Speaker
Description
The release of viral genome into the host cytoplasm and its translocation to the nucleus is strongly dependent on the fusion of Influenza A virus (IAV) envelope with host endosomal membranes. Recent publications have already delineated the importance of cellular cholesterol levels on the infectivity of IAV, as interferons (IFN) are also impairing cholesterol levels and its cellular distribution in endosomal/lysosomal (LE/L) compartments. Here, we analyzed the antiviral virility of itraconazole (Itra) and posaconazole (Posa) in the context of IAV and vesicular stomatitis virus (VSV) infection. Both compounds are well-known antifungal agents affecting cholesterol levels in host membranes. By increasing the cholesterol levels in LE/L Itra and Posa impair virus entry. Treatment either with Itra or Posa inhibits a very early step in IAV life cycle, namely prior to the transport of vRNPs to the nucleus. Because the IFN system is a crucial factor in limiting virus infection and also affecting LE/L cholesterol distribution, we further checked the antiviral potency of both compounds in three different mammalian cell lines including Vero cells, lacking an IFN-system. Strikingly, viral replication was also reduced in Vero cells treated with Itra or Posa suggesting that the antiviral effect is not only caused by modulating the IFN system, but could be improved in the presence of an IFN system as gene expression analysis of A549 cells revealed. We further elucidated the antiviral potency of Itra against IAV infection in mice. Intra-gastral application of Itra significantly reduces mortality and viral burden in the respiratory tract of IAV-infected mice. Our results established a protective function of Itra and Posa against IAV by impairing the LE/L cholesterol balance and by modulating the IFN system.
| Choose primary session | Vaccines and antivirals |
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| Choose secondary Session | Virus host cell interaction |
