2.50
Hdl Handle:
http://hdl.handle.net/10033/605276
Title:
cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells.
Authors:
Paijo, Jennifer; Döring, Marius; Spanier, Julia; Grabski, Elena; Nooruzzaman, Mohammed; Schmidt, Tobias; Witte, Gregor; Messerle, Martin; Hornung, Veit; Kaever, Volkhard; Kalinke, Ulrich ( 0000-0003-0503-9564 )
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.
Affiliation:
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.
Citation:
cGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells. 2016, 12 (4):e1005546 PLoS Pathog.
Journal:
PLoS pathogens
Issue Date:
Apr-2016
URI:
http://hdl.handle.net/10033/605276
DOI:
10.1371/journal.ppat.1005546
PubMed ID:
27058035
Type:
Article
Language:
en
ISSN:
1553-7374
Appears in Collections:
publications of the department of experimental infection research ([TC] EXPI)

Full metadata record

DC FieldValue Language
dc.contributor.authorPaijo, Jenniferen
dc.contributor.authorDöring, Mariusen
dc.contributor.authorSpanier, Juliaen
dc.contributor.authorGrabski, Elenaen
dc.contributor.authorNooruzzaman, Mohammeden
dc.contributor.authorSchmidt, Tobiasen
dc.contributor.authorWitte, Gregoren
dc.contributor.authorMesserle, Martinen
dc.contributor.authorHornung, Veiten
dc.contributor.authorKaever, Volkharden
dc.contributor.authorKalinke, Ulrichen
dc.date.accessioned2016-04-14T13:34:34Zen
dc.date.available2016-04-14T13:34:34Zen
dc.date.issued2016-04en
dc.identifier.citationcGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells. 2016, 12 (4):e1005546 PLoS Pathog.en
dc.identifier.issn1553-7374en
dc.identifier.pmid27058035en
dc.identifier.doi10.1371/journal.ppat.1005546en
dc.identifier.urihttp://hdl.handle.net/10033/605276en
dc.description.abstractHuman 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.en
dc.language.isoenen
dc.titlecGAS Senses Human Cytomegalovirus and Induces Type I Interferon Responses in Human Monocyte-Derived Cells.en
dc.typeArticleen
dc.contributor.departmentTWINCORE, Centre for Experimental and Clinical Infection Research, a joint venture between the Helmholtz Centre for Infection Research and the Hannover Medical School, Hannover, Germany.en
dc.identifier.journalPLoS pathogensen

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