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Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability

Movert, Elin LU ; Bolarin, Jaume Salgado ; Valfridsson, Christine LU ; Velarde, Jorge ; Skrede, Steinar ; Nekludov, Michael ; Hyldegaard, Ole ; Arnell, Per ; Svensson, Mattias and Norrby-Teglund, Anna , et al. (2023) In Nature Communications 14(1).
Abstract

Variability in disease severity caused by a microbial pathogen is impacted by each infection representing a unique combination of host and pathogen genomes. Here, we show that the outcome of invasive Streptococcus pyogenes infection is regulated by an interplay between human STING genotype and bacterial NADase activity. S. pyogenes-derived c-di-AMP diffuses via streptolysin O pores into macrophages where it activates STING and the ensuing type I IFN response. However, the enzymatic activity of the NADase variants expressed by invasive strains suppresses STING-mediated type I IFN production. Analysis of patients with necrotizing S. pyogenes soft tissue infection indicates that a STING genotype associated with reduced c-di-AMP-binding... (More)

Variability in disease severity caused by a microbial pathogen is impacted by each infection representing a unique combination of host and pathogen genomes. Here, we show that the outcome of invasive Streptococcus pyogenes infection is regulated by an interplay between human STING genotype and bacterial NADase activity. S. pyogenes-derived c-di-AMP diffuses via streptolysin O pores into macrophages where it activates STING and the ensuing type I IFN response. However, the enzymatic activity of the NADase variants expressed by invasive strains suppresses STING-mediated type I IFN production. Analysis of patients with necrotizing S. pyogenes soft tissue infection indicates that a STING genotype associated with reduced c-di-AMP-binding capacity combined with high bacterial NADase activity promotes a ‘perfect storm’ manifested in poor outcome, whereas proficient and uninhibited STING-mediated type I IFN production correlates with protection against host-detrimental inflammation. These results reveal an immune-regulating function for bacterial NADase and provide insight regarding the host-pathogen genotype interplay underlying invasive infection and interindividual disease variability.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Nature Communications
volume
14
issue
1
article number
4008
pages
10 pages
publisher
Nature Publishing Group
external identifiers
  • scopus:85164124684
  • pmid:37414832
ISSN
2041-1723
DOI
10.1038/s41467-023-39771-0
language
English
LU publication?
yes
id
be119cd2-4868-486c-8998-0b979162ba65
date added to LUP
2023-08-23 15:14:08
date last changed
2024-07-13 08:56:25
@article{be119cd2-4868-486c-8998-0b979162ba65,
  abstract     = {{<p>Variability in disease severity caused by a microbial pathogen is impacted by each infection representing a unique combination of host and pathogen genomes. Here, we show that the outcome of invasive Streptococcus pyogenes infection is regulated by an interplay between human STING genotype and bacterial NADase activity. S. pyogenes-derived c-di-AMP diffuses via streptolysin O pores into macrophages where it activates STING and the ensuing type I IFN response. However, the enzymatic activity of the NADase variants expressed by invasive strains suppresses STING-mediated type I IFN production. Analysis of patients with necrotizing S. pyogenes soft tissue infection indicates that a STING genotype associated with reduced c-di-AMP-binding capacity combined with high bacterial NADase activity promotes a ‘perfect storm’ manifested in poor outcome, whereas proficient and uninhibited STING-mediated type I IFN production correlates with protection against host-detrimental inflammation. These results reveal an immune-regulating function for bacterial NADase and provide insight regarding the host-pathogen genotype interplay underlying invasive infection and interindividual disease variability.</p>}},
  author       = {{Movert, Elin and Bolarin, Jaume Salgado and Valfridsson, Christine and Velarde, Jorge and Skrede, Steinar and Nekludov, Michael and Hyldegaard, Ole and Arnell, Per and Svensson, Mattias and Norrby-Teglund, Anna and Cho, Kyu Hong and Elhaik, Eran and Wessels, Michael R. and Råberg, Lars and Carlsson, Fredric}},
  issn         = {{2041-1723}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Nature Communications}},
  title        = {{Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability}},
  url          = {{http://dx.doi.org/10.1038/s41467-023-39771-0}},
  doi          = {{10.1038/s41467-023-39771-0}},
  volume       = {{14}},
  year         = {{2023}},
}