Varicella-zoster virus modulates NF-kappaB recruitment on selected cellular promoters.
Intercellular adhesion molecule 1 (ICAM-1) expression is down-regulated in the center of cutaneous varicella lesions despite the expression of proinflammatory cytokines such as gamma interferon and tumor necrosis factor alpha (TNF-alpha). To study the molecular basis of this down-regulation, the ICAM-1 induction of TNF-alpha was analyzed in varicella-zoster virus (VZV)-infected melanoma cells (MeWo), leading to the following observations: (i) VZV inhibits the stimulation of icam-1 mRNA synthesis; (ii) despite VZV-induced nuclear translocation of p65, p52, and c-Rel, p50 does not translocate in response to TNF-alpha; (iii) the nuclear p65 present in VZV-infected cells is no longer associated with p50 and is unable to bind the proximal NF-kappaB site of the icam-1 promoter, despite an increased acetylation and accessibility of the promoter in response to TNF-alpha; and (iv) VZV induces the nuclear accumulation of the NF-kappaB inhibitor p100. VZV also inhibits icam-1 stimulation of TNF-alpha by strongly reducing NF-kappaB nuclear translocation in MRC5 fibroblasts. Taken together, these data show that VZV interferes with several aspects of the immune response by inhibiting NF-kappaB binding and the expression of target genes. Targeting NF-kappaB activation, which plays a central role in innate and adaptive immune responses, leads to obvious advantages for the virus, particularly in melanocytes, which are a site of viral replication in the skin.
El Mjiyad
Nadia
N
GIGA-Research, Virology and Immunology Unit, GIGA B34, University of Liège, B-4000 Liège, Belgium.
Bontems
Sébastien
S
Gloire
Geoffrey
G
Horion
Julie
J
Vandevenne
Patricia
P
Dejardin
Emmanuel
E
Piette
Jacques
J
Sadzot-Delvaux
Catherine
C
D002460:Cell Line; D002467:Cell Nucleus / Q000737:chemistry; D005786:Gene Expression Regulation; D014645:Herpesvirus 3, Human / Q000276:immunology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000096:biosynthesis / Q000235:genetics; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000032:analysis; D052003:NF-kappa B p52 Subunit / Q000032:analysis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012333:RNA, Messenger / Q000096:biosynthesis; D051996:Transcription Factor RelA / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology
D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; D052003:NF-kappa B p52 Subunit; C489548:NFKB1 protein, human; D012333:RNA, Messenger; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1