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Browsing by Author "Ojha, Ravi Kant"

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  • Ojha, Ravi Kant (2019)
    One of the first cellular response to a variety of stress inducers is the inhibition of cap-dependent protein synthesis. This also occurs as a first defense mechanism against viruses, which must evolve counter-defense strategies to overcome the attempt of the cell to block viral protein production. On the other hand, viruses have developed strategies to overcome the host translational shutoff and are resistant to cellular stress. Some viruses use specific proteins that interfere with PKR activation and prevents eukaryotic initiation factor 2 alpha (eIF2a inactivation, while others utilize the internal ribosome entry site (IRES) to achieve translation independently of eIF2a. Following the lead of a previously performed genome-wide screen, I found that ouabain, a potent cardiotonic steroid that specifically inhibits the cellular Na+ K+ ATPase pump leading to decreased intracellular levels of K+ and inhibition of cellular bulk protein synthesis, inhibits viruses at post entry step of their life cycle. Three viruses were used: Respiratory syncytial virus (RSV, Paramyxoviridae), Semliki forest virus (SFV, Togaviridae), and Vesicular stomatitis virus (VSV, Rabdoviridae). Of the three viruses, VSV was the less inhibited by ouabain. The effect of the drug was specific for the Na+K+ATPase because point mutations that disrupted the ouabain binding site in the pump abrogated the antiviral effect of ouabain. In addition, the drug-induced inhibition of virus infection was reversed by exogenous addition of K+ ions, indicating the effect is dependent of the activity of the Na+K+ATPase. Follow up experiments using the small molecule regulator of proteostasis ISRIB, an inhibitor of the integrated stress response, indicated that the antiviral effect of ouabain does not involve the inactivation of the eIF2a, a central regulator of protein synthesis and stress responses. The finding that VSV can replicate in the presence of concentrations of ouabain that strongly inhibit other viruses suggest a mechanism of resistance that could be further investigated to shed light into the regulation of viral protein synthesis and mRNA regulation and potential use of cardiotonic steroids as antivirals or in oncolytic therapy.