Amphotericin B Increases Influenza A Virus Infection by Preventing IFITM3-Mediated Restriction

• Published in: Cell reports (Cambridge) Vol. 5; no. 4; pp. 895 - 908
• Main Authors: Lin, Tsai-Yu, Chin, Christopher R., Everitt, Aaron R., Clare, Simon, Perreira, Jill M., Savidis, George, Aker, Aaron M., John, Sinu P., Sarlah, David, Carreira, Erick M., Elledge, Stephen J., Kellam, Paul, Brass, Abraham L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 27.11.2013; Cell Press; Elsevier
• Subjects: 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; Cell Fusion; Cell Line; Cell Membrane - drug effects; Cell Membrane - metabolism; Chlorocebus aethiops; COS Cells; 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
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2013.10.033

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. [Display omitted] •Amphotericin B or AmBisome prevents IFITM3-mediated restriction of IAV•AmBisome overcomes the majority of IFN’s antiviral effects in vitro•IFITM1 decreases membrane fluidity and inhibits membrane fusion•AmBisome increases the morbidity and mortality of influenza IFITM3 is a ubiquitously expressed antiviral protein that inhibits multiple human pathogenic viruses, including influenza A virus (IAV). Brass and colleagues now show that a widely used antifungal therapy, AmBisome, prevents IFITM3 from blocking IAV replication and that mice given AmBisome succumb to a normally mild influenza virus infection. Therefore, patients receiving antifungal therapy with AmBisome may be functionally immunocompromised and thus more vulnerable to influenza as well as other IFITM3-restricted viral infections.