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

Author

Listed:
  • Elin Movert

    (Lund University)

  • Jaume Salgado Bolarin

    (Lund University)

  • Christine Valfridsson

    (Lund University)

  • Jorge Velarde

    (Division of Infectious Diseases, Boston Children’s Hospital, and Department of Pediatrics, Harvard Medical School)

  • Steinar Skrede

    (Haukeland University Hospital
    University of Bergen)

  • Michael Nekludov

    (Karolinska University Hospital)

  • Ole Hyldegaard

    (Head and Orthopedic Center, Rigshospitalet
    University of Copenhagen)

  • Per Arnell

    (Sahlgrenska University Hospital)

  • Mattias Svensson

    (Karolinska University Hospital)

  • Anna Norrby-Teglund

    (Karolinska University Hospital)

  • Kyu Hong Cho

    (Indiana State University)

  • Eran Elhaik

    (Lund University)

  • Michael R. Wessels

    (Division of Infectious Diseases, Boston Children’s Hospital, and Department of Pediatrics, Harvard Medical School)

  • Lars Råberg

    (Lund University)

  • Fredric Carlsson

    (Lund University)

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 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.

Suggested Citation

  • Elin Movert & Jaume Salgado Bolarin & Christine Valfridsson & Jorge Velarde & Steinar Skrede & Michael Nekludov & Ole Hyldegaard & Per Arnell & Mattias Svensson & Anna Norrby-Teglund & Kyu Hong Cho & , 2023. "Interplay between human STING genotype and bacterial NADase activity regulates inter-individual disease variability," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39771-0
    DOI: 10.1038/s41467-023-39771-0
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    References listed on IDEAS

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    1. Benjamin R. Morehouse & Apurva A. Govande & Adi Millman & Alexander F. A. Keszei & Brianna Lowey & Gal Ofir & Sichen Shao & Rotem Sorek & Philip J. Kranzusch, 2020. "STING cyclic dinucleotide sensing originated in bacteria," Nature, Nature, vol. 586(7829), pages 429-433, October.
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