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

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.

Interactions between Type 1 Interferons and the Th17 Response in Tuberculosis: Lessons Learned from Autoimmune Diseases

“…However, exaggerated innate responses are also observed in TB where IFN-α might be involved. This is supported by recent evidence showing that IRF7 drives excessive innate inflammation during bacterial infections and provides an interesting therapeutic target (334). Taken together, little is known about the separate effects of IFN-α and IFN-β in TB, but clinical and preclinical studies support a role for both in different disease contexts.…”

Teleost-Specific TLR19 Localizes to Endosome, Recognizes dsRNA, Recruits TRIF, Triggers both IFN and NF-κB Pathways, and Protects Cells from Grass Carp Reovirus Infection

“…Additionally, TLR19 overexpression promoted protein and phosphorylation levels of IRF3, whereas it inhibited the phosphorylation of IRF7. Efficient and self-limiting innate immune response to viral infection relies on a tight balance between IRF3 and IRF7 (53). TLR3 also enhanced mRNA expression of IRF3, not IRF7.…”

Increased susceptibility to intracellular bacteria and necrotic inflammation driven by a dysregulated macrophage response to TNF

“…Numerous studies reveal a role of the type I interferon (IFN-I) pathway in the immunopathology caused by intracellular bacteria, including Mtb [67][68][69][70], chronic viral infections [71][72][73] and autoimmunity (reviewed in [74][75][76]). Our studies reveal a mechanism of stress-mediated IFN-I pathway upregulation that makes macrophages less resilient to subsequent infection with intracellular bacteria and is associated with immunopathology in vivo.…”