Comprehending a Killer: The Akt/mTOR Signaling Pathways Are Temporally High-Jacked by the Highly Pathogenic 1918 Influenza Virus

Previous transcriptomic analyses suggested that the 1918 influenza A virus (IAV1918), one of themost devastating pandemic viruses of the 20th century, induces a dysfunctional cytokine storm and affects other innate immune response patterns. Because all viruses are obligate parasites that require host cells for replication, we globally assessed how IAV1918 induces host protein dysregulation. We performed quantitative mass spectrometry of IAV1918-infected cells tomeasure host protein dysregulation. Selected proteinswere validated by immunoblotting and phosphorylation levels of members of the PI3K/AKT/mTOR pathway were assessed. Compared to mock-infected controls, N170 proteins in the IAV1918-infected cells were dysregulated. Proteins mapped to amino sugar metabolism, purine metabolism, steroid biosynthesis, transmembrane receptors, phosphatases and transcription regulation. Immunoblotting demonstrated that IAV1918 induced a slight up-regulation of the lamin B receptor whereas all other tested virus strains induced a significant down-regulation. IAV1918 also strongly induced Rab5b expression whereas all other tested viruses induced minor up-regulation or downregulation. IAV1918 showed early reduced phosphorylation of PI3K/AKT/mTOR pathway members and was especially sensitive to rapamycin. These results suggest the 1918 strain requires mTORC1 activity in early replication events, and may explain the unique pathogenicity of this virus. Crown Copyright (C) 2018 Published by Elsevier B.V.