title: The periodontal pathogen Porphyromonas gingivalis induces the Epstein-Barr virus lytic switch transactivator ZEBRA by histone modification.
abstract: Epstein-Barr virus (EBV) is a ubiquitous human herpesvirus that usually results in latent infection of B cells. The EBV BZLF1 gene product ZEBRA is a master regulator of the transition from latency to the lytic replication cycle. In the latent state, hypoacetylation of histone proteins in the BZLF1 promoter by histone deacetylases (HDACs) is primarily involved in maintaining EBV latency. Although the mechanism that regulates the switch between latency and lytic replication has been a central research focus in EBV infection, the causal link between HDAC inhibition and the disruption of viral latency is not well understood. Periodontal disease is a complex chronic inflammatory disease caused by subgingival infection with oral anaerobic bacteria, typically Porphyromonas gingivalis. Periodontal disease occurs worldwide and is among the most prevalent microbial diseases in humans. In this study, we examined the biological effect of P. gingivalis infection on EBV reactivation and found that P. gingivalis induced expression of ZEBRA. This activity was associated with supernatant from bacterial culture, but not with other bacterial components such as lipopolysaccharide or fimbriae. We demonstrated that culture supernatant from P. gingivalis, which contained high concentrations of butyric acid, inhibited HDACs, thus increasing histone acetylation and the transcriptional activity of the BZLF1 gene. Chromatin immunoprecipitation assays revealed that HDACs were present in the BZLF1 promoter during latent state and that they were dissociated from the promoter concomitantly with the association of acetylated histone H3, upon stimulation by culture supernatant from P. gingivalis. Thus, P. gingivalis induced EBV reactivation via chromatin modification, and butyric acid-a bacterial metabolite-was responsible for this effect. These findings suggest that periodontal disease is a risk factor for EBV reactivation in infected individuals and might therefore contribute to progression of EBV-related diseases.
authors.affiliation: Department of Microbiology, Division of Immunology and Pathobiology, Dental Research Center, Nihon University School of Dentistry, 1-8-13 Kanda-Surugadai, Chiyoda-ku, Tokyo 102-8310, Japan. imai-k@dent.nihon-u.ac.jp
authors.forename: Kenichi
authors.initials: K
authors.lastname: Imai
authors.forename: Harumi
authors.initials: H
authors.lastname: Inoue
authors.forename: Muneaki
authors.initials: M
authors.lastname: Tamura
authors.forename: Marni E
authors.initials: ME
authors.lastname: Cueno
authors.forename: Hiroko
authors.initials: H
authors.lastname: Inoue
authors.forename: Osamu
authors.initials: O
authors.lastname: Takeichi
authors.forename: Kaoru
authors.initials: K
authors.lastname: Kusama
authors.forename: Ichiro
authors.initials: I
authors.lastname: Saito
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Ochiai
mesh_terms: D020148:Butyric Acid / Q000378:metabolism; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D016966:Porphyromonas gingivalis / Q000378:metabolism* / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015534:Trans-Activators / Q000378:metabolism*; D014764:Viral Proteins / Q000378:metabolism*
chemical_list: D006657:Histones; D015534:Trans-Activators; D014764:Viral Proteins; D020148:Butyric Acid; D006655:Histone Deacetylases