title: Primary macrophages rely on histone deacetylase 1 and 2 expression to induce type I interferon in response to gammaherpesvirus infection.
abstract: Type I interferon is induced shortly following viral infection and represents a first line of host defense against a majority of viral pathogens. Not surprisingly, both replication and latency of gammaherpesviruses, ubiquitous cancer-associated pathogens, are attenuated by type I interferon, although the mechanism of attenuation remains poorly characterized. Gammaherpesviruses also target histone deacetylases (HDACs), a family of pleiotropic enzymes that modify gene expression and several cell signaling pathways. Specifically, we have previously shown that a conserved gammaherpesvirus protein kinase interacts with HDAC1 and -2 to promote gammaherpesvirus replication in primary macrophages. In the current study, we have used genetic approaches to show that expression of HDAC1 and -2 is critical for induction of a type I interferon response following gammaherpesvirus infection of primary macrophages. Specifically, expression of HDAC1 and -2 was required for phosphorylation of interferon regulatory factor 3 (IRF3) and accumulation of IRF3 at the beta interferon promoter in gammaherpesvirus-infected primary macrophages. To our knowledge, this is the first demonstration of a specific role for HDAC1 and -2 in the induction of type I interferon responses in primary immune cells following virus infection. Furthermore, because HDAC1 and -2 are overexpressed in several types of cancer, our findings illuminate potential side effects of HDAC1- and -2-specific inhibitors that are currently under development as cancer therapy agents. IMPORTANCE Gammaherpesviruses establish chronic infection in a majority of the adult population and are associated with several malignancies. Infected cells counteract gammaherpesvirus infection via innate immune signaling mediated primarily through type I interferon. The induction of type I interferon expression proceeds through several stages using molecular mechanisms that are still incompletely characterized. In this study, we show that expression of HDAC1 and -2 by macrophages is required to mount a type I interferon response to incoming gammaherpesvirus. The involvement of HDAC1 and -2 in the type I interferon response highlights the pleiotropic roles of these enzymes in cellular signaling. Interestingly, HDAC1 and -2 are deregulated in cancer and are attractive targets of new cancer therapies. Due to the ubiquitous and chronic nature of gammaherpesvirus infection, the role of HDAC1 and -2 in the induction of type I interferon responses should be considered during the clinical development of HDAC1- and -2-specific inhibitors.
authors: Microbiology and Molecular Genetics, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
authors: Bryan C
authors: BC
authors: Mounce
authors: Wadzanai P
authors: WP
authors: Mboko
authors: Adam J
authors: AJ
authors: Kanack
authors: Vera L
authors: VL
authors: Tarakanova
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D018142:Gammaherpesvirinae; D006566:Herpesviridae Infections / Q000276:immunology*; D056284:Histone Deacetylase 1 / Q000378:metabolism*; D056464:Histone Deacetylase 2 / Q000378:metabolism*; D050838:Interferon Regulatory Factor-3 / Q000276:immunology / Q000378:metabolism; D007370:Interferon Type I / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010766:Phosphorylation; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2