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

Costa, Helena; Nascimento, Rute; Sinclair, John; Parkhouse, Robert Michael Evans

Publication

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

2013-09-12Journal article

dc.contributor.author	Costa, Helena
dc.contributor.author	Nascimento, Rute
dc.contributor.author	Sinclair, John
dc.contributor.author	Parkhouse, Robert Michael Evans
dc.date.accessioned	2015-10-26T16:30:42Z
dc.date.available	2015-10-26T16:30:42Z
dc.date.issued	2013-09-12
dc.description.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.	pt_PT
dc.description.sponsorship	FCT fellowship: (SFRH/BD/27677/2006).	pt_PT
dc.identifier	10.1371/journal.ppat.1003609
dc.identifier.citation	Costa H, Nascimento R, Sinclair J, Parkhouse RME (2013) Human Cytomegalovirus Gene UL76 Induces IL-8 Expression through Activation of the DNA Damage Response. PLoS Pathog 9(9): e1003609. doi:10.1371/journal.ppat.1003609	pt_PT
dc.identifier.doi	10.1371/journal.ppat.1003609
dc.identifier.uri	http://hdl.handle.net/10400.7/444
dc.language.iso	eng	pt_PT
dc.peerreviewed	yes	pt_PT
dc.publisher	PLOS	pt_PT
dc.relation	Mechanism and consequences of an IL-8 inducing herpesvirus gene
dc.relation.publisherversion	http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1003609	pt_PT
dc.rights.uri	http://creativecommons.org/licenses/by/4.0/	pt_PT
dc.subject	Humans	pt_PT
dc.subject	Cytomegalovirus	pt_PT
dc.subject	Genes, Reporter	pt_PT
dc.subject	DNA Damage	pt_PT
dc.title	Human Cytomegalovirus Gene UL76 Induces IL-8 Expression through Activation of the DNA Damage Response	pt_PT
dc.type	journal article
dspace.entity.type	Publication
oaire.awardTitle	Mechanism and consequences of an IL-8 inducing herpesvirus gene
oaire.awardURI	info:eu-repo/grantAgreement/FCT/3599-PPCDT/PTDC%2FSAU-MIC%2F110316%2F2009/PT
oaire.citation.endPage	10	pt_PT
oaire.citation.issue	9	pt_PT
oaire.citation.startPage	1	pt_PT
oaire.citation.title	Plos Pathogens	pt_PT
oaire.citation.volume	9	pt_PT
oaire.fundingStream	3599-PPCDT
project.funder.identifier	http://doi.org/10.13039/501100001871
project.funder.name	Fundação para a Ciência e a Tecnologia
rcaap.rights	openAccess	pt_PT
rcaap.type	article	pt_PT
relation.isProjectOfPublication	f3b11a73-f520-4f58-980c-1dca3567b25f
relation.isProjectOfPublication.latestForDiscovery	f3b11a73-f520-4f58-980c-1dca3567b25f