Journal
JOURNAL OF VIROLOGY
Volume 80, Issue 11, Pages 5588-5598Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.00060-06
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Funding
- NIAID NIH HHS [AI 059335, R01 AI035602, AI 35602, AI 21640, R01 AI021640] Funding Source: Medline
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Viral infection is associated with a vigorous inflammatory response characterized by cellular infiltration and release of the proinflammatory cytokines interleukin-1 (IL-1) and tumor necrosis factor alpha (TNF-alpha). In the present study, we identified a novel function of human cytomegalovirus (HCMV) that results in inhibition of IL-1 and TNF-alpha signaling pathways. The effect on these pathways was limited to cells infected with the virus, occurred at late times of infection, and was independent of cell type or virus strain. IL-1 and TNF-alpha signaling pathways converge at a point upstream of NF-kappa B activation and involve phosphoryllation and degradation of the NF-kappa B inhibitory molecule I kappa B alpha. The HCMV inhibition of IL-1 and TNF-alpha pathways corresponded to a suppression of NF-KB activation. Analysis of I kappa B alpha phosphorylation and degradation suggested that HCMV induced two independent blocks in NF-KB activation, which occurred upstream from the point of convergence of the IL-1 and TNF-alpha pathways. We believe that the ability of HCMV to inhibit these two major proinflammatory pathways reveals a critical aspect of HCMV biology, with possible importance for immune evasion, as well as establishment of infection in cell types persistently infected by this virus.
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