Authors: Atosa Esteki-Zadeh, Mohsen Karimi, Klas Strååt, Ole Ammerpohl, Manuel Zeitelhofer, Maja Jagodic, Marjan Mehrab-Mohseni, Louise Sjöholm, Afsar Rahbar, Cecilia Söderberg-Nauclér and Tomas J. Ekström

Atosa Esteki-Zadeh

Department of Clinical Neuroscience; Karolinska Institutet; Stockholm, Sweden
These authors contributed equally to this work.

Mohsen Karimi

Department of Clinical Neuroscience; Karolinska Institutet; Stockholm, Sweden; Department of Molecular Medicine and Surgery; Karolinska Institutet; Stockholm, Sweden
These authors contributed equally to this work.

Klas Strååt

Department of Medicine, Karolinska Institutet; Stockholm, Sweden

Ole Ammerpohl

Institute for Human Genetics; University Hospital Schleswig-Holstein; Kiel, Germany

Manuel Zeitelhofer

Department of Clinical Neuroscience; Karolinska Institutet; Stockholm, Sweden

Maja Jagodic

Department of Clinical Neuroscience; Karolinska Institutet; Stockholm, Sweden

Marjan Mehrab-Mohseni

Department of Clinical Neuroscience; Karolinska Institutet; Stockholm, Sweden

Louise Sjöholm

Department of Clinical Neuroscience; Karolinska Institutet; Stockholm, Sweden

Afsar Rahbar

Department of Medicine, Karolinska Institutet; Stockholm, Sweden

Cecilia Söderberg-Nauclér

Department of Medicine, Karolinska Institutet; Stockholm, Sweden
These authors share senior authorship.

Tomas J. Ekström

Corresponding author: tomas.ekstrom@ki.se
Department of Clinical Neuroscience; Karolinska Institutet; Stockholm, Sweden
These authors share senior authorship.

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.

Received: June 23, 2011; Accepted: March 20, 2012

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