title: Cytomegalovirus enhances macrophage TLR expression and MyD88-mediated signal transduction to potentiate inducible inflammatory responses.
abstract: Circulating monocytes carrying human CMV (HCMV) migrate into tissues, where they differentiate into HCMV-infected resident macrophages that upon interaction with bacterial products may potentiate tissue inflammation. In this study, we investigated the mechanism by which HCMV promotes macrophage-orchestrated inflammation using a clinical isolate of HCMV (TR) and macrophages derived from primary human monocytes. HCMV infection of the macrophages, which was associated with viral DNA replication, significantly enhanced TNF-α, IL-6, and IL-8 gene expression and protein production in response to TLR4 ligand (LPS) stimulation compared with mock-infected LPS-stimulated macrophages during a 6-d in vitro infection. HCMV infection also potentiated TLR5 ligand-stimulated cytokine production. To elucidate the mechanism by which HCMV infection potentiated inducible macrophage responses, we show that infection by HCMV promoted the maintenance of surface CD14 and TLR4 and TLR5, which declined over time in mock-infected macrophages, and enhanced both the intracellular expression of adaptor protein MyD88 and the inducible phosphorylation of IκBα and NF-κB. These findings provide additional information toward elucidating the mechanism by which HCMV potentiates bacteria-induced NF-κB-mediated macrophage inflammatory responses, thereby enhancing organ inflammation in HCMV-infected tissues.
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Veterans Affairs Medical Center, Birmingham, AL 35233; pdsmith@uab.edu lesmy@uab.edu.
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Smith
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Masako
authors.initials: M
authors.lastname: Shimamura
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Lois C
authors.initials: LC
authors.lastname: Musgrove
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Evida A
authors.initials: EA
authors.lastname: Dennis
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Diane
authors.initials: D
authors.lastname: Bimczok
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294; and.
authors.forename: Lea
authors.initials: L
authors.lastname: Novak
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: Mary
authors.initials: M
authors.lastname: Ballestas
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA 95616.
authors.forename: Anne
authors.initials: A
authors.lastname: Fenton
authors.affiliation: Department of Medical Microbiology and Immunology, University of California, Davis, Davis, CA 95616.
authors.forename: Satya
authors.initials: S
authors.lastname: Dandekar
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Alabama at Birmingham, Birmingham, AL 35294;
authors.forename: William J
authors.initials: WJ
authors.lastname: Britt
authors.affiliation: Division of Gastroenterology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294; and pdsmith@uab.edu lesmy@uab.edu.
authors.forename: Lesley E
authors.initials: LE
authors.lastname: Smythies
mesh_terms: D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D006801:Humans; D018836:Inflammation Mediators / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology* / Q000821:virology; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology; D051198:Toll-Like Receptor 5 / Q000276:immunology; D014779:Virus Replication
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D051197:Toll-Like Receptor 4; D051198:Toll-Like Receptor 5