IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

Abstract

Boosting innate immunity represents an important therapeutic alternative to antibiotics. However, the molecular selectivity of this approach is a major concern because innate immune responses often cause collateral tissue damage. We identify the transcription factor interferon regulatory factor 7 (IRF-7), a heterodimer partner of IRF-3, as a target for non-antibiotics-based therapy of bacterial infections. We found that the efficient and self-limiting innate immune response to bacterial infection relies on a tight balance between IRF-3 and IRF-7. Deletion of Irf3 resulted in overexpression of Irf7 and led to an IRF-7-driven hyperinflammatory phenotype, which was entirely prevented if Irf7 was deleted. We then identified a network of strongly up-regulated, IRF-7-dependent genes in Irf3-/- mice with kidney pathology, which was absent in Irf7-/- mice. IRF-3 and IRF-7 from infected kidney cell nuclear extracts were shown to bind OAS1, CCL5, andIFNB1 promoter oligonucleotides. These data are consistent in children with lowIRF7 expression in the blood: attenuating IRF7 promoter polymorphisms (rs3758650-T and rs10902179-G) negatively associated with recurrent pyelonephritis. Finally, we identified IRF-7 as a target for immunomodulatory therapy. Administering liposomal Irf7 siRNA to Irf3-/- mice suppressed mucosal IRF-7 expression, and the mice were protected against infection and renal tissue damage. These findings offer a response to the classical but unresolved question of "good versus bad inflammation" and identify IRF7 as a therapeutic target for protection against bacterial infection.

Detaljer

Författare
Enheter & grupper
Externa organisationer
  • Skåne University Hospital
  • Broad Institute
Forskningsområden

Ämnesklassifikation (UKÄ) – OBLIGATORISK

  • Immunologi inom det medicinska området
Originalspråkengelska
Artikelnummer336RA59
TidskriftScience Translational Medicine
Volym8
Utgivningsnummer336
StatusPublished - 2016
PublikationskategoriForskning
Peer review utfördJa

Relaterad forskningsoutput

Ines Ambite, 2019, Lund: Lund University, Faculty of Medicine. 87 s.

Forskningsoutput: AvhandlingDoktorsavhandling (sammanläggning)

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