title: Human cytomegalovirus infection is sensitive to the host cell DNA methylation state and alters global DNA methylation capacity.
abstract: Human Cytomegalovirus (HCMV) is a ubiquitous herpesvirus that infects and establishes latency in the majority of the human population and may cause fatal infections in immunocompromised patients. Recent data implies a close interaction between HCMV encoded proteins and cellular epigenetic mechanisms such as histone acetylation and deacetylation. In this study, we investigated the interactions between HCMV infection and the DNA methylation machinery in different host cells using several approaches. We found that colon cancer cell line HCT-116 lacking the DNMT1 and DNMT3b methyltransferases was susceptible to HCMV-AD169 infection, while wild-type cells were non-susceptible. Treatment of wild-type HCT-116 cells with 5-azacytidine rendered them susceptible to infection. Further investigation of HCMV infected MRC-5 fibroblasts demonstrated significant global hypomethylation, a phenomenon that was virus strain-specific and associated with the re-localization of DNMT1 and DNMT3b from the nucleus to the cytoplasm. The cytoplasmic accumulation of DNMT1 was also evident in in vitro infected macrophages and in epithelial cells in tissue samples from patients with inflammatory bowel disease and concomitant HCMV infection. Foscavir treatment of virus infected fibroblasts did not affect the majority of the virus induced nuclear exclusion of DNMT1, which suggest that it is dependent on viral IE gene products. In conclusion, HCMV infection results in profound effects on the host cell DNA methylation machinery and is associated with inflammation in vivo. Our results improve the understanding of cytomegalovirus pathogenesis and open the search for new antiviral therapy targets. These findings may also contribute to the further understanding of mechanisms involved in DNA methylation abnormalities in physiological and pathological conditions.
authors.affiliation: Department of Clinical Neuroscience; Karolinska Institutet; Stockholm, Sweden.
authors.forename: Atosa
authors.initials: A
authors.lastname: Esteki-Zadeh
authors.forename: Mohsen
authors.initials: M
authors.lastname: Karimi
authors.forename: Klas
authors.initials: K
authors.lastname: Strååt
authors.forename: Ole
authors.initials: O
authors.lastname: Ammerpohl
authors.forename: Manuel
authors.initials: M
authors.lastname: Zeitelhofer
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
authors.forename: Marjan
authors.initials: M
authors.lastname: Mehrab-Mohseni
authors.forename: Louise
authors.initials: L
authors.lastname: Sjöholm
authors.forename: Afsar
authors.initials: A
authors.lastname: Rahbar
authors.forename: Cecilia
authors.initials: C
authors.lastname: Söderberg-Nauclér
authors.forename: Tomas J
authors.initials: TJ
authors.lastname: Ekström
mesh_terms: D002460:Cell Line; D003587:Cytomegalovirus / Q000378:metabolism / Q000472:pathogenicity / Q000502:physiology*; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism*; D019175:DNA Methylation; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D045325:HCT116 Cells; D006801:Humans; D037521:Virulence Factors / Q000378:metabolism; D000097584:DNA Methyltransferase 3B
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D037521:Virulence Factors; D000097584:DNA Methyltransferase 3B; C000619380:DNMT1 protein, human