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

Sushil Khatiwada,Daniel L Rock,Shuhong Luo,Gustavo Delhon,Diego G Diel,Ponnuraj Nagendraprabhu,Sabal Chaulagain,Eduardo F Flores

doi:10.1371/journal.ppat.1006561

Abstract

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.

Highlights

Orf virus (ORFV), the prototype member of the genus Parapoxvirus (PPV) of the Poxviridae, is the etiologic agent of contagious pustular dermatitis or orf, a ubiquitous disease of sheep and goats [1]
Successful infection of the host by poxviruses relies on control of innate immune responses by virus-encoded immunomodulators
We identified a nuclear factor κB (NF-κB) inhibitor encoded by ORFV, ORFV073, that is unique to Parapoxvirus (PPV)

Summary

Introduction

Orf virus (ORFV), the prototype member of the genus Parapoxvirus (PPV) of the Poxviridae, is the etiologic agent of contagious pustular dermatitis or orf, a ubiquitous disease of sheep and goats [1]. Orf is characterized by inflammatory, often proliferative lesions affecting the skin and the oral mucosa [2]. Additional PRRs, such as the cyclic GMP-AMP Synthase (cGAS), retinoic acid -inducible gene 1 (RIG-I)-like receptors and NOD-like receptors (NLRs) recognize viral nucleic acid in the cytoplasm [8]. Engagement of these receptors initiates downstream proinflammatory signaling cascades [6,7], including the nuclear factor-kappa B (NF-κB) signaling pathway, which mediates innate immune responses and contributes to skin homeostasis [9,10]

Methods

Results

Discussion

Conclusion