Abstract
Influenza-associated mortality continues to occur annually despite available antiviral therapies. New therapies that improve host immunity could reduce influenza virus disease burden. Targeting macrophage migration inhibitory factor (MIF) has improved the outcomes of certain inflammatory diseases, but its role in influenza viral infection is unclear. Here, we showed that, during influenza viral infection, Mif-deficient mice have less inflammation, viral load, and mortality compared with WT control mice; conversely, Tg mice, overexpressing Mif in alveolar epithelial cells, had higher inflammation, viral load, and mortality. Antibody-mediated blockade of MIF in WT mice during influenza viral infection improved their survival. Mif-deficient murine lungs showed reduced levels of parkin, a mitophagy protein that negatively regulates antiviral signaling, prior to infection and augmented antiviral type I/III IFN levels in the airspaces after infection as compared with WT lungs. Additionally, in vitro assays with human lung epithelial cells showed that treatment with recombinant human MIF increased the percentage of influenza virus-infected cells. In conclusion, our study reveals that MIF impairs antiviral host immunity and increases inflammation during influenza infection and suggests that targeting MIF could be therapeutically beneficial during influenza viral infection.
Keywords:
Cytokines; Immunology; Infectious disease; Influenza; Innate immunity.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Alveolar Epithelial Cells / immunology
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Alveolar Epithelial Cells / metabolism
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Alveolar Epithelial Cells / pathology
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Alveolar Epithelial Cells / virology
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Animals
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Antiviral Agents / pharmacology*
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Antiviral Agents / therapeutic use
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Cell Line, Tumor
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Disease Models, Animal
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Humans
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Influenza A Virus, H1N1 Subtype / immunology
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Influenza A Virus, H1N1 Subtype / isolation & purification
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Influenza A Virus, H1N1 Subtype / pathogenicity*
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Influenza, Human / drug therapy
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Influenza, Human / immunology
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Influenza, Human / mortality*
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Influenza, Human / virology
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Intramolecular Oxidoreductases / antagonists & inhibitors
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Intramolecular Oxidoreductases / genetics
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Intramolecular Oxidoreductases / immunology*
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Intramolecular Oxidoreductases / metabolism
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Lung / immunology
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Lung / pathology
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Macrophage Migration-Inhibitory Factors / antagonists & inhibitors
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Macrophage Migration-Inhibitory Factors / genetics
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Macrophage Migration-Inhibitory Factors / immunology*
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Macrophage Migration-Inhibitory Factors / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Primary Cell Culture
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Recombinant Proteins / immunology
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Recombinant Proteins / metabolism
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Survival Analysis
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Ubiquitin-Protein Ligases / genetics
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Ubiquitin-Protein Ligases / immunology
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Ubiquitin-Protein Ligases / metabolism
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Viral Load
Substances
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Antiviral Agents
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Macrophage Migration-Inhibitory Factors
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Recombinant Proteins
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Ubiquitin-Protein Ligases
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parkin protein
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Intramolecular Oxidoreductases
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MIF protein, human
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Mif protein, mouse