Heme oxygenase-1 metabolite biliverdin, not iron, inhibits porcine reproductive and respiratory syndrome virus replication.

Abstract

Porcinereproductiveandrespiratorysyndromevirus (PRRSV) causes significant economic losses to the pork industry worldwide. Previously, we demonstrated that heme oxygenase-1 (HO-1) interferes with PRRSV replication. To elucidate the mechanisms involved, here we assess whether the HO-1 downstream metabolites biliverdin (BV) and/or iron mediate the HO-1 antiviral effect. We demonstrate a BV concentration-dependent suppression of PRRSV replication and show that virions are not directly inactivated by BV. Additionally, BV or N-acetyl cysteine (NAC) significantly reduced reactive oxygen species (ROS) in PRRSV-infected MARC-145 cells; however, because NAC did not reduce viral load, the BV antiviral effect is independent of decreased ROS levels. Moreover, a secondary metabolite of BV, bilirubin (BR), specifically mediates this anti-PRRSV activity via a nitric oxide (NO)-dependent cGMP/PKG signaling pathway. While increased iron via addition of FeCl3 did not interfere with PRRSV replication, iron depletion by deferoxamine (DFO) after cobalt-protoporphyrin IX induction of HO-1 did not restore PRRSV replication. Collectively, our findings identify a HO-1-BV/BR-NO-cGMP/PKG cascade as a novel pathway underlying the host cell antiviral effect. These results provide a unique insight into the molecular mechanisms underlying the antiviral effects of the stress-responsive protein HO-1 during PRRSV infection.

• Authors: Angke Zhang, Hong Duan, Na Li, Lijuan Zhao, Fengxing Pu, Baicheng Huang, Chunyan Wu, Yuchen Nan, Taofeng Du, Yang Mu, Qin Zhao, Yani Sun, Gaiping Zhang, Julian A Hiscox, En-Min Zhou, Shuqi Xiao
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 102 Pg. 149-161 (01 2017) ISSN: 1873-4596 [Electronic] United States
• PMID: 27908781 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016 Elsevier Inc. All rights reserved.

Chemical References

• Iron
• Heme Oxygenase-1
• Biliverdine

Topics

• Animals
• Biliverdine (metabolism)
• Heme Oxygenase-1 (genetics, metabolism)
• Iron (metabolism)
• Porcine Reproductive and Respiratory Syndrome (genetics, pathology, virology)
• Porcine respiratory and reproductive syndrome virus (genetics, pathogenicity)
• Swine
• Virus Replication (genetics)