Intracisternally Localized Bacterial DNA Containing CpG Motifs Induces Meningitis

Abstract

Unmethylated CpG motifs are frequently found in bacterial DNA, and have recently been shown to exert immunostimulatory effects on leukocytes. Since bacterial infections in the CNS will lead to local release of prokaryotic DNA, we wanted to investigate whether such an event might trigger meningitis. To that end, we have intracisternally injected mice and rats with bacterial DNA and oligonucleotides containing CpG motifs. Histopathological signs of meningitis were evident within 12 h and lasted for at least 14 days, and were characterized by an influx of monocytic, Mac-3+ cells and by a lack of T lymphocytes. To study the mechanisms whereby unmethylated CpG DNA gives rise to meningitis, we deleted the monocyte/macrophage population leading to abrogation of brain inflammation. Also, interaction with NF-κB using antisense technology led to down-regulation of proinflammatory cytokine production and frequency of meningitis. Furthermore, specific interactions with vascular selectin expression and inhibition of NO synthase led to a significant amelioration of meningitis, altogether indicating that this condition is dependent on macrophages and their products. In contrast, neutrophils, NK cells, T/B lymphocytes, IL-12, and complement system were not instrumental in meningitis triggered by bacterial DNA containing CpG motifs. This study proves that bacterial DNA containing unmethylated CpG motifs induces meningitis, and indicates that this condition is mediated in vivo by activated macrophages.

Bacterial CpG-DNA Aggravates Immune Complex Glomerulonephritis

“…We therefore hypothesized that CpG-DNA would aggravate a preexisting immune complex GN, a hypothesis confirmed by our results. The worsening of glomerular damage was associated with marked macrophage infiltration, a finding also noted by others using CpG-ODN in various disease models (23)(24)(25). Further analysis revealed, as a novel mechanism, that CpG-DNA-TLR9 interaction induced chemokine and chemokine receptor expression in macrophages.…”

Signaling Danger

“…TLR activation may therefore play a major role during septic shock, systemic inflammatory response syndromes, and local immune responses (8,(82)(83)(84)(85)(86)(87)(88)(89)(90). In macrophages, the expression of CCchemokines and CC-chemokine receptors by TLR9 activation may contribute to additional leukocyte infiltration to the site of injury as it has been observed in several disease models, including GN (87)(88)(89)(90).…”

Stimulation of the Secretion of Pro‐Inflammatory Cytokines by Bifidobacterium Strains

“…Furthermore, animal studies have indicated that the cell wall from different strains of B. adolescentis caused different pro-inflammatory responses because of the differences in the component of peptidoglycan (22). Besides differences in cell wall components, unmethylated CpG motifs frequently found in bacterial DNA have recently been shown to exert immunostimulatory effects on leukocytes through interaction with the toll-like receptor on the surfaces of leukocytes (4). These motifs are present in varying amounts in different bacterial species and strains and may be another explanation for the observed differences in immune stimulation by the tested bifidobacteria.…”