title: Human heme oxygenase 1 is a potential host cell factor against dengue virus replication.
abstract: Dengue virus (DENV) infection and replication induces oxidative stress, which further contributes to the progression and pathogenesis of the DENV infection. Modulation of host antioxidant molecules may be a useful strategy for interfering with DENV replication. In this study, we showed that induction or exogenous overexpression of heme oxygenase-1 (HO-1), an antioxidant enzyme, effectively inhibited DENV replication in DENV-infected Huh-7 cells. This antiviral effect of HO-1 was attenuated by its inhibitor tin protoporphyrin (SnPP), suggesting that HO-1 was an important cellular factor against DENV replication. Biliverdin but not carbon monoxide and ferrous ions, which are products of the HO-1 on heme, mediated the HO-1-induced anti-DENV effect by non-competitively inhibiting DENV protease, with an inhibition constant (Ki) of 8.55 ± 0.38 μM. Moreover, HO-1 induction or its exogenous overexpression, rescued DENV-suppressed antiviral interferon response. Moreover, we showed that HO-1 induction by cobalt protoporphyrin (CoPP) and andrographolide, a natural product, as evidenced by a significant delay in the onset of disease and mortality, and virus load in the infected mice's brains. These findings clearly revealed that a drug or therapy that induced the HO-1 signal pathway was a promising strategy for treating DENV infection.
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chin-Kai
authors.initials: CK
authors.lastname: Tseng
authors.affiliation: Doctoral Degree Program in Marine Biotechnology, College of Marine Sciences, National Sun Yat-Sen University, Kaohsiung, Taiwan.
authors.forename: Chun-Kuang
authors.initials: CK
authors.lastname: Lin
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yu-Hsuan
authors.initials: YH
authors.lastname: Wu
authors.affiliation: Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.|School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center for Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan.|Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, HsinChu, Taiwan.|Center for Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yen-Hsu
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wei-Chun
authors.initials: WC
authors.lastname: Chen
authors.affiliation: Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Center of Infectious Disease and Signaling Research, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Kung-Chia
authors.initials: KC
authors.lastname: Young
authors.affiliation: Department of Biotechnology, College of Life Science, Kaohsiung Medical University, Kaohsiung, Taiwan.|Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan.|Research Center for Natural Products and Drug Development, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Jin-Ching
authors.initials: JC
authors.lastname: Lee
mesh_terms: D000818:Animals; D001664:Biliverdine / Q000494:pharmacology; D002248:Carbon Monoxide / Q000494:pharmacology; D003715:Dengue / Q000201:enzymology / Q000401:mortality / Q000821:virology; D003716:Dengue Virus / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D004195:Disease Models, Animal; D004224:Diterpenes / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D007501:Iron / Q000494:pharmacology; D008665:Metalloporphyrins / Q000494:pharmacology; D008813:Mice, Inbred ICR; D011524:Protoporphyrins / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D012697:Serine Endopeptidases / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology; D000085242:Viral Proteases
chemical_list: D001664:Biliverdine; D002248:Carbon Monoxide; D004224:Diterpenes; D004791:Enzyme Inhibitors; D051547:Heme Oxygenase-1; D016898:Interferon-alpha; D007501:Iron; D008665:Metalloporphyrins; D011524:Protoporphyrins; D011719:Pyrazines; D011758:Pyrroles; D012697:Serine Endopeptidases; C484301:cyclohexyl-octahydro-pyrrolo(1,2-a)pyrazine; C030419:andrographolide; C032628:tin protoporphyrin IX; C496541:HMOX1 protein, human; C504449:NS3 protease, dengue virus; D000085242:Viral Proteases