title: Carbon Monoxide Inhibits Porcine Reproductive and Respiratory Syndrome Virus Replication by the Cyclic GMP/Protein Kinase G and NF-κB Signaling Pathway.
abstract: Porcine reproductive and respiratory syndrome virus (PRRSV) causes significant economic losses to the pork industry worldwide each year. Our previous research demonstrated that heme oxygenase-1 (HO-1) can suppress PRRSV replication via an unknown molecular mechanism. In this study, inhibition of PRRSV replication was demonstrated to be mediated by carbon monoxide (CO), a downstream metabolite of HO-1. Using several approaches, we demonstrate that CO significantly inhibited PRRSV replication in both a PRRSV permissive cell line, MARC-145, and the predominant cell type targeted during in vivo PRRSV infection, porcine alveolar macrophages (PAMs). Our results showed that CO inhibited intercellular spread of PRRSV; however, it did not affect PRRSV entry into host cells. Furthermore, CO was found to suppress PRRSV replication via the activation of the cyclic GMP/protein kinase G (cGMP/PKG) signaling pathway. CO significantly inhibits PRRSV-induced NF-κB activation, a required step for PRRSV replication. Moreover, CO significantly reduced PRRSV-induced proinflammatory cytokine mRNA levels. In conclusion, the present study demonstrates that CO exerts its anti-PRRSV effect by activating the cellular cGMP/PKG signaling pathway and by negatively regulating cellular NF-κB signaling. These findings not only provide new insights into the molecular mechanism of HO-1 inhibition of PRRSV replication but also suggest potential new control measures for future PRRSV outbreaks.
  
  
  OBJECTIVE
  PRRSV causes great economic losses each year to the swine industry worldwide. Carbon monoxide (CO), a metabolite of HO-1, has been shown to have antimicrobial and antiviral activities in infected cells. Our previous research demonstrated that HO-1 can suppress PRRSV replication. Here we show that endogenous CO produced through HO-1 catalysis mediates the antiviral effect of HO-1. CO inhibits PRRSV replication by activating the cellular cGMP/PKG signaling pathway and by negatively regulating cellular NF-κB signaling. These findings not only provide new insights into the molecular mechanism of HO-1 inhibition of PRRSV replication but also suggest potential new control measures for future PRRSV outbreaks.
authors: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.|Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, Yangling, Shaanxi, China.
authors: Angke
authors: A
authors: Zhang
authors: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.|Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, Yangling, Shaanxi, China.
authors: Lijuan
authors: L
authors: Zhao
authors: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.|Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, Yangling, Shaanxi, China.
authors: Na
authors: N
authors: Li
authors: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.|Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, Yangling, Shaanxi, China.
authors: Hong
authors: H
authors: Duan
authors: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.|Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, Yangling, Shaanxi, China.
authors: Hongliang
authors: H
authors: Liu
authors: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.|Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, Yangling, Shaanxi, China.
authors: Fengxing
authors: F
authors: Pu
authors: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China.|College of Animal Science and Veterinary Medicine, Henan Agricultural University, Zhengzhou, Henan, China.
authors: Gaiping
authors: G
authors: Zhang
authors: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China zhouem@nwsuaf.edu.cn xiaoshuqi@nwsuaf.edu.cn.|Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, Yangling, Shaanxi, China.
authors: En-Min
authors: EM
authors: Zhou
authors: College of Veterinary Medicine, Northwest A&F University, Yangling, Shaanxi, China zhouem@nwsuaf.edu.cn xiaoshuqi@nwsuaf.edu.cn.|Experimental Station of Veterinary Pharmacology and Veterinary Biotechnology, Ministry of Agriculture, China, Yangling, Shaanxi, China.
authors: Shuqi
authors: S
authors: Xiao
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000378:metabolism / Q000494:pharmacology*; D002248:Carbon Monoxide / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D006152:Cyclic GMP / Q000378:metabolism; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics* / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism / Q000821:virology; D005786:Gene Expression Regulation; D051547:Heme Oxygenase-1 / Q000235:genetics* / Q000378:metabolism; D054884:Host-Pathogen Interactions; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000235:genetics* / Q000378:metabolism; D009942:Organometallic Compounds / Q000378:metabolism / Q000494:pharmacology; D019316:Porcine respiratory and reproductive syndrome virus / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013552:Swine; D053586:Virus Internalization; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D016207:Cytokines; D016328:NF-kappa B; D009942:Organometallic Compounds; D011719:Pyrazines; D011758:Pyrroles; D012333:RNA, Messenger; C484301:cyclohexyl-octahydro-pyrrolo(1,2-a)pyrazine; C447082:tricarbonyldichlororuthenium (II) dimer; D002248:Carbon Monoxide; D051547:Heme Oxygenase-1; D017869:Cyclic GMP-Dependent Protein Kinases; D006152:Cyclic GMP
keywords: HO-1; NF-κB; PRRSV; cGMP/PKG; carbon monoxide