Nitazoxanide, an antiviral thiazolide, depletes ATP-sensitive intracellular Ca2+ stores

- NTZ depletes intracellular Ca2+ stores, thereby raising levels of cytosolic Ca2+.
- NTZ-mediated Ca2+ mobilisation disrupts ER/Golgi glycoprotein trafficking.
- NTZ induces ER stress, PKR phosphorylation, and TCTP expression.
- Ca2+ mobilisation may therefore be responsible for the antiviral activity of NTZ.

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 Ca2+ stores. In addition to PKR and eIF2α phosphorylation, consequences of NTZ-mediated Ca2+ 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 Ca2+-binding proteins, including the ER chaperone Bip and the cytosolic pro-survival and anti-viral protein TCTP. Depletion of intracellular Ca2+ stores is the primary consequence of NTZ treatment and is likely to underpin all antiviral mechanisms attributed to the thiazolide.