title: Phosphoinositide-3 kinase inhibition modulates responses to rhinovirus by mechanisms that are predominantly independent of autophagy.
abstract: Human rhinoviruses (HRV) are a major cause of exacerbations of airways disease. Aspects of cell signalling responses to HRV infection remain unclear, particularly with regard to signalling via PI3K, and the PI3K-dependent pathway, autophagy. We investigated the roles of PI3K and autophagy in the responses of epithelial cells to major and minor group HRV infection. The PI3K inhibitor 3-MA, commonly used to inhibit autophagy, markedly reduced HRV-induced cytokine induction. Further investigation of potential targets of 3-MA and comparison of results using this inhibitor to a panel of general and class I-selective PI3K inhibitors showed that several PI3Ks cooperatively regulate responses to HRV. Targeting by siRNA of the autophagy proteins Beclin-1, Atg7, LC3, alone or in combination, or targeting of the autophagy-specific class III PI3K had at most only modest effects on HRV-induced cell signalling as judged by induction of proinflammatory cytokine production. Our data indicate that PI3K and mTOR are involved in induction of proinflammatory cytokines after HRV infection, and that autophagy has little role in the cytokine response to HRV or control of HRV replication.
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection and Immunity, Faculty of Medicine, Dentistry and Health, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Saila
authors.initials: S
authors.lastname: Ismail
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection and Immunity, Faculty of Medicine, Dentistry and Health, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Clare A
authors.initials: CA
authors.lastname: Stokes
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection and Immunity, Faculty of Medicine, Dentistry and Health, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Prestwich
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection and Immunity, Faculty of Medicine, Dentistry and Health, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Rebecca L
authors.initials: RL
authors.lastname: Roberts
authors.affiliation: Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Cambridge, CB2 2QQ, United Kingdom.
authors.forename: Jatinder K
authors.initials: JK
authors.lastname: Juss
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection and Immunity, Faculty of Medicine, Dentistry and Health, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Ian
authors.initials: I
authors.lastname: Sabroe
authors.affiliation: Academic Unit of Respiratory Medicine, Department of Infection and Immunity, Faculty of Medicine, Dentistry and Health, University of Sheffield, Beech Hill Road, Sheffield, S10 2RX, United Kingdom.
authors.forename: Lisa C
authors.initials: LC
authors.lastname: Parker
mesh_terms: D001343:Autophagy; D002460:Cell Line; D016207:Cytokines / Q000276:immunology; D004847:Epithelial Cells / Q000276:immunology / Q000382:microbiology* / Q000473:pathology; D054884:Host-Pathogen Interactions; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000276:immunology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010850:Picornaviridae Infections / Q000201:enzymology* / Q000276:immunology / Q000503:physiopathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D012229:Rhinovirus / Q000502:physiology*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000276:immunology
chemical_list: D016207:Cytokines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human