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,...
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| Language: | English |
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Public Library of Science (PLoS)
2013-09-01
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| Series: | PLoS Pathogens |
| Online Access: | https://doi.org/10.1371/journal.ppat.1003609 |
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| author | Helena Costa Rute Nascimento John Sinclair Robert Michael Evans Parkhouse |
| author_facet | Helena Costa Rute Nascimento John Sinclair Robert Michael Evans Parkhouse |
| author_sort | Helena Costa |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-1526ed9d69794d19b948030effb6069a |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2013-09-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Pathogens |
| spelling | doaj-art-1526ed9d69794d19b948030effb6069a2025-08-20T03:46:43ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-09-0199e100360910.1371/journal.ppat.1003609Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response.Helena CostaRute NascimentoJohn SinclairRobert Michael Evans ParkhouseHuman 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.https://doi.org/10.1371/journal.ppat.1003609 |
| spellingShingle | Helena Costa Rute Nascimento John Sinclair Robert Michael Evans Parkhouse Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response. PLoS Pathogens |
| title | Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response. |
| title_full | Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response. |
| title_fullStr | Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response. |
| title_full_unstemmed | Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response. |
| title_short | Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response. |
| title_sort | human cytomegalovirus gene ul76 induces il 8 expression through activation of the dna damage response |
| url | https://doi.org/10.1371/journal.ppat.1003609 |
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