How to Inhibit Nuclear Factor-Kappa B Signaling: Lessons from Poxviruses

Abstract

The Nuclear Factor-kappa B (NF-κB) family of transcription factors regulates key host inflammatory and antiviral gene expression programs, and thus, is often activated during viral infection through the action of pattern-recognition receptors and cytokine–receptor interactions. In turn, many viral pathogens encode strategies to manipulate and/or inhibit NF-κB signaling. This is particularly exemplified by vaccinia virus (VV), the prototypic poxvirus, which encodes at least 18 different inhibitors of NF-κB signaling. While many of these poxviral NF-κB inhibitors are not required for VV replication in cell culture, they are virtually all modulate VV virulence in animal models, underscoring the important influence of poxvirus–NF-κB pathway interactions on viral pathogenesis. Here, we review the diversity of mechanisms through which VV-encoded antagonists inhibit initial NF-κB pathway activation and NF-κB signaling intermediates, as well as the activation and function of NF-κB transcription factor complexes.

Antagonizing the SAMD9 pathway is key to myxoma virus host shut-off and immune evasion

“…This is not surprising, as mammalian poxviruses employ different strategies to evade host surveillance and defense mechanisms, such as lessons learned from poxvirus inhibition of NF-κB signaling. 44 In this study, we revealed the unique translation state induced by ΔM062R, which is different from what was observed during infection by VACV-ΔC7LΔK1L, the mutant VACV without both inhibitors of SAMD9. 29 Although ΔM062R viral infection is abortive, we did not observe abnormality in host protein synthesis and accumulation.…”

Poxvirus A51R proteins regulate microtubule stability and antagonize a cell-intrinsic antiviral response

“…RAW-Dual cells also express secreted embryonic alkaline phosphatase (SEAP) under a nuclear factor kB (NF-κB)-responsive promoter. Since the NF-κB pathway is extensively antagonized by poxviruses, 52 we measured SEAP levels in infected cultures but again observed no differences between ΔA51R FA51R and ΔA51R FA51RTriple infections ( Figure S7E ). Moreover, secretion of TNF-α, which is largely NF-κB dependent during poxvirus infection, 52 was not significantly different between ΔA51R FA51R and ΔA51R FA51RTriple infections ( Figure S7F ).…”

“…Since the NF-κB pathway is extensively antagonized by poxviruses, 52 we measured SEAP levels in infected cultures but again observed no differences between ΔA51R FA51R and ΔA51R FA51RTriple infections ( Figure S7E ). Moreover, secretion of TNF-α, which is largely NF-κB dependent during poxvirus infection, 52 was not significantly different between ΔA51R FA51R and ΔA51R FA51RTriple infections ( Figure S7F ). Finally, because ECTV infection is known to trigger autophagy in macrophages, 53 we analyzed VV replication in RAW cells with a KO of autophagy-related gene 5 ( ATG5 ), which is required for autophagy.…”

Oncolytic vaccinia virus immunotherapy antagonizes image-guided radiotherapy in mouse mammary tumor models

“…At present, the most likely explanation for what is causing this effect relates to the observation that it is time dependent and dissipates if VACV exposure is delayed for three weeks ( Fig 3 ). Orthopoxviruses like VACV encode a remarkable number of genes capable of inhibiting elements of both the innate and adaptive immune systems [ 40 ] including type I/II IFN and NFKB signaling [ 41 , 42 ] and effector T-cell functions (e.g., [ 43 ]). Several apoptotic inhibitors are encoded by these viruses [ 44 ].…”