Pathogenic potential of interferon αβ in acute influenza infection.
Influenza symptoms vary from mild disease to death; however, determinants of severity are unclear. Type I interferons (IFNαβ) are recognized as key antiviral cytokines. Here we show that, surprisingly, influenza-infected 129 mice have increased lung damage, morbidity and mortality, yet higher levels of IFNαβ, than C57BL/6 mice. Consistently, IFNα treatment of influenza-infected C57BL/6 mice increases morbidity. IFNαβ receptor deficiency in 129 mice decreases morbidity, lung damage, proinflammatory cytokines and lung-infiltrating inflammatory cells, and reduces expression of the death-inducing receptor DR5 on lung epithelia and its ligand TRAIL on inflammatory monocytes. Depletion of PDCA-1+ cells or interruption of TRAIL-DR5 interaction protects infected 129 mice. Selective lack of IFNαβ signalling in stromal cells abolishes epithelial DR5 upregulation and apoptosis, reducing host susceptibility. Hence, excessive IFNαβ signalling in response to acute influenza infection can result in uncontrolled inflammation and TRAIL-DR5-mediated epithelial cell death, which may explain morbidity and has important implications for treatment of severe disease.
Division of Immunoregulation, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Sophia
S
Davidson
Division of Immunoregulation, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Stefania
S
Crotta
Division of Immunoregulation, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Teresa M
TM
McCabe
Division of Immunoregulation, MRC National Institute for Medical Research, Mill Hill, London NW7 1AA, UK.
Andreas
A
Wack
D000818:Animals; D004195:Disease Models, Animal; D053118:Influenza A Virus, H1N1 Subtype; D053122:Influenza A Virus, H3N2 Subtype; D007370:Interferon Type I / Q000276:immunology*; D008168:Lung / Q000276:immunology* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D009976:Orthomyxoviridae Infections / Q000276:immunology* / Q000473:pathology; D011024:Pneumonia, Viral / Q000276:immunology* / Q000473:pathology; D053633:Receptor, Interferon alpha-beta / Q000235:genetics / Q000276:immunology; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D012720:Severity of Illness Index; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000276:immunology
C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D053221:TNF-Related Apoptosis-Inducing Ligand; C505654:Tnfsf10 protein, mouse; D053633:Receptor, Interferon alpha-beta