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.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.
Highlights
Human cytomegalovirus (HCMV) is a b-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 innate and adaptive immunity, and host cell biology, for example, the cell cycle and apoptosis [1]
The importance of herpesviruses is evident by their prevalence in the human population and the diverse range of diseases that they provoke
Summary
Human cytomegalovirus (HCMV) is a b-herpesvirus that infects healthy individuals, usually asymptomatically, but can cause severe or fatal disease in immunocompromised individuals. The induction of the interleukin-8 (IL-8) during HCMV infection is important for viral replication and possibly contributes to the efficient dissemination of the virus by neutrophils [2,3]. Interleukin-8 is a pro-inflammatory chemokine that attracts primarily neutrophils, and monocytes and cytotoxic T cells, by interacting with the CXC chemokine receptors CXCR1 and CXCR2 [4]. Expression of IL-8 is low or absent under normal conditions, it is highly inducible by a wide range of extracellular stimuli, such as the pro-inflammatory cytokine IL-1, the tumor necrosis factor alpha (TNFa) [5], bacteria and viruses [6,7]. Activation of IL-8 expression in the majority of cell types is critically controlled by the NF-kB transcription factor. The AP-1 and NF-IL-6 transcription factors may contribute to optimal IL-8 activation, depending on the stimulus or the cell type [4]
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