Prion Protein Is a Novel Modulator of Influenza: Potential Implications for Anti-Influenza Therapeutics

Worldwide spread of influenza A virus (IAV) strains, which are resistant to currently available anti- influenza agents such as viral neuraminidase inhibitors, has encouraged identification of new target molecules for anti-influenza agents. Reactive oxygen species (ROS) causing oxidative stress play a pivotal role in the pathogenesis of lung injuries induced by infection with IAVs, therefore suggesting that anti-oxidative therapeutics targeting cellular molecules could be beneficial against IAV infection without inducing drug-resistant IAV strains. We recently found that the normal cellular prion protein, PrP^C, whose conformational conversion into the amyloidogenic isoform, PrP^Sc, in the brain is a key pathogenic event in prion diseases, is expressed by lung epithelial cells and exerts a protective role against IAV infection in mice by reducing ROS in infected lungs. The Cu content and activity of anti- oxidative enzyme Cu/Zn-superoxide dismutase, or SOD1, were lower in the lungs of PrP^C-knockout mice, suggesting that the anti-oxidative activity of PrP^C is probably attributable to its function of activating SOD1 through regulating Cu content in lungs. Here, we introduce PrP^C as a novel modulator of influenza and its potential implication for anti-oxidative therapies for IAV infection. We also introduce other candidate targets reported for anti- oxidative anti-influenza therapies.