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

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, Eran Elhaik, Michael R. Wessels, Lars Råberg and Fredric Carlsson ()
Additional contact information
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
Michael Nekludov: Karolinska University Hospital
Ole Hyldegaard: Head and Orthopedic Center, Rigshospitalet
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

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-39771-0 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39771-0

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-39771-0

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().