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

Summary, in English

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.

• Författare: Manoj Puthia; Ines Ambite; Caterina Cafaro; Daniel Butler; Yujing Huang; Nataliya Lutay; Gustav Rydström; Birgitta Gullstrand; Bhairavi Swaminathan; Aftab Nadeem; Björn Nilsson; Catharina Svanborg
• Avdelning/ar: Hematogenomics; Avdelningen för mikrobiologi, immunologi och glykobiologi - MIG; Avdelningen för hematologi och transfusionsmedicin
• Publiceringsår: 2016
• Språk: Engelska
• Publikation/Tidskrift/Serie: Science Translational Medicine
• Volym: 8
• Issue: 336
• Länkar: http://dx.doi.org/10.1126/scitranslmed.aaf1156
• Dokumenttyp: Artikel i tidskrift
• Förlag: American Association for the Advancement of Science (AAAS)
• Ämne: Immunology in the medical area
• Status: Published
• Forskningsgrupp: Hematogenomics
• ISBN/ISSN/Övrigt: ISSN: 1946-6234