title: IRF-3, IRF-7, and IPS-1 promote host defense against acute human metapneumovirus infection in neonatal mice.
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.
authors.affiliation: 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.
authors.forename: Kirsten M
authors.initials: KM
authors.lastname: Spann
authors.affiliation: School of Biomedical Sciences, University of Queensland, St. Lucia, Australia.
authors.forename: Zhixuan
authors.initials: Z
authors.lastname: Loh
authors.affiliation: School of Biomedical Sciences, University of Queensland, St. Lucia, Australia.
authors.forename: Jason P
authors.initials: JP
authors.lastname: Lynch
authors.affiliation: Woolcock Institute of Medical Research, Sydney Medical School, The University of Sydney, Sydney, Australia.
authors.forename: Ashik
authors.initials: A
authors.lastname: Ullah
authors.affiliation: School of Biomedical Sciences, University of Queensland, St. Lucia, Australia.
authors.forename: Vivian
authors.initials: V
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Engin
authors.initials: E
authors.lastname: Baturcam
authors.affiliation: School of Biomedical Sciences, University of Queensland, St. Lucia, Australia.
authors.forename: Rhiannon B
authors.initials: RB
authors.lastname: Werder
authors.affiliation: School of Biomedical Sciences, University of Queensland, St. Lucia, Australia.
authors.forename: Natthida
authors.initials: N
authors.lastname: Khajornjiraphan
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Australia; QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
authors.forename: Penny
authors.initials: P
authors.lastname: Rudd
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Yeuh-Ming
authors.initials: YM
authors.lastname: Loo
authors.affiliation: Australian Infectious Diseases Research Centre, University of Queensland, St. Lucia, Australia; QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
authors.forename: Andreas
authors.initials: A
authors.lastname: Suhrbier
authors.affiliation: Department of Immunology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Michael
authors.initials: M
authors.lastname: Gale
authors.affiliation: 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.
authors.forename: John W
authors.initials: JW
authors.lastname: Upham
authors.affiliation: 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.
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
mesh_terms: D000208:Acute Disease; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000276:immunology*; D000818:Animals; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000235:genetics / Q000276:immunology*; D050839:Interferon Regulatory Factor-7 / Q000235:genetics / Q000276:immunology*; D007372:Interferons / Q000235:genetics / Q000276:immunology; D029121:Metapneumovirus / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D018184:Paramyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; D007372:Interferons; C512612:MAVS protein, mouse; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse