IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections.
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.
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden.
Manoj
M
Puthia
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden.
Ines
I
Ambite
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden.
Caterina
C
Cafaro
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden.
Daniel
D
Butler
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden.
Yujing
Y
Huang
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden.
Nataliya
N
Lutay
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden.
Gustav
G
Rydström
Section of Rheumatology, Department of Clinical Sciences, Lund University and Skåne University Hospital, 221 85 Lund, Sweden.
Birgitta
B
Gullstrand
Division of Hematology and Transfusion Medicine, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden.
Bhairavi
B
Swaminathan
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden.
Aftab
A
Nadeem
Division of Hematology and Transfusion Medicine, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden. Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA.
Björn
B
Nilsson
Department of Microbiology, Immunology and Glycobiology, Institute of Laboratory Medicine, Lund University, 223 62 Lund, Sweden. catharina.svanborg@med.lu.se.
Catharina
C
Svanborg
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics / Q000502:physiology*; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000378:metabolism; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D011704:Pyelonephritis / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology
D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7