The Role of Nitric Oxide in Bacterial Meningitis in Children

Kornelisse, René F.; Hoekman, K.; Visser, John; Hop, W. C. J.; Huijmans, J. G. M.; Straaten, P. J. C. Van Der; Heijden, Albert J. van der; Sukhai, R. N.; Neijens, H. J.; Groot, R de

doi:10.1093/infdis/174.1.120

Cited by 84 publications

(44 citation statements)

References 43 publications

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“…53). NOS2 induction, and the subsequent generation of NO, in particular, were argued to contribute to pathology in S. pneumoniae BM (55,87). We found that induction of mRNA for NOS2, but not COX2, was strongly diminished in infected IFN-g gene-deficient animals at both 48 and 72 h p.i.…”

Section: Discussionmentioning

confidence: 69%

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Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

Mitchell

Yau

McQuillan

et al. 2012

The Journal of Immunology

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The pathology associated with Streptococcus pneumoniae meningitis results largely from activation of immune-associated pathways. We systematically investigated the production of IFN subtypes, as well as their influence on pathology, in a mouse model of S. pneumoniae meningitis. Despite the occurrence of a mixed IFN type I/II gene signature, no evidence for production or involvement of type I IFNs in disease progression was found. In contrast, type II IFN (IFN-γ) was strongly induced, and IFN-γ−/− mice were significantly protected from severe disease. Using intracellular cytokine staining and targeted cell-depletion approaches, NK cells were found to be the dominant source of IFN-γ. Furthermore, production of IFN-γ was found to be dependent upon ASC and IL-18, indicating that an ASC-dependent inflammasome pathway was responsible for mediating IFN-γ induction. The influence of IFN-γ gene deletion on a range of processes known to be involved in bacterial meningitis pathogenesis was examined. Although neutrophil numbers in the brain were similar in infected wild-type and IFN-γ−/− mice, both monocyte recruitment and CCL2 production were less in infected IFN-γ−/− mice compared with infected wild-type controls. Additionally, gene expression of NO synthase was strongly diminished in infected IFN-γ−/− mice compared with infected controls. Finally, bacterial clearance was enhanced in IFN-γ−/− mice, although the underlying mechanism remains unclear. Together, these data suggest that inflammasome-dependent IFN-γ contributes via multiple pathways to pathology during S. pneumoniae meningitis.

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Section: Discussionmentioning

confidence: 69%

“…53). In particular, IFN-g induces NO synthase-2 (NOS2) (54), and increased NO production secondary to NOS2 induction was argued to contribute to pathology during pneumococcal meningitis (55).…”

mentioning

confidence: 99%

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

Mitchell

Yau

McQuillan

et al. 2012

The Journal of Immunology

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“…It has been demonstrated that TNF-␣ can initiate meningeal inflammation (7), resulting in breach of the blood-brain barrier leading to brain edema and increased intracranial pressure (2); and it plays a critical role in neuronal apoptosis in the hippocampus (57). Nitrite levels are usually significantly elevated in CSF of patients with bacterial meningitis and in experimental meningitis (34,58). Inhibition of iNOS has been shown to attenuate alteration of the blood-brain barrier permeability and meningeal inflammation (58).…”

Section: Discussionmentioning

confidence: 99%

Intracisternally Localized Bacterial DNA Containing CpG Motifs Induces Meningitis

Deng

Liu

Tarkowski

2001

The Journal of Immunology

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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.

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“…Once in the subarachnoid space, where the principal humoral and cellular host defense mechanisms are absent (432,555), meningococci proliferate uncontrolled (57). The evolving endotoxin liberation elicits compartmentalized (i.e., confined to the subarachnoid space) activation of proinflammatory cytokines such as TNF, IL-1, IL-6, IL-8, nitric oxide, monocyte colony-stimulating factor, and platelet-activating factor and anti-inflammatory cytokines such as IL-1Ra, IL-10, IL-12, TNFsR-p55, TNFsR-p75, and IL-1sR type II (IL-1sRII) (12,57,192,264,295,429,498,502,517,(519)(520)(521). Among these, TNF and IL-1 enhance the permeability of the blood-brain barrier and promote the influx of neutrophils by upregulation of adherence molecules (258,374,377,428).…”

Section: Pathophysiology Of Meningococcal Meningitismentioning

confidence: 99%

Update on Meningococcal Disease with Emphasis on Pathogenesis and Clinical Management

Deuren¹,

Brandtzæg²,

Meer³

2000

Clinical Microbiology Reviews

398

236

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The Role of Nitric Oxide in Bacterial Meningitis in Children

Cited by 84 publications

References 43 publications

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

Inflammasome-Dependent IFN-γ Drives Pathogenesis inStreptococcus pneumoniaeMeningitis

Intracisternally Localized Bacterial DNA Containing CpG Motifs Induces Meningitis

Update on Meningococcal Disease with Emphasis on Pathogenesis and Clinical Management

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