Prion protein protects mice from lethal infection with influenza A viruses

Abstract

The cellular prion protein, designated PrPC, is a membrane glycoprotein expressed abundantly in brains and to a lesser extent in other tissues. Conformational conversion of PrPCinto the amyloidogenic isoform is a key pathogenic event in prion diseases. However, the physiological functions of PrPCremain largely unknown, particularly in non-neuronal tissues. Here, we show that PrPCis expressed in lung epithelial cells, including alveolar type 1 and 2 cells and bronchiolar Clara cells. Compared with wild-type (WT) mice, PrPC-null mice (Prnp0/0) were highly susceptible to influenza A viruses (IAVs), with higher mortality. Infected Prnp0/0lungs were severely injured, with higher inflammation and higher apoptosis of epithelial cells, and contained higher reactive oxygen species (ROS) than control WT lungs. Treatment with a ROS scavenger or an inhibitor of xanthine oxidase (XO), a major ROS-generating enzyme in IAV-infected lungs, rescued Prnp0/0mice from the lethal infection with IAV. Moreover, Prnp0/0mice transgenic for PrP with a deletion of the Cu-binding octapeptide repeat (OR) region, Tg(PrPΔOR)/Prnp0/0mice, were also highly susceptible to IAV infection. These results indicate that PrPChas a protective role against lethal infection with IAVs through the Cu-binding OR region by reducing ROS in infected lungs. Cu content and the activity of anti-oxidant enzyme Cu/Zn-dependent superoxide dismutase, SOD1, were lower in Prnp0/0and Tg(PrPΔOR)/Prnp0/0lungs than in WT lungs. It is thus conceivable that PrPCfunctions to maintain Cu content and regulate SOD1 through the OR region in lungs, thereby reducing ROS in IAV-infected lungs and eventually protecting them from lethal infection with IAVs. Our current results highlight the role of PrPCin protection against IAV infection, and suggest that PrPCmight be a novel target molecule for anti-influenza therapeutics.