Ebolavirus VP35 suppresses IFN production from conventional but not plasmacytoid dendritic cells.
Ebolaviruses naturally infect a wide variety of cells including macrophages and dendritic cells (DCs), and the resulting cytokine and interferon-α/β (IFN) responses of infected cells are thought to influence viral pathogenesis. The VP35 protein impairs RIG-I-like receptor-dependent signaling to inhibit IFN production, and this function has been suggested to promote the ineffective host immune response characteristic of ebolavirus infection. To assess the impact of VP35 on innate immunity in biologically relevant primary cells, we used a recombinant Newcastle disease virus encoding VP35 (NDV/VP35) to infect macrophages and conventional DCs, which primarily respond to RNA virus infection via RIG-I-like pathways. VP35 suppressed not only IFN but also tumor necrosis factor (TNF)-α secretion, which are normally produced from these cells upon NDV infection. Additionally, in cells susceptible to the activity of VP35, IRF7 activation is impaired. In contrast, NDV/VP35 infection of plasmacytoid DCs, which activate IRF7 and produce IFN through TLR-dependent signaling, leads to robust IFN production. When plasmacytoid DCs deficient for TLR signaling were infected, NDV/VP35 was able to inhibit IFN production. Consistent with this, VP35 was less able to inhibit TLR-dependent versus RIG-I-dependent signaling in vitro. These data demonstrate that ebolavirus VP35 suppresses both IFN and cytokine production in multiple primary human cell types. However, cells that utilize the TLR pathway can circumvent this inhibition, suggesting that the presence of multiple viral sensors enables the host to overcome viral immune evasion mechanisms.
Department of Microbiology, Mount Sinai School of Medicine, One Gustave L Levy Place, New York, NY 10029, USA.
Lawrence W
LW
Leung
Man-Seong
MS
Park
Osvaldo
O
Martinez
Charalampos
C
Valmas
Carolina B
CB
López
Christopher F
CF
Basler
D000818:Animals; D002460:Cell Line; D002522:Chlorocebus aethiops; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D029043:Ebolavirus / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D019142:Hemorrhagic Fever, Ebola / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D050839:Interferon Regulatory Factor-7 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D007372:Interferons / Q000096:biosynthesis*; D008264:Macrophages / Q000821:virology; D051379:Mice; D009522:Newcastle disease virus / Q000235:genetics; D011971:Receptors, Immunologic; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000235:genetics / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014709:Vero Cells; D054334:Viral Regulatory and Accessory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
C494234:IRF7 protein, human; D050839:Interferon Regulatory Factor-7; D011971:Receptors, Immunologic; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; C080980:VP35 protein, filovirus; D054334:Viral Regulatory and Accessory Proteins; D007372:Interferons; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58; D053487:DEAD-box RNA Helicases
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