Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability. / Movert, Elin; Bolarin, Jaume Salgado; Valfridsson, Christine; Velarde, Jorge; Skrede, Steinar; Nekludov, Michael; Hyldegaard, Ole; Arnell, Per; Svensson, Mattias; Norrby-Teglund, Anna; Cho, Kyu Hong; Elhaik, Eran; Wessels, Michael R.; Råberg, Lars; Carlsson, Fredric.
I: Nature Communications, Bind 14, 4008, 2023.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability
AU - Movert, Elin
AU - Bolarin, Jaume Salgado
AU - Valfridsson, Christine
AU - Velarde, Jorge
AU - Skrede, Steinar
AU - Nekludov, Michael
AU - Hyldegaard, Ole
AU - Arnell, Per
AU - Svensson, Mattias
AU - Norrby-Teglund, Anna
AU - Cho, Kyu Hong
AU - Elhaik, Eran
AU - Wessels, Michael R.
AU - Råberg, Lars
AU - Carlsson, Fredric
N1 - Publisher Copyright: © 2023, The Author(s).
PY - 2023
Y1 - 2023
N2 - 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.
AB - 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.
U2 - 10.1038/s41467-023-39771-0
DO - 10.1038/s41467-023-39771-0
M3 - Journal article
C2 - 37414832
AN - SCOPUS:85164124684
VL - 14
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
M1 - 4008
ER -
ID: 366830627