title: Nrf2-dependent induction of innate host defense via heme oxygenase-1 inhibits Zika virus replication.
abstract: We identified primary human monocyte-derived macrophages (MDM) as vulnerable target cells for Zika virus (ZIKV) infection. We demonstrate dramatic effects of hemin, the natural inducer of the heme catabolic enzyme heme oxygenase-1 (HO-1), in the reduction of ZIKV replication in vitro. Both LLC-MK2 monkey kidney cells and primary MDM exhibited hemin-induced HO-1 expression with major reductions of >90% in ZIKV replication, with little toxicity to infected cells. Silencing expression of HO-1 or its upstream regulatory gene, nuclear factor erythroid-related factor 2 (Nrf2), attenuated hemin-induced suppression of ZIKV infection, suggesting an important role for induction of these intracellular mediators in retarding ZIKV replication. The inverse correlation between hemin-induced HO-1 levels and ZIKV replication provides a potentially useful therapeutic modality based on stimulation of an innate cellular response against Zika virus infection.
authors.affiliation: Food and Drug Administration, Silver Spring, MD, United States.
authors.forename: Hanxia
authors.initials: H
authors.lastname: Huang
authors.affiliation: Food and Drug Administration, Silver Spring, MD, United States.
authors.forename: Barry
authors.initials: B
authors.lastname: Falgout
authors.affiliation: Food and Drug Administration, Silver Spring, MD, United States.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Takeda
authors.affiliation: National Institutes of Health, Bethesda, MD, United States.
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Yamada
authors.affiliation: Food and Drug Administration, Silver Spring, MD, United States. Electronic address: subhash.dhawan@fda.hhs.gov.
authors.forename: Subhash
authors.initials: S
authors.lastname: Dhawan
mesh_terms: D002478:Cells, Cultured; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006427:Hemin / Q000494:pharmacology*; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology; D008264:Macrophages / Q000276:immunology / Q000821:virology*; D051267:NF-E2-Related Factor 2 / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects* / Q000276:immunology; D000071244:Zika Virus / Q000276:immunology*; D000071243:Zika Virus Infection / Q000188:drug therapy* / Q000821:virology
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D034741:RNA, Small Interfering; D006427:Hemin; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1
keywords: Heme oxygenase-1; Macrophages; Monocytes; Nuclear factor erythroid-related factor 2; Zika