a11-4c23-8584-84144bbff2ca
date added to LUP
2025-01-29 14:33:36
date last changed
2025-07-17 04:15:27
@article{c2ff75bd-1a11-4c23-8584-84144bbff2ca,
  abstract     = {{<p>Introduction: Streptococcus pyogenes (group A streptococcus; GAS) is a pathogen causing over half a million deaths annually worldwide. Human immune cells respond to GAS infection by activating the NLRP3 inflammasome leading to the release of pro-inflammatory cytokines that control infection. We investigated the role of C4b-binding protein (C4BP) and factor H (FH) in the inflammasome response to GAS, as they are recruited by GAS to prevent complement deposition and limit phagocytosis. Methods: The inflammasome response was investigated using primary human cells and the strain GAS-AP1. Cytokine responses were evaluated by ELISA. C4BP internalisation was investigated using confocal microscopy. Activation of the NLRP3 inflammasome components was assessed by Western blotting. Results: Interleukin-1β (IL-1β) release, induced by GASAP1, was inhibited by FH which interferes with priming of human cells. In contrast, C4BP restricted the IL-1β response without affecting cell priming. C4BP was engulfed by cells together with bacteria and excluded from low-pH vesicles but localised within the cytosol and near the ASC speck inflammasome complex. C4BP did not inhibit either the inflammasome complex assembly or caspase-1 activation. However, C4BP limited the cleavage of gasdermin D N-terminal fragments by interfering with caspase-1 enzymatic activity. Conclusion: Given that the amount of IL-1β modulates the severity of GAS infection, our results provide new insights into the effect of FH and internalised C4BP to control GAS sensing by inflammasomes.</p>}},
  author       = {{Bettoni, Serena and Dziedzic, Mateusz and Bierschenk, Damien and Chrobak, Maja and Magda, Michal and Laabei, Maisem and King, Ben C. and Riesbeck, Kristian and Blom, Anna M.}},
  issn         = {{1662-811X}},
  keywords     = {{C4b-binding protein; Factor H; Interleukin-1β; NLRP3; Streptococcus pyogenes}},
  language     = {{eng}},
  number       = {{1}},
  pages        = {{554--572}},
  publisher    = {{Karger}},
  series       = {{Journal of Innate Immunity}},
  title        = {{C4b-Binding Protein and Factor H Attenuate NLRP3 Inflammasome-Mediated Signalling Response during Group A Streptococci Infection in Human Cells}},
  url          = {{http://dx.doi.org/10.1159/000542434}},
  doi          = {{10.1159/000542434}},
  volume       = {{16}},
  year         = {{2024}},
}