| First Author | Davidson S | Year | 2014 |
| Journal | Nat Commun | Volume | 5 |
| Pages | 3864 | PubMed ID | 24844667 |
| Mgi Jnum | J:225220 | Mgi Id | MGI:5691871 |
| Doi | 10.1038/ncomms4864 | Citation | Davidson S, et al. (2014) Pathogenic potential of interferon alphabeta in acute influenza infection. Nat Commun 5:3864 |
| abstractText | Influenza symptoms vary from mild disease to death; however, determinants of severity are unclear. Type I interferons (IFNalphabeta) 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 IFNalphabeta, than C57BL/6 mice. Consistently, IFNalpha treatment of influenza-infected C57BL/6 mice increases morbidity. IFNalphabeta 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 IFNalphabeta signalling in stromal cells abolishes epithelial DR5 upregulation and apoptosis, reducing host susceptibility. Hence, excessive IFNalphabeta 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. |
