Amphotericin B increases influenza A virus infection by preventing IFITM3-mediated restriction

Tsai-Yu Lin; Christopher R Chin; Aaron R Everitt; Simon Clare; Jill M Perreira; George Savidis; Aaron M Aker; Sinu P John; David Sarlah; Erick M Carreira; Stephen J Elledge; Paul Kellam; Abraham L Brass

doi:10.1016/j.celrep.2013.10.033

Amphotericin B increases influenza A virus infection by preventing IFITM3-mediated restriction

Cell Rep. 2013 Nov 27;5(4):895-908. doi: 10.1016/j.celrep.2013.10.033. Epub 2013 Nov 21.

Authors

Affiliations

¹ Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, MA 01655, USA.
² 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.
³ Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton CB10 1SA, UK.
⁴ Ragon Institute of Massachusetts General Hospital, M.I.T. and Harvard University, Charlestown, MA 02129, USA.
⁵ Eidgenössische Technische Hochschule, Deutsch English Department of Chemistry and Applied Biosciences, 8093 Zurich, Switzerland.
⁶ 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.
⁷ 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.
⁸ 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.

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholine / pharmacology
Amphotericin B / administration & dosage
Amphotericin B / adverse effects*
Animals
Anti-Bacterial Agents / pharmacology
Antifungal Agents / administration & dosage
Antifungal Agents / adverse effects*
Antigens, Differentiation / metabolism
Biological Transport / drug effects
COS Cells
Cell Fusion
Cell Line
Cell Membrane / drug effects
Cell Membrane / metabolism
Chlorocebus aethiops
HeLa Cells
Humans
Immunocompromised Host*
Influenza A Virus, H1N1 Subtype / immunology*
Influenza, Human / immunology
Interferons / immunology
Membrane Proteins / antagonists & inhibitors
Membrane Proteins / genetics*
Mice
Mice, Inbred C57BL
Mice, Knockout
Nystatin / pharmacology
Orthomyxoviridae Infections / immunology*
RNA Interference
RNA, Small Interfering
Sodium / metabolism
Tetraethylammonium / pharmacology
Virus Internalization / drug effects*
Virus Replication / drug effects

Substances

Anti-Bacterial Agents
Antifungal Agents
Antigens, Differentiation
Membrane Proteins
RNA, Small Interfering
fragilis protein, mouse
leu-13 antigen
liposomal amphotericin B
Nystatin
Tetraethylammonium
Amphotericin B
Interferons
Sodium
Acetylcholine

Abstract

Publication types

MeSH terms

Substances

Grants and funding