Research ArticleInfectious Disease

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

Science Translational Medicine  27 Apr 2016:
Vol. 8, Issue 336, pp. 336ra59
DOI: 10.1126/scitranslmed.aaf1156

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Beyond antibiotics

Antibiotics are the cornerstone of antibacterial therapy; however, the increasing development of resistant bacterial strains stresses the need for alternate approaches. Now, Puthia et al. target bacterial infection by boosting innate immunity. They found that a tight balance between the transcription factor interferon regulatory factor 7 (IRF-7) and its heterodimeric partner IRF-3 is critical for an efficient and self-limiting innate immune response to bacterial infection. Dysregulation of this balance contributed to kidney pathology in infected mice, and IRF7 attenuating polymorphisms associate with recurrent pyelonephritis in human children. Indeed, targeting IRF-7 protected mice against infection and renal tissue damage, suggesting that IRF7 could be a therapeutic target for protection against bacterial infection.

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, and IFNB1 promoter oligonucleotides. These data are consistent in children with low IRF7 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.

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