Hypochlorous acid inhibits viral replication by interfering with viral protein assembly in non-myeloid cells

Abstract

Hypochlorous acid (HOCl) has antibacterial and antiviral properties and is generated by myeloid cells as an innate immune response with the help of myeloperoxidase (MPO). We have earlier shown that antiviral activity in non-myeloid cells can be augmented by increasing the availability of chloride ions.

Here, we show that availability of sodium chloride (NaCl) has a dose-dependent promotion effect on HOCl production in different infected human epithelial cells.

The promotion effect starts at an early stage of viral replication and increase over time. This suggests that as an innate antiviral response, cells convert chloride ions into HOCl. This antiviral effect weakens after knockdown of genes of MPO, dual oxidases 1 and 2 (DUOX1 and DUOX2), suggesting these enzymes are involved in intracellular HOCl production in non-myeloid cells.

NaCl had no inhibitory effect on the modified foot-and-mouth disease virus (FMDV) replicon which can replicate viral genes without producing any infectious viral particles. Inhibition of herpes simplex virus type 1 (HSV-1) capsid assembly was seen in the presence of NaCl. These results indicate HOCl prevents the assembly of viral proteins without damaging gene expression. HOCl is only detected in the cytoplasm (and not within the nucleus) of HSV-1 infected cells, indicating viral proteins are potentially denatured, resulting in proteins that are unable to assemble correctly. These data give us evidence for the mechanism behind the NaCl mediated antiviral innate immune response in non-myeloid cells. We developed a NaCl-resistant HSV-1 strain by propagating viruses in media with additional NaCl concentrations. A reduced antiviral effect was observed when cells were infected with this specific HSV-1 strain in the presence of NaCl. This suggests our passaging successfully developed mutations related to the NaCl mediated innate antiviral response in HSV-1.