1. Amphotericin B increases influenza A virus infection by preventing IFITM3-mediated restriction.
- Author
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Lin TY, Chin CR, Everitt AR, Clare S, Perreira JM, Savidis G, Aker AM, John SP, Sarlah D, Carreira EM, Elledge SJ, Kellam P, and Brass AL
- Subjects
- Acetylcholine pharmacology, Amphotericin B administration & dosage, Animals, Anti-Bacterial Agents pharmacology, Antifungal Agents administration & dosage, 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, Influenza, Human immunology, Interferons immunology, Membrane Proteins antagonists & inhibitors, Mice, Mice, Inbred C57BL, Mice, Knockout, Nystatin pharmacology, RNA Interference, RNA, Small Interfering, Sodium metabolism, Tetraethylammonium pharmacology, Virus Replication drug effects, Amphotericin B adverse effects, Antifungal Agents adverse effects, Immunocompromised Host, Influenza A Virus, H1N1 Subtype immunology, Membrane Proteins genetics, Orthomyxoviridae Infections immunology, Virus Internalization drug effects
- 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., (Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2013
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