title: Modulation of sterol biosynthesis regulates viral replication and cytokine production in influenza A virus infected human alveolar epithelial cells.
abstract: Highly pathogenic H5N1 viruses continue to transmit zoonotically, with mortality higher than 60%, and pose a pandemic threat. Antivirals remain the primary choice for treating H5N1 diseases and have their limitations. Encouraging findings highlight the beneficial effects of combined treatment of host targeting agents with immune-modulatory activities. This study evaluated the undefined roles of sterol metabolic pathway in viral replication and cytokine induction by H5N1 virus in human alveolar epithelial cells. The suppression of the sterol biosynthesis by Simvastatin in human alveolar epithelial cells led to reduction of virus replication and cytokine production by H5N1 virus. We further dissected the antiviral role of different regulators of the sterol metabolism, we showed that Zometa, FPT inhibitor III, but not GGTI-2133 had anti-viral activities against both H5N1 and H1N1 viruses. More importantly, FPT inhibitor III treatment significantly suppressed cytokine production by H5N1 virus infected alveolar epithelial cells. Since both viral replication itself and the effects of viral hyper-induction of cytokines contribute to the immunopathology of severe H5N1 disease, our findings highlights the therapeutic potential of FPT inhibitor III for severe human H5N1 diseases. Furthermore, our study is the first to dissect the roles of different steps in the sterol metabolic pathway in H5N1 virus replication and cytokine production.
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Kenrie P Y
authors.initials: KP
authors.lastname: Hui
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Denise I T
authors.initials: DI
authors.lastname: Kuok
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Sara S R
authors.initials: SS
authors.lastname: Kang
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Hung-Sing
authors.initials: HS
authors.lastname: Li
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Mandy M T
authors.initials: MM
authors.lastname: Ng
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Christine H T
authors.initials: CH
authors.lastname: Bui
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: J S Malik
authors.initials: JS
authors.lastname: Peiris
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Renee W Y
authors.initials: RW
authors.lastname: Chan
authors.affiliation: Centre of Influenza Research, School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China. Electronic address: mchan@hku.hk.
authors.forename: Michael C W
authors.initials: MC
authors.lastname: Chan
mesh_terms: D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis* / Q000276:immunology; D004164:Diphosphonates / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D053118:Influenza A Virus, H1N1 Subtype / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D053124:Influenza A Virus, H5N1 Subtype / Q000187:drug effects* / Q000276:immunology / Q000502:physiology*; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D011650:Pulmonary Alveoli / Q000187:drug effects / Q000378:metabolism / Q000821:virology*; D019821:Simvastatin / Q000494:pharmacology; D013261:Sterols / Q000096:biosynthesis*; D014779:Virus Replication / Q000187:drug effects; D000077211:Zoledronic Acid
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D004164:Diphosphonates; C547856:GGTI-2133; D007093:Imidazoles; D009281:Naphthalenes; D013261:Sterols; D000077211:Zoledronic Acid; D019821:Simvastatin; D007930:Leucine
keywords: Cytokine; Farnesyl transferase inhibitor; Influenza A virus; Statin; Sterol biosynthesis; Zometa