title: Clarithromycin inhibits type a seasonal influenza virus infection in human airway epithelial cells.
abstract: Human influenza viruses attach to sialic acid with an alpha2,6linkage (SAalpha2,6Gal) on the airway epithelial cells, and the entry of the viruses into the cells and uncoating of the viruses require low pH of endosomes. Bafilomycin A(1), a macrolide antibiotic and a specific inhibitor of vacuolar H(+)-ATPase, inhibits growth of type A and type B human influenza viruses in Madin-Darby canine kidney cells. However, the inhibitory effects of clinically used macrolide antibiotics on influenza virus infection in human airways have not been studied. To examine the effects of clarithromycin on seasonal human influenza virus infection, cultured human tracheal epithelial cells were infected with type A influenza virus (H3N2). Influenza virus infection increased viral titers and the content of cytokines, including interleukin (IL)-1beta and IL-6, in supernatant fluids, and viral RNA in the cells. Clarithromycin reduced viral titers and the content of cytokines in supernatant fluids, viral RNA in the cells, and the susceptibility to virus infection. Clarithromycin reduced the expression of SAalpha2,6Gal, a receptor for human influenza virus, on the mucosal surface of human tracheae, and the number and fluorescence intensity of acidic endosomes in the cells from which viral ribonucleoproteins enter into the cytoplasm. Furthermore, clarithromycin reduced nuclear factor-kappaB (NF-kappaB) proteins, including p50 and p65, in the nuclear extracts. These results suggest that clarithromycin may inhibit seasonal human influenza virus infection by reducing SAalpha2,6Gal partly through the inhibition of NF-kappaB, and increasing pH in endosomes in airway epithelial cells. Clarithromycin may modulate airway inflammation in influenza virus infection.
authors.affiliation: Department of Advanced Preventive Medicine for Infectious Disease, Tohoku University School of Medicine, 2-1 Seiryo-machi, Aoba-ku 980-8575, Japan. myamaya@m.tains.tohoku.ac.jp
authors.forename: Mutsuo
authors.initials: M
authors.lastname: Yamaya
authors.forename: Kyoko
authors.initials: K
authors.lastname: Shinya
authors.forename: Yukimasa
authors.initials: Y
authors.lastname: Hatachi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kubo
authors.forename: Masanori
authors.initials: M
authors.lastname: Asada
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Yasuda
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Nishimura
authors.forename: Ryoichi
authors.initials: R
authors.lastname: Nagatomi
mesh_terms: D000368:Aged; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002478:Cells, Cultured; D017291:Clarithromycin / Q000494:pharmacology*; D016207:Cytokines / Q000378:metabolism; D004285:Dogs; D011992:Endosomes / Q000737:chemistry / Q000187:drug effects; D004847:Epithelial Cells / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D053122:Influenza A Virus, H3N2 Subtype / Q000187:drug effects* / Q000502:physiology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D012367:RNA, Viral / Q000187:drug effects; D011991:Receptors, Virus / Q000096:biosynthesis; D020545:Respiratory Mucosa / Q000166:cytology / Q000187:drug effects* / Q000821:virology; D014132:Trachea / Q000166:cytology / Q000187:drug effects / Q000821:virology
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D016328:NF-kappa B; D012367:RNA, Viral; D011991:Receptors, Virus; D017291:Clarithromycin