Abstract
Antivirals that are currently used to treat influenza virus infections target components of the virus which can mutate rapidly. Consequently, there has been an increase in the number of resistant strains to one or many antivirals in recent years. Here we compared the antiviral effects of lysosomotropic alkalinizing agents (LAAs) and calcium modulators (CMs), which interfere with crucial events in the influenza virus replication cycle, against avian, swine, and human viruses of different subtypes in MDCK cells. We observed that treatment with LAAs, CMs, or a combination of both, significantly inhibited viral replication. Moreover, the drugs were effective even when they were administered 8 h after infection. Finally, analysis of the expression of viral acidic polymerase (PA) revealed that both drugs classes interfered with early events in the viral replication cycle. This study demonstrates that targeting broad host cellular pathways can be an efficient strategy to inhibit influenza replication. Furthermore, it provides an interesting avenue for drug development where resistance by the virus might be reduced since the virus is not targeted directly.
Highlights
Influenza A viruses (IAV) cause acute respiratory tract infections that are generally mild but that can lead to severe lung pathology, respiratory distress, and death [1]
We first compared the efficacy of novel lysosomotropic alkalinizing agents (LAAs) to interfere with IAV replication in a viral plaque inhibition assay in Madin-Darby Canine Kidney cells (MDCK) cells which provides a direct evaluation of ability of compounds to block viral plaque formation
In agreement with previous studies [20,26], bafilomycin A and chloroquine completely inhibited the replication of PR8, X-31, and A/ H1N1/2009 in the low micromolar range (Fig. 1 B–C, Table 1)
Summary
Influenza A viruses (IAV) cause acute respiratory tract infections that are generally mild but that can lead to severe lung pathology, respiratory distress, and death [1]. In addition to seasonal outbreaks which have major global health, social and economic impacts, IAV bear the potential to develop into new pandemic strains, as highlighted by the frequent emergence of H5N1 viruses, the new H7N9 virus, and the 2009 H1N1 pandemic virus (A(H1N1)pdm09) [2,3,4]. Even though vaccination is the best strategy to protect against infection, the generation of vaccines against seasonal IAV is a time-consuming process required annually and the emergence of pandemic IAV represents an additional challenge in terms of vaccine development and availability. There are currently two classes of antivirals available to treat IAV infection that target either the M2 ion channel (adamantanes) or viral neuraminidase (oseltamivir, zanamivir, peramivir and laninamivir) [5,6]. Resistance to neuraminidase inhibitors is continuously reported in newly emerging influenza viruses [5]. There is a need to develop new antiviral strategies to overcome resistance
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
