Human Cytomegalovirus Gene UL76 Induces IL-8 Expression through Activation of the DNA Damage Response

Human cytomegalovirus (hcmv),a β-herpesvirus,has evolved many strategies to subvert both innate and adaptive host immunity in order to ensure its survival and propagation within the host. induction of il-8 is particularly important during hcmv infection as neutrophils,primarily attracted by il-8,play a key role in virus dissemination. moreover,il-8 has a positive effect in the replication of hcmv. this work has identified an hcmv gene (ul76),with the relevant property of inducing il-8 expression at both transcriptional and protein levels. up-regulation of il-8 by ul76 results from activation of the nf-kb pathway as inhibition of both ikk-β activity or degradation of ikβα abolishes the il-8 induction and,concomitantly,expression of ul76 is associated with the translocation of p65 to the nucleus where it binds to the il-8 promoter. furthermore,the ul76-mediated induction of il-8 requires atm and is correlated with the phosphorylation of nemo on serine 85,indicating that ul76 activates nf-kb pathway by the dna damage response,similar to the impact of genotoxic drugs. more importantly,a ul76 deletion mutant virus was significantly less efficient in stimulating il-8 production than the wild type virus. in addition,there was a significant reduction of il-8 secretion when atm -/- cells were infected with wild type hcmv,thus,indicating that atm is also involved in the induction of il-8 by hcmv.in conclusion,we demonstrate that expression of ul76 gene induces il-8 expression as a result of the dna damage response and that both ul76 and atm have a role in the mechanism of il-8 induction during hcmv infection. hence,this work characterizes a new role of the activation of dna damage response in the context of host-pathogen interactions. © 2013 costa et al.