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

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.

Orf virus infection of human keratinocytes and dermal fibroblasts: Limited virus detection and interference with intercellular adhesion molecule‐1 up‐regulation

“…ICAM‐1 expression is regulated by the NF‐κB pathway . ORFV encodes at least five NF‐κB inhibitors, which can block NF‐κB signalling . Thus, blocking of ICAM‐1 expression by ORFV on its host cell may be linked to a successful inhibition of the NF‐κB pathway in infected KC and FB.…”

Orf virus: A promising new therapeutic agent

“…ORFV exerts its effects through encoding novel inhibitors to subvert the pro‐inflammatory NF‐κB signaling pathway, a crucial regulator of host innate immune response. The ORFV 002, 024, 073, 119, and 121 genes have been reported to play roles in NF‐κB pathway regulation …”

“…The gene expression profiles of ovine fetal turbinate cells infected with OV‐IA82Δ073 were analyzed by microarray assay. The results showed that the expression of chemokines and other pro‐inflammatory genes was significantly increased in cells infected with IA82Δ073 (IA82 strain with ORFV073 gene deletion), and most of the gene expression changes were regulated by the NF‐κB transcription factor family . ORFV073 affected neither the phosphorylation of p65 in the cytoplasm nor the nuclear transfer of p65, further suggesting that ORFV073 was located in the nucleus when inhibiting NF‐κB signal transduction.…”

“…ORFV genes have been reported to play roles in NF-κB pathway regulation. [62][63][64][65][66][67][68] The ORFV002 gene, located in the nucleus, encodes a protein inhibiting activation of the NF-κB pathway by TNF-α and ORFV infection. ORFV002 may interfere with the interaction between NF-κB-p65 and P300 in the nucleus, thereby blocking the acetylation of NF-κB-p65 Lys310 when ORFV002 Ser276 is phosphorylated.…”

“…The results showed that the expression of chemokines and other pro-inflammatory genes was significantly increased in cells infected with IA82Δ073 (IA82 strain with ORFV073 gene deletion), and most of the gene expression changes were regulated by the NF-κB transcription factor family. 66 Inactivated ORFV preparations regulate the immune status of horses in vivo and in vitro. 70 Drugs based on ORFV for a variety of infectious animal diseases have been developed, too.…”