Inhibition of the NF-kappaB pathway by varicella-zoster virus in vitro and in human epidermal cells in vivo. – PubMed

Inhibition of the NF-kappaB pathway by varicella-zoster virus in vitro and in human epidermal cells in vivo. - PubMed

Inhibition of the NF-kappaB pathway by varicella-zoster virus in vitro and in human epidermal cells in vivo. - PubMed
The immune response to latent herpesvirus infections was compared in human trigeminal ganglia (TG) and dorsal root ganglia (DRG) of 15 dead individuals. Dendritic cells (DC) are essential for inducing antiviral immune responses; however, the contribution of DC subsets to immune control during natural cutaneous VZV infection has not been investigated. One critical difference is the VZV ORF66 kinase targeting of the major regulatory VZV IE62 protein to control its nuclear import and assembly into the VZV virion, which is so far unprecedented in the alphaherpesviruses. gEΔ27-90, which lacks the gE domain that interacts with a putative receptor insulin-degrading enzyme (IDE), replicated as extensively as rOka, producing infectious virions and significant cytopathic effects within 14 days of inoculation. Satellite cell infection and polykaryon formation in neuron-satellite cell complexes provide mechanisms to amplify VZV entry into neuronal cell bodies, which is necessary for VZV transfer to skin in the affected dermatome during herpes zoster. In a process that was dependent upon the presence of infectious VZV, these proteins rapidly became sequestered in the cytoplasm of VZV-infected cells. NLRP3 was also expressed extensively in infected skin xenografts in the severe combined immunodeficiency mouse model of VZV pathogenesis in vivo.

IkappaBalpha levels did not diminish even though the protein became phosphorylated and ubiquitinated, as determined based on detection of the characteristic high-molecular-weight form of the protein, and the 26S proteasome remained functional in VZV-infected cells. VZV infection also inhibited the characteristic degradation of IkappaBalpha that is induced by exposure of fibroblasts to tumor necrosis factor alpha. First, these results show that during natural infection, both dual infection of cells and superinfection inhibition can co-occur at the cellular level. We suggest that VZV has evolved a mechanism to limit host cell antiviral defenses by sequestering NF-kappaB proteins in the cytoplasm, a strategy that appears to be unique among the herpesviruses.

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