Differential Regulation of Interferon Responses by Ebola and Marburg Virus VP35 Proteins

Cell Rep. 2016 Feb 23;14(7):1632-1640. doi: 10.1016/j.celrep.2016.01.049. Epub 2016 Feb 11.

Abstract

Suppression of innate immune responses during filoviral infection contributes to disease severity. Ebola (EBOV) and Marburg (MARV) viruses each encode a VP35 protein that suppresses RIG-I-like receptor signaling and interferon-α/β (IFN-α/β) production by several mechanisms, including direct binding to double stranded RNA (dsRNA). Here, we demonstrate that in cell culture, MARV infection results in a greater upregulation of IFN responses as compared to EBOV infection. This correlates with differences in the efficiencies by which EBOV and MARV VP35s antagonize RIG-I signaling. Furthermore, structural and biochemical studies suggest that differential recognition of RNA elements by the respective VP35 C-terminal IFN inhibitory domain (IID) rather than affinity for RNA by the respective VP35s is critical for this observation. Our studies reveal functional differences in EBOV versus MARV VP35 RNA binding that result in unexpected differences in the host response to deadly viral pathogens.

Keywords: RIG-I like receptor; VP35; filovirus; immune evasion; pattern associated molecular pattern (PAMP); type I interferon.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Cell Line
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases / chemistry
  • DEAD-box RNA Helicases / genetics*
  • DEAD-box RNA Helicases / immunology
  • Ebolavirus / genetics*
  • Ebolavirus / immunology
  • Gene Expression Regulation
  • Host-Pathogen Interactions
  • Humans
  • Interferon-alpha / antagonists & inhibitors
  • Interferon-alpha / biosynthesis
  • Interferon-alpha / immunology*
  • Interferon-beta / antagonists & inhibitors
  • Interferon-beta / biosynthesis
  • Interferon-beta / immunology*
  • Marburgvirus / genetics*
  • Marburgvirus / immunology
  • Models, Molecular
  • Molecular Sequence Data
  • Monocytes
  • Protein Binding
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • RNA, Double-Stranded / chemistry
  • RNA, Double-Stranded / genetics*
  • RNA, Double-Stranded / immunology
  • Receptors, Immunologic
  • Sequence Alignment
  • Signal Transduction
  • Species Specificity
  • Viral Regulatory and Accessory Proteins / chemistry
  • Viral Regulatory and Accessory Proteins / genetics*
  • Viral Regulatory and Accessory Proteins / immunology

Substances

  • Interferon-alpha
  • RNA, Double-Stranded
  • Receptors, Immunologic
  • VP35 protein, filovirus
  • Viral Regulatory and Accessory Proteins
  • Interferon-beta
  • RIGI protein, human
  • DEAD Box Protein 58
  • DEAD-box RNA Helicases