RESUMO
The Epstein-Barr virus (EBV) establishes persistent latent infection in peripheral blood memory B cells, may cause infectious mononucleosis, and is associated with cancers including endemic Burkitt's lymphoma (BL). Although latent EBV transforms B cells in vitro, additional factors including immunocompromised status or, as in endemic BL, a co-infection with the malaria parasite Plasmodium falciparum seem to be required for the development of EBV-associated cancers. Toll-like receptors (TLRs) like TLR9 are capable to recognize EBV and launch innate immune responses, which may limit the spread of the virus and may contribute to control outgrowth of latently EBV-infected B cells. On the other hand, EBV may interfere with the expression and functionality of TLR9, thereby manipulating host immune responses towards favoring long-term survival of the virus. Triggering of TLR9 by bacterial, viral or P. falciparum DNA may impact on the proliferation of EBV-infected B cells and on the balance between latent and lytic EBV. Thus, TLR9 signaling in EBV-infected B cells may be beneficial for the host but also for the highly adapted human gammaherpesvirus EBV.
Assuntos
Infecções por Vírus Epstein-Barr/fisiopatologia , Receptor Toll-Like 9/fisiologia , Herpesvirus Humano 4/isolamento & purificação , HumanosRESUMO
Toll-like receptors (TLRs) are key receptors of the innate immune system and show cell subset-specific expression. We investigated the messenger RNA (mRNA) expression of TLR genes in human haematopoietic stem cells (HSC), in naïve B cells, in memory B cells, in plasma cells from palatine tonsils and in plasma cells from peripheral blood. HSC and plasma cells showed unrestricted expression of TLR1-TLR9, in contrast to B cells which lacked TLR3, TLR4 and TLR8 but expressed mRNA of all other TLRs. We demonstrated, for the first time, that TLR triggering of terminally differentiated plasma cells augments immunoglobulin production. Thus, boosting the immediate antibody response by plasma cells upon pathogen recognition may point to a novel role of TLRs.
Assuntos
Imunoglobulinas/biossíntese , Plasmócitos/imunologia , Receptores Toll-Like/biossíntese , Linfócitos B/imunologia , Diferenciação Celular/imunologia , Células Cultivadas , Regulação da Expressão Gênica/imunologia , Células-Tronco Hematopoéticas/imunologia , Humanos , Imunoglobulina G/biossíntese , Imunoglobulina M/biossíntese , Memória Imunológica/imunologia , RNA Mensageiro/genética , Receptores Toll-Like/genética , Receptores Toll-Like/imunologiaRESUMO
The B-lymphotropic Epstein-Barr virus (EBV) encodes two isoforms of latent membrane protein 2 (LMP2), LMP2A and LMP2B, which are expressed during latency in B cells. The function of LMP2B is largely unknown, whereas LMP2A blocks B-cell receptor (BCR) signaling transduction and induction of lytic EBV infection, thereby promoting B-cell survival. Transfection experiments on LMP2B in EBV-negative B cells and the silencing of LMP2B in EBV-harboring Burkitt's lymphoma-derived Akata cells suggest that LMP2B interferes with the function of LMP2A, but the role of LMP2B in the presence of functional EBV has not been established. Here, LMP2B, LMP2A, or both were overexpressed in EBV-harboring Akata cells to study the function of LMP2B. The overexpression of LMP2B increased the magnitude of EBV switching from its latent to its lytic form upon BCR cross-linking, as indicated by a more-enhanced upregulation and expression of EBV lytic genes and significantly increased production of transforming EBV compared to Akata vector control cells or LMP2A-overexpressing cells. Moreover, LMP2B lowered the degree of BCR cross-linking required to induce lytic EBV infection. Finally, LMP2B colocalized with LMP2A as demonstrated by immunoprecipitation and immunofluorescence and restored calcium mobilization upon BCR cross-linking, a signaling process inhibited by LMP2A. Thus, our findings suggest that LMP2B negatively regulates the function of LMP2A in preventing the switch from latent to lytic EBV replication.
Assuntos
Herpesvirus Humano 4/fisiologia , Proteínas da Matriz Viral/metabolismo , Ativação Viral , Cálcio/metabolismo , Linhagem Celular Tumoral , Humanos , Proteínas da Matriz Viral/genética , Latência ViralRESUMO
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.
