title: cGAS-STING Signaling Regulates Initial Innate Control of Cytomegalovirus Infection.
abstract: Several innate sensing pathways contribute to the control of early cytomegalovirus (CMV) infection, leading to a multiphasic type I interferon (IFN-I) response that limits viral replication and promotes host defenses. Toll-like receptor (TLR)-dependent pathways induce IFN-I production in CMV-infected plasmacytoid dendritic cells; however, the initial burst of IFN-I that occurs within the first few hours in vivo is TLR independent and emanates from stromal cells. Here we show that primary human endothelial cells mount robust IFN-I responses to human CMV that are dependent upon cyclic GMP-AMP synthase (cGAS), STING, and interferon regulatory factor 3 (IRF3) signaling. Disruption of STING expression in endothelial cells by clustered regularly interspaced short palindromic repeat (CRISPR)-Cas9 revealed that it is essential for the induction of IFN-I and restriction of CMV replication. Consistently, STING was necessary to mount the first phase of IFN-I production and curb CMV replication in infected mice. Thus, DNA sensing through STING is critical for primary detection of both human and mouse CMV in nonhematopoietic cells and drives the initial wave of IFN-I that is key for controlling early viral replicationin vivo.
  
  
  
  Cytomegalovirus (CMV) is one of the most common viral pathogens, with the majority of people contracting the virus in their lifetime. Although acute infection is mostly asymptomatic in healthy persons, significant pathology is observed in immunocompromised individuals, and chronic CMV infection may exacerbate a myriad of inflammatory conditions. Here we show that primary human endothelial cells mount robust IFN-I responses against CMV via a cGAS/STING/IRF3 pathway. Disruption of STING expression by CRISPRs revealed an essential role in eliciting IFN-I responses and restricting CMV replication. Consistently, in mice, STING is necessary for the first phase of IFN-I production that limits early CMV replication. Our results demonstrate a pivotal role for the cGAS-STING pathway in the initial detection of CMV infection.
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Chan-Wang J
authors.identifier: 0000-0003-3876-6741
authors.initials: CW
authors.lastname: Lio
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Bryan
authors.initials: B
authors.lastname: McDonald
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Mariko
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Rekha
authors.initials: R
authors.lastname: Dhanwani
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Nikita
authors.initials: N
authors.lastname: Sharma
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Huang
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA Functional Genomics Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Pham
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Chris A
authors.initials: CA
authors.lastname: Benedict
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA Functional Genomics Center, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA soniasharma@lji.org.
authors.forename: Sonia
authors.initials: S
authors.lastname: Sharma
mesh_terms: D000818:Animals; D003586:Cytomegalovirus Infections / Q000276:immunology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000276:immunology* / Q000821:virology*; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D007113:Immunity, Innate; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D007370:Interferon Type I / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009713:Nucleotidyltransferases / Q000378:metabolism*; D015398:Signal Transduction; D000099197:STING Protein; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase
chemical_list: D050838:Interferon Regulatory Factor-3; D007370:Interferon Type I; D008565:Membrane Proteins; D009713:Nucleotidyltransferases; C494232:IRF3 protein, human; C532857:STING1 protein, human; D000099197:STING Protein; C578390:cGAS protein, human; D000099235:Cyclic Guanosine Monophosphate-Adenosine Monophosphate Synthase