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

Manoj Puthia, Ines Ambite, Caterina Cafaro, Daniel Butler, Yujing Huang, Nataliya Lutay, Gustav Rydström, Birgitta Gullstrand, Bhairavi Swaminathan, Aftab Nadeem, Björn Nilsson, Catharina Svanborg

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskriftPeer review

20 Citeringar (SciVal)

Sammanfattning

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.

Originalspråkengelska
Artikelnummer336RA59
TidskriftScience Translational Medicine
Volym8
Utgåva336
DOI
StatusPublished - 2016

Ämnesklassifikation (UKÄ)

  • Immunologi inom det medicinska området

Fingeravtryck

Utforska forskningsämnen för ”IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections”. Tillsammans bildar de ett unikt fingeravtryck.

Citera det här