A Toll-like receptor recognizes bacterial DNA

Abstract

DNA from bacteria has stimulatory effects on mammalian immune cells, which depend on the presence of unmethylated CpG dinucleotides in the bacterial DNA. In contrast, mammalian DNA has a low frequency of CpG dinucleotides, and these are mostly methylated; therefore, mammalian DNA does not have immuno-stimulatory activity. CpG DNA induces a strong T-helper-1-like inflammatory response. Accumulating evidence has revealed the therapeutic potential of CpG DNA as adjuvants for vaccination strategies for cancer, allergy and infectious diseases. Despite its promising clinical use, the molecular mechanism by which CpG DNA activates immune cells remains unclear. Here we show that cellular response to CpG DNA is mediated by a Toll-like receptor, TLR9. TLR9-deficient (TLR9-/-) mice did not show any response to CpG DNA, including proliferation of splenocytes, inflammatory cytokine production from macrophages and maturation of dendritic cells. TLR9-/- mice showed resistance to the lethal effect of CpG DNA without any elevation of serum pro-inflammatory cytokine levels. The in vivo CpG-DNA-mediated T-helper type-1 response was also abolished in TLR9-/- mice. Thus, vertebrate immune systems appear to have evolved a specific Toll-like receptor that distinguishes bacterial DNA from self-DNA.

NF-κB and the immune response

“…TLR9 recognizes bacterial DNA containing unmethylated CpG motifs, and TLR9-deficient mice are not responsive to CpG DNA challenge (Hemmi et al, 2000). The low frequency and high rate of methylation of CpG motifs prevent recognition of mammalian DNA by TLR9 under physiological circumstances.…”

Recognition of Staphylococcus aureus-derived peptidoglycan (PGN) but not intact bacteria is mediated by CD14 in microglia

“…Although studies have established that TLR2 is required for cellular responses to S. aureus (Akira and Hemmi, 2003;Kaisho and Akira, 2002), recent evidence has revealed that DNA can influence cellular activation by engaging the intracellular PRR TLR9 (Athman and Philpott, 2004;Dziarski, 2003;Hemmi et al, 2000). Intact S. aureus presents microglia with a complex milieu of antigens including DNA containing non-methylated CpG motifs, the only known bacterial ligand of TLR9, suggesting that S. aureus may induce immunological responses through this receptor.…”

A STING-activating nanovaccine for cancer immunotherapy

“…Conventional PEG- b -poly(D, L-lactic acid) (PEG-PLA) micelles had a weak response (4.2%) 9 . OVA-PC7A NP induced approximately 20-fold higher CTL response over OVA-Alum (4.3%) or OVA-LPS that stimulates the TLR4 pathway (3.7%) 10 , and 3.6-fold higher than OVA-CpG that stimulates the TLR9 pathway (23%) 11 . OVA-specific antibody responses from the sera of immunized mice showed that mice vaccinated with PC7A NP generated similar titers of OVA-specific IgG1 response comparable to those by Alum or LPS (Fig.…”