title: Nitazoxanide, an antiviral thiazolide, depletes ATP-sensitive intracellular Ca(2+) stores.
abstract: Nitazoxanide (NTZ) inhibits influenza, Japanese encephalitis, hepatitis B and hepatitis C virus replication but effects on the replication of other members of the Flaviviridae family has yet to be defined. The pestivirus bovine viral diarrhoea virus (BVDV) is a surrogate model for HCV infection and NTZ induced PKR and eIF2α phosphorylation in both uninfected and BVDV-infected cells. This led to the observation that NTZ depletes ATP-sensitive intracellular Ca(2+) stores. In addition to PKR and eIF2α phosphorylation, consequences of NTZ-mediated Ca(2+) mobilisation included induction of chronic sub-lethal ER stress as well as perturbation of viral protein N-linked glycosylation and trafficking. To adapt to NTZ-mediated ER stress, NTZ treated cells upregulated translation of Ca(2+)-binding proteins, including the ER chaperone Bip and the cytosolic pro-survival and anti-viral protein TCTP. Depletion of intracellular Ca(2+) stores is the primary consequence of NTZ treatment and is likely to underpin all antiviral mechanisms attributed to the thiazolide.
authors: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, Oxfordshire OX1 3QU, UK. Electronic address: Omodele.Ashiru@nibsc.org.
authors: Omodele
authors: O
authors: Ashiru
authors: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, Oxfordshire OX1 3QU, UK. Electronic address: jonathon.howe@bioch.ox.ac.uk.
authors: Jonathon D
authors: JD
authors: Howe
authors: Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, South Parks Road, Oxford, Oxfordshire OX1 3QU, UK. Electronic address: terry.butters@bioch.ox.ac.uk.
authors: Terry D
authors: TD
authors: Butters
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism*; D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D003593:Cytoplasm / Q000737:chemistry* / Q000187:drug effects*; D030241:Diarrhea Virus 1, Bovine Viral / Q000187:drug effects; D004721:Endoplasmic Reticulum / Q000187:drug effects; D006031:Glycosylation / Q000187:drug effects; D006801:Humans; D009574:Nitro Compounds; D021381:Protein Transport / Q000187:drug effects; D013844:Thiazoles / Q000378:metabolism*; D000090324:Tumor Protein, Translationally-Controlled 1; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D009574:Nitro Compounds; C000715647:TPT1 protein, human; D013844:Thiazoles; D000090324:Tumor Protein, Translationally-Controlled 1; D000255:Adenosine Triphosphate; C041747:nitazoxanide; D002118:Calcium
keywords: ER stress; Flaviviridae; Intracellular Ca(2+); N-linked glycans; PKR; TCTP