Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
06 07 2023
06 07 2023
Historique:
received:
16
08
2022
accepted:
28
06
2023
medline:
10
7
2023
pubmed:
7
7
2023
entrez:
6
7
2023
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 37414832
doi: 10.1038/s41467-023-39771-0
pii: 10.1038/s41467-023-39771-0
pmc: PMC10326033
doi:
Substances chimiques
Bacterial Proteins
0
NAD+ Nucleosidase
EC 3.2.2.5
STING1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4008Informations de copyright
© 2023. The Author(s).
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