title: Amphotericin B increases influenza A virus infection by preventing IFITM3-mediated restriction.
abstract: The IFITMs inhibit influenza A virus (IAV) replication in vitro and in vivo. Here, we establish that the antimycotic heptaen, amphotericin B (AmphoB), prevents IFITM3-mediated restriction of IAV, thereby increasing viral replication. Consistent with its neutralization of IFITM3, a clinical preparation of AmphoB, AmBisome, reduces the majority of interferon's protective effect against IAV in vitro. Mechanistic studies reveal that IFITM1 decreases host-membrane fluidity, suggesting both a possible mechanism for IFITM-mediated restriction and its negation by AmphoB. Notably, we reveal that mice treated with AmBisome succumbed to a normally mild IAV infection, similar to animals deficient in Ifitm3. Therefore, patients receiving antifungal therapy with clinical preparations of AmphoB may be functionally immunocompromised and thus more vulnerable to influenza, as well as other IFITM3-restricted viral infections.
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Tsai-Yu
authors.initials: TY
authors.lastname: Lin
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA; Ragon Institute of Massachusetts General Hospital, M.I.T. and Harvard University, Charlestown, MA 02129, USA.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Chin
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Everitt
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Clare
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Perreira
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: George
authors.initials: G
authors.lastname: Savidis
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
authors.forename: Aaron M
authors.initials: AM
authors.lastname: Aker
authors.affiliation: Ragon Institute of Massachusetts General Hospital, M.I.T. and Harvard University, Charlestown, MA 02129, USA.
authors.forename: Sinu P
authors.initials: SP
authors.lastname: John
authors.affiliation: Eidgenössische Technische Hochschule, Deutsch English Department of Chemistry and Applied Biosciences, 8093 Zurich, Switzerland.
authors.forename: David
authors.initials: D
authors.lastname: Sarlah
authors.affiliation: Eidgenössische Technische Hochschule, Deutsch English Department of Chemistry and Applied Biosciences, 8093 Zurich, Switzerland.
authors.forename: Erick M
authors.initials: EM
authors.lastname: Carreira
authors.affiliation: Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Division of Genetics, Brigham and Women's Hospital, 77 Avenue Louis Pasteur, Boston, MA 02115, USA; Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, MD 20815, USA.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Elledge
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK; MRC/UCL Centre for Medical Molecular Virology, Division of Infection & Immunity, University College London, Gower Street, London W1CE 6BT, UK.
authors.forename: Paul
authors.initials: P
authors.lastname: Kellam
authors.affiliation: Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA; Ragon Institute of Massachusetts General Hospital, M.I.T. and Harvard University, Charlestown, MA 02129, USA. Electronic address: abraham.brass@umassmed.edu.
authors.forename: Abraham L
authors.initials: AL
authors.lastname: Brass
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000666:Amphotericin B / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D000935:Antifungal Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000943:Antigens, Differentiation / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D019556:COS Cells; D002459:Cell Fusion; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D016867:Immunocompromised Host; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology; D007372:Interferons / Q000276:immunology; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009761:Nystatin / Q000494:pharmacology; D009976:Orthomyxoviridae Infections / Q000276:immunology*; D034622:RNA Interference; D034741:RNA, Small Interfering; D012964:Sodium / Q000378:metabolism; D019789:Tetraethylammonium / Q000494:pharmacology; D053586:Virus Internalization / Q000187:drug effects*; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D000943:Antigens, Differentiation; D008565:Membrane Proteins; D034741:RNA, Small Interfering; C462181:fragilis protein, mouse; C062010:leu-13 antigen; C068538:liposomal amphotericin B; D009761:Nystatin; D019789:Tetraethylammonium; D000666:Amphotericin B; D007372:Interferons; D012964:Sodium; D000109:Acetylcholine