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.

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    • "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. "
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    • "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). "
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    • "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]. "
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