title: 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 FeCl3did 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.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Angke
authors.initials: A
authors.lastname: Zhang
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Duan
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Lijuan
authors.initials: L
authors.lastname: Zhao
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Fengxing
authors.initials: F
authors.lastname: Pu
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Baicheng
authors.initials: B
authors.lastname: Huang
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Chunyan
authors.initials: C
authors.lastname: Wu
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Yuchen
authors.initials: Y
authors.lastname: Nan
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Taofeng
authors.initials: T
authors.lastname: Du
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Mu
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Qin
authors.initials: Q
authors.lastname: Zhao
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China.
authors.forename: Yani
authors.initials: Y
authors.lastname: Sun
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan 450002, China.
authors.forename: Gaiping
authors.initials: G
authors.lastname: Zhang
authors.affiliation: Department of Infection Biology, Institute of Infection and Global Health, University of Liverpool, Liverpool L3 5RF, UK.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Hiscox
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China. Electronic address: zhouem@nwsuaf.edu.cn.
authors.forename: En-Min
authors.initials: EM
authors.lastname: Zhou
authors.affiliation: College of Veterinary Medicine, Northwest A&F University, 22 Xinong Road, Yangling, Shaanxi 712100, China; Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, 22 Xinong Road, Yangling, Shaanxi 712100, China. Electronic address: xiaoshuqi@nwsuaf.edu.cn.
authors.forename: Shuqi
authors.initials: S
authors.lastname: Xiao
mesh_terms: D000818:Animals; D001664:Biliverdine / Q000378:metabolism; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D007501:Iron / Q000378:metabolism; D019318:Porcine Reproductive and Respiratory Syndrome / Q000235:genetics* / Q000473:pathology / Q000821:virology; D019316:Porcine respiratory and reproductive syndrome virus / Q000235:genetics* / Q000472:pathogenicity; D013552:Swine; D014779:Virus Replication / Q000235:genetics*
chemical_list: D007501:Iron; D051547:Heme Oxygenase-1; D001664:Biliverdine
keywords: Antiviral effect; Bilirubin; Biliverdin; Heme oxygenase-1; Iron; Nitric oxide; PRRSV; Reactive oxygen species