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

Puthia, Manoj LU ; Ambite, Ines LU orcid ; Cafaro, Caterina LU ; Butler, Daniel LU ; Huang, Yujing LU ; Lutay, Nataliya LU ; Rydström, Gustav LU ; Gullstrand, Birgitta LU ; Swaminathan, Bhairavi LU and Nadeem, Aftab LU , et al. (2016) In Science Translational Medicine 8(336).
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... (More)

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.

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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Translational Medicine
volume
8
issue
336
article number
336RA59
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • pmid:27122612
  • wos:000374833500004
  • scopus:84964897265
ISSN
1946-6234
DOI
10.1126/scitranslmed.aaf1156
language
English
LU publication?
yes
id
de64a0a3-cd74-4109-a303-9f0841a44b24
date added to LUP
2016-06-02 08:14:13
date last changed
2025-03-09 15:15:21
@article{de64a0a3-cd74-4109-a303-9f0841a44b24,
  abstract     = {{<p>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<sup>-/-</sup> mice with kidney pathology, which was absent in Irf7<sup>-/-</sup> 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<sup>-/-</sup> 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.</p>}},
  author       = {{Puthia, Manoj and Ambite, Ines and Cafaro, Caterina and Butler, Daniel and Huang, Yujing and Lutay, Nataliya and Rydström, Gustav and Gullstrand, Birgitta and Swaminathan, Bhairavi and Nadeem, Aftab and Nilsson, Björn and Svanborg, Catharina}},
  issn         = {{1946-6234}},
  language     = {{eng}},
  number       = {{336}},
  publisher    = {{American Association for the Advancement of Science (AAAS)}},
  series       = {{Science Translational Medicine}},
  title        = {{IRF7 inhibition prevents destructive innate immunity-A target for nonantibiotic therapy of bacterial infections}},
  url          = {{http://dx.doi.org/10.1126/scitranslmed.aaf1156}},
  doi          = {{10.1126/scitranslmed.aaf1156}},
  volume       = {{8}},
  year         = {{2016}},
}