Neurotropic influenza A virus infection causes prion protein misfolding into infectious prions in neuroblastoma cells

Misfolding of the cellular prion protein, PrP(C), into the amyloidogenic isoform, PrP(Sc), which forms infectious protein aggregates, the so-called prions, is a key pathogenic event in prion diseases. No pathogens other than prions have been identified to induce misfolding of PrP(C) into PrP(Sc) and propagate infectious prions in infected cells. Here, we found that infection with a neurotropic influenza A virus strain (IAV/WSN) caused misfolding of PrP(C) into PrP(Sc) and generated infectious prions in mouse neuroblastoma cells through a hit-and-run mechanism. The structural and biochemical characteristics of IAV/WSN-induced PrP(Sc) were different from those of RML and 22L laboratory prions-evoked PrP(Sc), and the pathogenicity of IAV/WSN-induced prions were also different from that of RML and 22L prions, suggesting IAV/WSN-specific formation of PrP(Sc) and infectious prions. Our current results may open a new avenue for the role of viral infection in misfolding of PrP(C) into PrP(Sc) and formation of infectious prions.