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Am J Pathol. 2014 Jun;184(6):1795-806. doi: 10.1016/j.ajpath.2014.02.026. Epub 2014 Apr 13.

IRF-3, IRF-7, and IPS-1 promote host defense against acute human metapneumovirus infection in neonatal mice.

Author information

1
Clinical Medical Virology Centre, University of Queensland, St. Lucia, Australia; Sir Albert Sakzewski Virus Research Centre, Children's Hospital Queensland, Australia; Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Australia. Electronic address: k.spann@uq.edu.au.
2
School of Biomedical Sciences, University of Queensland, St. Lucia, Australia.
3
Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, Sydney, Australia.
4
Clinical Medical Virology Centre, University of Queensland, St. Lucia, Australia; Sir Albert Sakzewski Virus Research Centre, Children's Hospital Queensland, Australia; Queensland Childrens Medical Research Institute, University of Queensland, Herston, Australia.
5
Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Australia; QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
6
Department of Immunology, University of Washington School of Medicine, Seattle, Washington.
7
Lung and Allergy Research Centre, Translational Research Institute, School of Medicine, University of Queensland, Brisbane, Australia; Department of Respiratory Medicine, Princess Alexandra Hospital, Brisbane, Australia.
8
Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Australia; School of Biomedical Sciences, University of Queensland, St. Lucia, Australia. Electronic address: s.phipps@uq.edu.au.

Abstract

Human metapneumovirus (hMPV) is a leading cause of respiratory tract disease in children and is associated with acute bronchiolitis, pneumonia, and asthma exacerbations, yet the mechanisms by which the host immune response to hMPV is regulated are poorly understood. By using gene-deleted neonatal mice, we examined the contributions of the innate receptor signaling molecules interferon (IFN)-β promoter stimulator 1 (IPS-1), IFN regulatory factor (IRF) 3, and IRF7. Viral load in the lungs was markedly greater in IPS-1(-/-) > IRF3/7(-/-) > IRF3(-/-), but not IRF7(-/-), mice compared with wild-type mice. IFN-β and IFN-λ2/3 (IL-28A/B) production was attenuated in the bronchoalveolar lavage fluid in all factor-deficient mice compared with wild-type mice at 1 day after infection, although IFN-λ2/3 was greater in IRF3/7(-/-) mice at 5 days after infection. IRF7(-/-) and IRF3/7(-/-) mice presented with airway eosinophilia, whereas only IRF3/7(-/-) mice developed an exaggerated type 1 and 17 helper T-cell response, characterized by natural killer T-cell and neutrophilic inflammation. Despite having the highest viral load, IPS-1(-/-) mice did not develop a proinflammatory cytokine or granulocytic response to hMPV infection. Our findings demonstrate that IFN-β, but not IFN-λ2/3, produced via an IPS-1-IRF3 signaling pathway, is important for hMPV clearance. In the absence of a robust type I IFN-α/β response, targeting the IPS-1 signaling pathway may limit the overexuberant inflammatory response that occurs as a consequence of viral persistence.

PMID:
24726644
DOI:
10.1016/j.ajpath.2014.02.026
[Indexed for MEDLINE]

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