TLR9 Contributes to Antiviral Immunity during Gammaherpesvirus Infection

Institute of Molecular Immunology, Clinical Cooperation Group Hematopoietic Cell Transplantation, GSF-National Research Center for Environment and Health, Munich, Germany.
The Journal of Immunology (Impact Factor: 4.92). 02/2008; 180(1):438-43. DOI: 10.4049/jimmunol.180.1.438
Source: PubMed


The human gammaherpesviruses Kaposi's sarcoma-associated herpesvirus and EBV cause important infections. As pathogenetic studies of the human infections are restricted, murine gammaherpesvirus 68 serves as a model to study gammaherpesvirus pathogenesis. TLRs are a conserved family of receptors detecting microbial molecular patterns. Among the TLRs, TLR9 recognizes unmethylated CpG DNA motifs present in bacterial and viral DNA. The aim of this study was to assess the role of TLR9 in gammaherpesvirus pathogenesis. Upon stimulation with murine gammaherpesvirus 68, Flt3L-cultured bone marrow cells (dendritic cells) from TLR9-/- mice secreted reduced levels of IL-12, IFN-alpha, and IL-6, when compared with dendritic cells from wild-type mice. Intranasal infection of TLR9-/- and wild-type mice did not reveal any differences during lytic and latent infection. In contrast, when infected i.p., TLR9-/- mice showed markedly higher viral loads both during lytic and latent infection. Thus, we show for the first time that TLR9 is involved in gammaherpesvirus pathogenesis and contributes to organ-specific immunity.

Full-text preview

Available from:
  • Source
    • "TLR9 is a type of pathogen-associated molecular patterns (PAMPs) present in eukaryotic cells that recognizes unmethylated CpG sequences in viral and bacterial DNA, and interaction between TLR9 and the microbial ligand leads eventually to Th1-biased cellular and humoral immunity [50]. In mice, TLR9 is known to contribute to antiviral and antibacterial immunity, and TLR9 deletion can cause enhanced gammaherpesvirus pathogenesis and Gram-negative bacterial pneumonia [51], [52]. Myd88 is a universal adapter protein in the signaling pathways of almost all TLRs, including TLR9. "
    [Show abstract] [Hide abstract]
    ABSTRACT: NK-lysin is an antimicrobial protein produced by cytotoxic T lymphocytes and natural killer cells. In this study, we examined the biological property of a peptide, NKLP27, derived from tongue sole (Cynoglossus semilaevis) NK-lysin. NKLP27 is composed of 27 amino acids and shares little sequence identity with known NK-lysin peptides. NKLP27 possesses bactericidal activity against both Gram-negative and Gram-positive bacteria including common aquaculture pathogens. The bactericidal activity of NKLP27 was dependent on the C-terminal five residues, deletion of which dramatically reduced the activity of NKLP27. During its interaction with the target bacterial cells, NKLP27 destroyed cell membrane integrity, penetrated into the cytoplasm, and induced degradation of genomic DNA. In vivo study showed that administration of tongue sole with NKLP27 before bacterial and viral infection significantly reduced pathogen dissemination and replication in tissues. Further study revealed that fish administered with NKLP27 exhibited significantly upregulated expression of the immune genes including those that are known to be involved in antibacterial and antiviral defense. These results indicate that NKLP27 is a novel antimicrobial against bacterial and viral pathogens, and that the observed effect of NKLP27 on bacterial DNA and host gene expression adds new insights to the action mechanism of fish antimicrobial peptides.
    Full-text · Article · Sep 2014 · PLoS ONE
  • Source
    • "However, controversial findings have been reported indicating that CD40 ligation can restrain the growth of EBV-transformed LCLs by switching the viral transcription program from the full lymphoblastoid to a more limited latency program (Pokrovskaja et al. 2002). Full activation of B cells infected with EBV also can be triggered endogenously by direct recognition of EBV related pathogen associated molecular pattern (PAMP) via TLR2 (Gaudreault et al. 2007), TLR7 (Martin et al. 2007) and TLR9 (Guggemoos et al. 2008; Gargano et al. 2009), under physiological conditions, or exogenously by other microbial components at the sites of EBV infection (Stenfors and Raisanen 1993; Iskra et al. 2010). Recently, it has been shown that triggering TLR9 and probably other components of the innate immune system inhibits switch of latent EBV infection to lytic replication and promotes EBV-driven B cell transformation and tumor development (Ladell et al. 2007). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Infection of human B cells with Epstein-Barr virus (EBV) induces polyclonal activation in almost all infected cells, but a small proportion of infected cells are transformed to immortalized lymphoblastoid cell lines. Since B cells are activated also by CD40 ligand (CD40L) and Toll-like receptor (TLR) agonists via a similar signaling pathway, it is likely that costimulation through these molecules could result in synergistic enhancement of the transformation efficiency of EBV. In this study, the stimulatory effect of TLR7/8 (R848), TLR9 (CpG) agonists and/or CD40L on transformation efficiency of EBV in normal human B cells was assessed using the limiting dilution assay. Costimulation of peripheral blood mononuclear cells (PBMCs) with CpG and R848, but not CD40L, increased significantly the frequency of EBV transformed B cells (p < 0.001). Neither synergistic nor additive effects were observed between TLR agonists and CD40L and also TLR7/8 and TLR9 agonists. Costimulation with R848, CpG and CD40L enhanced the proliferative response of B cells infected with EBV. This effect was more evident when enriched B cells were employed, compared to PBMCs. The promoting effect of TLR agonists stimulation, implies that EBV may take advantage of the genes induced by the TLR stimulation pathway for viral latency and oncogenesis.
    Full-text · Article · Feb 2013 · Cytotechnology
  • Source
    • "Innate immune receptors could recognize various non-self, pathogen-associated molecular patterns of the viruses [48]. Toll-like receptors (TLR) 2, 3, 7 and 9 likely have important roles in recognizing and activating responses to both CMV [49-54] and EBV [55-59]. Additionally, the protein DAI (ZBP1), and the AIM2 inflammasome are crucial sensors of viral double-stranded DNA in defense against CMV infection [48,60-63]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Progression of joint damage despite appropriate therapy remains a significant problem for patients with rheumatoid arthritis (RA). This study was undertaken to identify profiles of immune response that correlate with radiographic joint damage as a first step toward the discovery of new pathogenic mechanisms of joint destruction in RA. The study included 58 patients with RA and 15 healthy controls. The profiles of cytokine release from peripheral blood mononuclear cells (PBMC) in response to stimulation for 48 hours with one of six stimuli, or in media alone, were measured. Immune response profiles identified for each stimulus were correlated with radiographic joint damage as defined by the Sharp-van der Heijde score (SHS), before and after multivariable adjustment. For profiles correlated with the SHS, the distributions of individual cytokines were evaluated in patients according to the severity of joint damage and compared to healthy controls. The immune response profile for cytomegalovirus (CMV)/Epstein-Barr virus (EBV) stimulation was correlated with both the SHS total and erosion scores (r = 0.31, P = 0.018 and r = 0.33, P = 0.011, respectively). After adjusting for age, sex, disease duration, autoantibody status, CMV/EBV serological status, current disease activity, disability and treatments, the correlation of the CMV/EBV immune response and the SHS erosion score became stronger (r = 0.43, P < 0.003). The CMV/EBV immune response correlated with CMV IgG (r = 0.44, P < 0.001), but not with EBV IgG. The most important cytokines for the CMV/EBV immune response profile were IFN-γ, IL-2, IL-4, IL-5, IL-13 and IL-17A, all of which are associated with T-cell immunity. Both the summary immune response score and the individual responses of IFN-γ and IL-13 to CMV/EBV stimulation were associated with greater joint damage. A profile of immune response to purified CMV/EBV lysates is associated with radiographic joint damage. The correlation of this immune response to CMV serology implies possible involvement of latent CMV infection. Therefore, the findings suggest that the immune response to latent CMV infection could play a fundamental role in the progression of inflammation and structural joint damage in patients with RA.
    Full-text · Article · Jan 2012 · Arthritis research & therapy
Show more