Immune activation suppresses initiation of lytic Epstein-Barr virus infection.
Primary infection with Epstein-Barr virus (EBV) is asymptomatic in children with immature immune systems but may manifest as infectious mononucleosis, a vigorous immune activation, in adolescents or adults with mature immune systems. Infectious mononucleosis and chronic immune activation are linked to increased risk for EBV-associated lymphoma. Here we show that EBV initiates progressive lytic infection by expression of BZLF-1 and the late lytic genes gp85 and gp350/220 in cord blood mononuclear cells (CBMC) but not in peripheral blood mononuclear cells (PBMC) from EBV-naive adults after EBV infection ex vivo. Lower levels of proinflammatory cytokines in CBMC, used to model a state of minimal immune activation and immature immunity, than in PBMC were associated with lytic EBV infection. Triggering the innate immunity specifically via Toll-like receptor-9 of B cells substantially suppressed BZLF-1 mRNA expression in acute EBV infection ex vivo and in anti-IgG-stimulated chronically latently EBV-infected Akata Burkitt lymphoma cells. This was mediated in part by IL-12 and IFN-gamma. These results identify immune activation as critical factor for the suppression of initiation of lytic EBV infection. We hypothesize that immune activation contributes to EBV-associated lymphomagenesis by suppressing lytic EBV and in turn promotes latent EBV with transformation potential.
Ladell
Kristin
K
Laboratory for Experimental Infectious Diseases and Cancer Research of the Division of Infectious Diseases, University Children's Hospital of Zurich, 8032 Zurich, Switzerland.
Dorner
Marcus
M
Zauner
Ludwig
L
Berger
Christoph
C
Zucol
Franziska
F
Bernasconi
Michele
M
Niggli
Felix K
FK
Speck
Roberto F
RF
Nadal
David
D
D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism / Q000821:virology; D002051:Burkitt Lymphoma / Q000473:pathology; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D020031:Epstein-Barr Virus Infections / Q000276:immunology* / Q000821:virology; D005312:Fetal Blood / Q000166:cytology; D015967:Gene Expression Regulation, Viral; D004854:Herpesvirus 4, Human / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D007113:Immunity, Innate; D007963:Leukocytes, Mononuclear / Q000378:metabolism / Q000821:virology; D012333:RNA, Messenger / Q000096:biosynthesis; D051217:Toll-Like Receptor 9 / Q000502:physiology; D015534:Trans-Activators / Q000096:biosynthesis / Q000235:genetics; D014759:Viral Envelope Proteins / Q000378:metabolism; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics; D014779:Virus Replication
C063676:BZLF1 protein, Herpesvirus 4, Human; D016207:Cytokines; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; C495371:TLR9 protein, human; D051217:Toll-Like Receptor 9; D015534:Trans-Activators; D014759:Viral Envelope Proteins; D014764:Viral Proteins