Pathogenic potential of interferon αβ in acute influenza infection

• Published in: Nature communications Vol. 5; no. 1; p. 3864
• Main Authors: Davidson, Sophia, Crotta, Stefania, McCabe, Teresa M, Wack, Andreas
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21-05-2014; Nature Pub. Group
• Subjects: 13/106; 13/21; 13/31; 14; 14/1; 14/105; 14/63; 631/250/127/1212; 631/250/255/1578; 64/60; 692/420/2780; Animals; Disease Models, Animal; Humanities and Social Sciences; Influenza A Virus, H1N1 Subtype; Influenza A Virus, H3N2 Subtype; Interferon Type I - immunology; Lung - immunology; Lung - pathology; Mice; Mice, 129 Strain; multidisciplinary; Orthomyxoviridae Infections - immunology; Orthomyxoviridae Infections - pathology; Pneumonia, Viral - immunology; Pneumonia, Viral - pathology; Receptor, Interferon alpha-beta - genetics; Receptor, Interferon alpha-beta - immunology; Receptors, TNF-Related Apoptosis-Inducing Ligand - immunology; Science; Science (multidisciplinary); Severity of Illness Index; STAT1 Transcription Factor - genetics; STAT1 Transcription Factor - immunology; TNF-Related Apoptosis-Inducing Ligand - immunology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms4864

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.
Interferon αβ(IFNαβ) is known as a potent anti-viral factor, yet its role in influenza infection remains controversial. Here, the authors show that the IFNαβ response is a critical host factor, which, when excessive, causes strong inflammation and severe disease in a mouse model of acute influenza infection.