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

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.

When we found that AmphoB prevented IFITM3's antiviral actions, it suggested that patients treated with AmphoB formulations might be at greater risk for influenza (Everitt et al., 2012 ). Therefore, we tested a clinical preparation of AmphoB, AmBisome, in vivo and found that similar to Ifitm3 À/À mice, WT littermates treated with AmBisome developed severe illness from a normally nonpathogenic IAV strain. Individuals with a variant of IFITM3 are more likely to be hospitalized with influenza, suggesting that IFITM3 plays a role in protecting human populations (Everitt et al., 2012) ; indeed, this IFITM3 allele (rs12254-C) was recently reported to convey a large population-attributable risk of 54.25% in the Chinese population (Zhang et al., 2013) . Moreover, IFITM3 is critical for protecting CD8 + resident memory T cell populations during IAV infections in vivo, arguing that AmphoB's antagonism of IFITM3 may impair the adaptive immune system as well (Wakim et al., 2013) . Collectively, these data suggest that patients receiving antifungal therapy with liposomal AmphoB may be functionally immunosuppressed and therefore more vulnerable to influenza. Many patients receiving AmBisome have lost their adaptive and innate immune defenses, so the role of intrinsic immune factors may be critical in protecting them against IAV (Moen et al., 2009 ). In addition, some of these patients are also on prophylactic AmBisome therapy and so may potentially be incurring greater IAV infection risks. It is our hope that the reporting of the mechanism and the in vivo consequences of this interaction between IFITM3 and amphotericin B may help stimulate translational studies and potentially guide patient care.