A parapoxviral virion protein inhibits NF-κB signaling early in infection

Poxviruses have evolved unique proteins and mechanisms to counteract the nuclear factor κB (NF-κB) signaling pathway, which is an essential regulatory pathway of host innate immune responses. Here, we describe a NF-κB inhibitory virion protein of orf virus (ORFV), ORFV073, which functions very early...

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Bibliographic Details
Published in:PLoS pathogens 2017-08, Vol.13 (8), p.e1006561-e1006561
Main Authors: Khatiwada, Sushil, Delhon, Gustavo, Nagendraprabhu, Ponnuraj, Chaulagain, Sabal, Luo, Shuhong, Diel, Diego G, Flores, Eduardo F, Rock, Daniel L
Format: Article
Language:English
Subjects:
Animals
Biology and Life Sciences
Ecthyma, Contagious - immunology
Ecthyma, Contagious - virology
HeLa Cells
Humans
Immune Evasion - physiology
Immunoprecipitation
Medicine and Health Sciences
NF-kappa B - immunology
Orf virus - immunology
Orf virus - metabolism
Orf virus - pathogenicity
Physical Sciences
Real-Time Polymerase Chain Reaction
Research and Analysis Methods
Sheep
Signal Transduction - immunology
Viral Proteins - immunology
Virion - immunology
Virulence - physiology
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Summary:Poxviruses have evolved unique proteins and mechanisms to counteract the nuclear factor κB (NF-κB) signaling pathway, which is an essential regulatory pathway of host innate immune responses. Here, we describe a NF-κB inhibitory virion protein of orf virus (ORFV), ORFV073, which functions very early in infected cells. Infection with ORFV073 gene deletion virus (OV-IA82Δ073) led to increased accumulation of NF-κB essential modulator (NEMO), marked phosphorylation of IκB kinase (IKK) subunits IKKα and IKKβ, IκBα and NF-κB subunit p65 (NF-κB-p65), and to early nuclear translocation of NF-κB-p65 in virus-infected cells (≤ 30 min post infection). Expression of ORFV073 alone was sufficient to inhibit TNFα induced activation of the NF-κB signaling in uninfected cells. Consistent with observed inhibition of IKK complex activation, ORFV073 interacted with the regulatory subunit of the IKK complex NEMO. Infection of sheep with OV-IA82Δ073 led to virus attenuation, indicating that ORFV073 is a virulence determinant in the natural host. Notably, ORFV073 represents the first poxviral virion-associated NF-κB inhibitor described, highlighting the significance of viral inhibition of NF-κB signaling very early in infection.
ISSN:1553-7374
1553-7366
1553-7374
DOI:10.1371/journal.ppat.1006561