title: Transplant-induced reactivation of murine cytomegalovirus immediate early gene expression is associated with recruitment of NF-κB and AP-1 to the major immediate early promoter.
abstract: Reactivation of latent human cytomegalovirus is a significant infectious complication of organ transplantation and current therapies target viral replication once reactivation of latent virus has already occurred. The specific molecular pathways that activate viral gene expression in response to transplantation are not well understood. Our studies aim to identify these factors, with the goal of developing novel therapies that prevent transcriptional reactivation in transplant recipients. Murine cytomegalovirus (MCMV) is a valuable model for studying latency and reactivation of CMV in vivo. We previously demonstrated that transplantation of MCMV-latently infected kidneys into allogeneic recipients induces reactivation of immediate early (IE) gene expression and epigenetic reprogramming of the major immediate early promoter (MIEP) within 48 h. We hypothesize that these events are mediated by activation of signalling pathways that lead to binding of transcription factors to the MIEP, including AP-1 and NF-κB. Here we show that transplantation induces rapid activation of several members of the AP-1 and NF-κB transcription factor family and we demonstrate that canonical NF-κB (p65/p50), the junD component of AP-1, and nucleosome remodelling complexes are recruited to the MIEP following transplantation. Proteomic analysis of recipient plasma and transcriptome analysis of kidney RNA identified five extracellular ligands, including TNF, IL-1β, IL-18, CD40L and IL-6, and three intracellular signalling pathways associated with reactivation of IE gene expression. Identification of the factors that mediate activation of these signalling pathways may eventually lead to new therapies to prevent reactivation of CMV and its sequelae.
authors.affiliation: Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Xue-Feng
authors.initials: XF
authors.lastname: Liu
authors.affiliation: Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Chunfa
authors.initials: C
authors.lastname: Jie
authors.affiliation: Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Shixian
authors.initials: S
authors.lastname: Yan
authors.affiliation: Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Jiao-Jing
authors.initials: JJ
authors.lastname: Wang
authors.affiliation: Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Xueqiong
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, LaJolla, CA, USA.
authors.forename: Sunil
authors.initials: S
authors.lastname: Kurian
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, LaJolla, CA, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Salomon
authors.affiliation: Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Abecassis
authors.affiliation: Department of Microbiology and Immunology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.|Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Hummel
mesh_terms: D000818:Animals; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D005260:Female; D005786:Gene Expression Regulation / Q000276:immunology; D006566:Herpesviridae Infections / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D054884:Host-Pathogen Interactions; D017874:Immediate-Early Proteins / Q000235:genetics* / Q000276:immunology; D020382:Interleukin-18 / Q000235:genetics / Q000276:immunology; D053583:Interleukin-1beta / Q000235:genetics / Q000276:immunology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D016030:Kidney Transplantation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018146:Muromegalovirus / Q000235:genetics* / Q000276:immunology; D016328:NF-kappa B / Q000235:genetics* / Q000276:immunology; D009707:Nucleosomes / Q000235:genetics / Q000276:immunology; D011401:Promoter Regions, Genetic; D020543:Proteome / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000276:immunology; D014184:Transplantation, Homologous; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology; D014763:Viral Matrix Proteins / Q000235:genetics / Q000276:immunology; D014775:Virus Activation; D017735:Virus Latency
chemical_list: D017874:Immediate-Early Proteins; D020382:Interleukin-18; D053583:Interleukin-1beta; D015850:Interleukin-6; D016328:NF-kappa B; D009707:Nucleosomes; D020543:Proteome; D018808:Transcription Factor AP-1; D014409:Tumor Necrosis Factor-alpha; D014763:Viral Matrix Proteins; C577686:interleukin-6, mouse; D023201:CD40 Ligand