Carbon monoxide and biliverdin suppress bovine viral diarrhoea virus replication

Abstract

Bovine viral diarrhoea virus (BVDV) causes significant economic losses to the cattle industry worldwide. Previously, we demonstrated that heme oxygenase-1 (HO-1) can inhibit BVDV replication via an unknown molecular mechanism. To elucidate the mechanism involved, we assess whether the HO-1 downstream metabolites carbon monoxide (CO), biliverdin (BV) and iron affect BVDV replication. We treated Madin-Darby bovine kidney (MDBK) cells with an exogenous CO donor, CORM-2. We found that CORM-2 but not its inactive form (iCORM-2) inhibited BVDV replication in a dose-dependent and time duration-dependent manner, suggesting a CO-specific mediation of the CORM-2 antiviral effect. Direct incubation of BVDV with high-dose CORM-2 reduced virus titres, suggesting that CORM-2 attenuates BVDV growth by both physically inactivating virus particles in the extracellular environment and affecting intracellular BVDV replication, but mainly via an intracellular mechanism. Exogenous BV treatment, both post-infection and co-incubation with BVDV, inhibited BVDV replication in a dose-dependent manner, indicating that BV has potent antiviral activity against BVDV. Direct incubation of BVDV with BV had no significant effect on virus titres, indicating that BV is not virucidal and attenuates BVDV growth by affecting intracellular BVDV replication. Furthermore, BV was found to affect BVDV penetration but not attachment. However, increased iron via addition of FeCl3 did not interfere with BVDV replication. Collectively, the results of the present study demonstrate that the HO-1 metabolites BV and CO, but not iron, inhibit BVDV replication. These findings not only provide new insights into the molecular mechanism of HO-1 inhibition of BVDV replication but also suggest potential new control measures for future BVDV infection.

The Cytoprotective Enzyme Heme Oxygenase-1 Suppresses Pseudorabies Virus Replication in vitro

“…Both BV and CO mediated the antiviral activity of HO-1, as demonstrated by inhibition of PRV replication via BV or CORM-2 treatment in cell-based assays. As a downstream metabolite of HO-1, BV has been reported to exert antiviral activity against several domestic animal viruses, including BVDV (Ma et al, 2017). Considering that the majority of organs retain BVR activity to transform BV into BR (Maines, 2005), and the BV-BVR signaling pathway is the only source of intracellular BR (Maines, 2005), the present study set out to determine whether the antiviral activity of BV against PRV attributed to its conversion into BR rather than a direct effect of BV, in PK-15 and ST cells.…”

Can Activation of NRF2 Be a Strategy against COVID-19?

“…Because this binding pocket is highly conserved in SARS-CoV-2 [ 64 ] a similar mechanism may confer NRF2/HO-1-mediated antiviral activity against COVID-19. Furthermore, CO elicits antiviral responses against positive-sense single-stranded RNA (+ssRNA) viruses such as E71 [ 65 ] and bovine viral diarrhea virus (BVDV9) [ 66 ], and this effect is phenocopied by the CO donor, CO-releasing molecule 2 (CORM-2), through a mechanism that depends on the activation of soluble guanylyl cyclase (sGC), which increases the local levels of cGMP and activates protein kinase G (PKG) ( Figure 2 ). In turn, PKG inhibits NADPH oxidase (NOX) [ 67 ], preventing an increase in ROS levels ( Figure 2 ) that otherwise would contribute to inflammation.…”

MicroRNA‐155 inhibits dengue virus replication by inducing heme oxygenase‐1‐mediated antiviral interferon responses

“…Heme oxygenase‐1 (HO‐1) is an important enzyme to eliminate the cytotoxicity of oxidative stress as well as immuno‐modulatory and anti‐inflammatory properties . HO‐1 metabolites, including biliverdin, carbon monoxide (CO), and ferrous iron (Fe 2+ ), also display antiviral activity against several viruses through various mechanisms . The transcription of HO‐1 is highly inducible and its promoter has multiple antioxidant‐response elements (AREs) that serve as binding sites for the transcription activator Nrf2 and the transcriptional repressor protein BACH1 .…”