title: Suppression of interferon lambda signaling by SOCS-1 results in their excessive production during influenza virus infection.
abstract: Innate cytokine response provides the first line of defense against influenza virus infection. However, excessive production of cytokines appears to be critical in the pathogenesis of influenza virus. Interferon lambdas (IFN-λ) have been shown to be overproduced during influenza virus infection, but the precise pathogenic processes of IFN-λ production have yet to be characterized. In this report, we observed that influenza virus induced robust expression of IFN-λ in alveolar epithelial cells (A549) mainly through a RIG-I-dependent pathway, but IFN-λ-induced phosphorylation of the signal transducer and activator of transcription protein 1 (STAT1) was dramatically inhibited in the infected cells. Remarkably, influenza virus infection induced robust expression of suppressor of cytokine signaling-1 (SOCS-1), leading to inhibition of STAT1 activation. Interestingly, the virus-induced SOCS-1 expression was cytokine-independent at early stage of infection both in vitro and in vivo. Using transgenic mouse model and distinct approaches altering the expression of SOCS-1 or activation of STAT signaling, we demonstrated that disruption of the SOCS-1 expression or expression of constitutively active STAT1 significantly reduced the production of IFN-λ during influenza virus infection. Furthermore, we revealed that disruption of IFN-λ signaling pathway by increased SOCS-1 protein resulted in the activation of NF-κB and thereby enhanced the IFN-λ expression. Together, these data imply that suppression of IFN-λ signaling by virus-induced SOCS-1 causes an adaptive increase in IFN-λ expression by host to protect cells against the viral infection, as a consequence, leading to excessive production of IFN-λ with impaired antiviral response.
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Wei
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Song
authors.initials: S
authors.lastname: Wang
authors.affiliation: College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, China.
authors.forename: Qinghuang
authors.initials: Q
authors.lastname: Chen
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Yuhai
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, China.
authors.forename: Xiaojuan
authors.initials: X
authors.lastname: Chi
authors.affiliation: Key Laboratory of Human Disease Comparative Medicine, Ministry of Health, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences & Comparative Medical Center, Peking Union Medical College, Beijing, China.
authors.forename: Lianfeng
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, Louisiana, United States of America.
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China.
authors.forename: George F
authors.initials: GF
authors.lastname: Gao
authors.affiliation: CAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing, China ; College of Animal Science, Fujian Agriculture and Forestry University, Fuzhou, China.
authors.forename: Ji-Long
authors.initials: JL
authors.lastname: Chen
mesh_terms: D000818:Animals; D004847:Epithelial Cells / Q000276:immunology / Q000473:pathology / Q000821:virology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D053118:Influenza A Virus, H1N1 Subtype / Q000235:genetics / Q000276:immunology*; D007372:Interferons / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D009976:Orthomyxoviridae Infections / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D011650:Pulmonary Alveoli / Q000276:immunology / Q000473:pathology / Q000821:virology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: C491590:Socs1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D007372:Interferons