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

Date Published: September 12, 2013

Publisher: Public Library of Science

Author(s): Helena Costa, Rute Nascimento, John Sinclair, Robert Michael Evans Parkhouse, William J. Britt.

http://doi.org/10.1371/journal.ppat.1003609

Abstract

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.

Partial Text

Human cytomegalovirus (HCMV) is a β-herpesvirus that infects healthy individuals, usually asymptomatically, but can cause severe or fatal disease in immunocompromised individuals. Primary HCMV infection, as with other herpesviruses, is followed by establishment of lifelong latency with periodic reactivation and, in order to successfully establish itself in the host, the virus has evolved a broad range of host evasion strategies, modulating not only innate and adaptive immunity, but also host cell biology, for example, the cell cycle and apoptosis [1].

The UL24 gene family is one of the approximately 40 core genes that are conserved in all three herpesviruses subfamilies and the only one which still has no assigned function [13]. Previously, functional assays demonstrated that all homologues of UL24 gene family induce cell cycle arrest [18], [19]. This work identifies another, and at first sight, apparently unrelated function of the UL24 homologue from HCMV (UL76), the induction of the expression of IL-8. Further exploration of the mechanism, however, suggests that both activities may result from viral activation of the DNA Damage response.

 

Source:

http://doi.org/10.1371/journal.ppat.1003609

 

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