Human heme oxygenase 1 is a potential host cell factor against dengue virus replication

Sci Rep. 2016 Aug 24:6:32176. doi: 10.1038/srep32176.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biliverdine / pharmacology
  • Carbon Monoxide / pharmacology
  • Dengue / enzymology
  • Dengue / mortality
  • Dengue / virology
  • Dengue Virus / drug effects
  • Dengue Virus / pathogenicity
  • Dengue Virus / physiology*
  • Disease Models, Animal
  • Diterpenes / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Heme Oxygenase-1 / antagonists & inhibitors
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Host-Pathogen Interactions / drug effects
  • Host-Pathogen Interactions / physiology*
  • Humans
  • Interferon-alpha / metabolism
  • Iron / pharmacology
  • Metalloporphyrins / pharmacology
  • Mice, Inbred ICR
  • Protoporphyrins / pharmacology
  • Pyrazines / pharmacology
  • Pyrroles / pharmacology
  • Serine Endopeptidases / metabolism
  • Virus Replication* / drug effects
  • Virus Replication* / physiology


  • Diterpenes
  • Enzyme Inhibitors
  • Interferon-alpha
  • Metalloporphyrins
  • Protoporphyrins
  • Pyrazines
  • Pyrroles
  • cyclohexyl-octahydro-pyrrolo(1,2-a)pyrazine
  • andrographolide
  • Carbon Monoxide
  • tin protoporphyrin IX
  • Iron
  • HMOX1 protein, human
  • Heme Oxygenase-1
  • NS3 protease, dengue virus
  • Serine Endopeptidases
  • Biliverdine