title: cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells.
abstract: Human cytomegalovirus (HCMV) infections of healthy individuals are mostly unnoticed and result in viral latency. However, HCMV can also cause devastating disease, e.g., upon reactivation in immunocompromised patients. Yet, little is known about human immune cell sensing of DNA-encoded HCMV. Recent studies indicated that during viral infection the cyclic GMP/AMP synthase (cGAS) senses cytosolic DNA and catalyzes formation of the cyclic di-nucleotide cGAMP, which triggers stimulator of interferon genes (STING) and thus induces antiviral type I interferon (IFN-I) responses. We found that plasmacytoid dendritic cells (pDC) as well as monocyte-derived DC and macrophages constitutively expressed cGAS and STING. HCMV infection further induced cGAS, whereas STING expression was only moderately affected. Although pDC expressed particularly high levels of cGAS, and the cGAS/STING axis was functional down-stream of STING, as indicated by IFN-I induction upon synthetic cGAMP treatment, pDC were not susceptible to HCMV infection and mounted IFN-I responses in a TLR9-dependent manner. Conversely, HCMV infected monocyte-derived cells synthesized abundant cGAMP levels that preceded IFN-I production and that correlated with the extent of infection. CRISPR/Cas9- or siRNA-mediated cGAS ablation in monocytic THP-1 cells and primary monocyte-derived cells, respectively, impeded induction of IFN-I responses following HCMV infection. Thus, cGAS is a key sensor of HCMV for IFN-I induction in primary human monocyte-derived DC and macrophages.
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Paijo
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
authors.forename: Marius
authors.initials: M
authors.lastname: Döring
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Spanier
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
authors.forename: Elena
authors.initials: E
authors.lastname: Grabski
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
authors.forename: Mohammed
authors.initials: M
authors.lastname: Nooruzzaman
authors.affiliation: Institute for Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Schmidt
authors.affiliation: Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Gregor
authors.initials: G
authors.lastname: Witte
authors.affiliation: Institute of Virology, Hannover Medical School, Hannover, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Messerle
authors.affiliation: Institute for Molecular Medicine, University Hospital, University of Bonn, Bonn, Germany.|Gene Center and Department of Biochemistry, Ludwig-Maximilians-Universität München, Munich, Germany.
authors.forename: Veit
authors.initials: V
authors.lastname: Hornung
authors.affiliation: Research Core Unit Metabolomics, Hannover Medical School, Hannover, Germany.
authors.forename: Volkhard
authors.initials: V
authors.lastname: Kaever
authors.affiliation: Institute for Experimental Infection Research, TWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Kalinke
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003586:Cytomegalovirus Infections / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007370:Interferon Type I / Q000096:biosynthesis* / Q000276:immunology; D009000:Monocytes / Q000276:immunology* / Q000821:virology*; D009713:Nucleotidyltransferases / Q000276:immunology*; D034741:RNA, Small Interfering; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053719:Tandem Mass Spectrometry; D014162:Transfection; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D007370:Interferon Type I; D009713:Nucleotidyltransferases; D034741:RNA, Small Interfering; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase