Prion protein protects mice from lethal infection with influenza A viruses.

Junji Chida,Hideyuki Hara,Toshihiro Ito,Etsuhisa Takahashi,Keiji Uchiyama,Yukiko Tomioka,Suehiro Sakaguchi,Nandita Rani Das,Hironori Miyata,Hiroshi Kido,Masashi Yano,Daniel R Perez

doi:10.1371/journal.ppat.1007049

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 PrPC into the amyloidogenic isoform is a key pathogenic event in prion diseases. However, the physiological functions of PrPC remain largely unknown, particularly in non-neuronal tissues. Here, we show that PrPC is 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 Prnp0/0 lungs 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 Prnp0/0 mice from the lethal infection with IAV. Moreover, Prnp0/0 mice transgenic for PrP with a deletion of the Cu-binding octapeptide repeat (OR) region, Tg(PrPΔOR)/Prnp0/0 mice, were also highly susceptible to IAV infection. These results indicate that PrPC has 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 Prnp0/0 and Tg(PrPΔOR)/Prnp0/0 lungs than in WT lungs. It is thus conceivable that PrPC functions 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 PrPC in protection against IAV infection, and suggest that PrPC might be a novel target molecule for anti-influenza therapeutics.

Highlights

The normal cellular prion protein, designated PrPC, is a membrane glycoprotein tethered to the outer cell membrane via a glycosylphosphatidylinositol anchor moiety and expressed most abundantly in brains, by neurons, and to a lesser extent in non-neuronal tissues including hearts, kidneys, and lungs [1,2]
We show that the cellular prion protein PrPC has a protective role against lethal infection with influenza A viruses (IAVs) through the octapeptide repeat (OR) region by abrogating lung epithelial cell apoptosis induced by reactive oxygen species (ROS) in infected lungs
Double staining with anti-podoplanin, anti-surfactant protein C (SP-C), or anti-Clara cell 10-kDa protein (CC10) antibodies, which detect alveolar type 1 and 2 epithelial cells (AT1 and AT2 cells) and bronchiolar Clara epithelial cells, respectively, revealed expression of PrPC in these lung epithelial cells (Fig 1C)

Summary

Introduction

The normal cellular prion protein, designated PrPC, is a membrane glycoprotein tethered to the outer cell membrane via a glycosylphosphatidylinositol anchor moiety and expressed most abundantly in brains, by neurons, and to a lesser extent in non-neuronal tissues including hearts, kidneys, and lungs [1,2]. PrPC expression has been reported in non-cardiomyocytes in hearts [8], in glomeruli, proximal convoluted tubules and collecting ducts in kidneys [8,9], activated hepatic stellate cells in livers [10], in lymphoid nodules [11] and perilymphoid zones of the red pulp [8] in spleens, and in neuronal cells in the lamina propia and parasympathetic ganglions [8], some epithelial cells [12], Peyer’s patches [12] and enteric glial cells [13] in intestines. The exact function of PrPC remains to be clarified

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