title: Dengue virus (DV) replication in monocyte-derived macrophages is not affected by tumor necrosis factor alpha (TNF-alpha), and DV infection induces altered responsiveness to TNF-alpha stimulation.
abstract: Tumor necrosis factor alpha (TNF-alpha) is believed to play a significant role in the pathogenesis of dengue virus (DV) infection, with elevated levels of TNF-alpha in the sera of DV-infected patients paralleling the severity of disease and TNF-alpha release being coincident with the peak of DV production from infected monocyte-derived macrophages (MDM) in vitro. Since macrophages are a primary cell target in vivo for DV infection, we investigated the potential antiviral role of TNF-alpha in regulating DV replication in MDM. While pretreatment of MDM with TNF-alpha had a minor inhibitory effect, addition of TNF-alpha to MDM with established DV infection had no effect on DV replication as measured by DV RNA levels or progeny virus production. Blocking endogenous TNF-alpha using short interfering RNA or inhibitory TNF-alpha antibodies also had no effect on infectious DV production or viral RNA synthesis. Together, these results demonstrate that DV replication in MDM is not affected by TNF-alpha. Additionally, normal cellular TNF-alpha signaling, measured by quantitation of TNF-alpha-induced stimulation of transcription from an NF-kappaB-responsive reporter plasmid or NF-kappaB protein nuclear translocation, was blocked in DV-infected MDM and Huh7 cells. Thus, DV replication in MDM is not affected by TNF-alpha, and infected cells do not respond normally to TNF-alpha stimulation. It is therefore unlikely that the increased production of TNF-alpha seen in DV infection directly effects DV clearance by reducing DV replication, and the ability of DV to alter TNF-alpha responsiveness highlights another example of viral subversion of cellular functions.
authors.affiliation: Infectious Diseases Laboratories, Institute of Medical and Veterinary Science, Frome Road, Adelaide, SA 5000, Australia. satiya.wati@imvs.sa.gov.au
authors.forename: Satiya
authors.initials: S
authors.lastname: Wati
authors.forename: Peng
authors.initials: P
authors.lastname: Li
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Burrell
authors.forename: Jillian M
authors.initials: JM
authors.lastname: Carr
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002467:Cell Nucleus / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002522:Chlorocebus aethiops; D003715:Dengue / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003716:Dengue Virus / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D051379:Mice; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000494:pharmacology; D012367:RNA, Viral / Q000096:biosynthesis / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology / Q000494:pharmacology*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects / Q000502:physiology*
chemical_list: D000906:Antibodies; D016328:NF-kappa B; D034741:RNA, Small Interfering; D012367:RNA, Viral; D014409:Tumor Necrosis Factor-alpha