Reprogramming the Host Response in Bacterial Meningitis: How Best To Improve Outcome?

Flier, Michiel van der; Geelen, Sibyl P. M.; Kimpen, Jan L. L.; Hoepelman, I. M.; Tuomanen, Elaine

doi:10.1128/cmr.16.3.415-429.2003

Cited by 75 publications

(52 citation statements)

References 180 publications

(191 reference statements)

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“…Along with other cells, BMEC can produce pro-inflammatory cytokines as a result of stimulation by other cytokines (e.g. TNF-, IL-1 ) [7,40] or direct interaction with microbial pathogens [7,39]. The present study demonstrates for the first time that H. parasuis induces the production of IL-8 and IL-6 by PBMEC.…”

Section: Discussionmentioning

confidence: 53%

Interactions ofHaemophilus parasuisand its LOS with porcine brain microvascular endothelial cells

et al. 2008

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-Haemophilus parasuis is a swine pathogen that causes Glässer's disease, which is characterized by polyserositis and meningitis. The pathogenesis of the H. parasuis infection is poorly understood. To cause meningitis, H. parasuis has to cross the blood-brain barrier (BBB) to gain access to the central nervous system (CNS). We recently showed that H. parasuis adheres to and invades porcine brain microvascular endothelial cells (PBMEC). The aim of this study was to evaluate the role of H. parasuis lipooligosaccharide (LOS) in the adhesion to PBMEC and to determine if H. parasuis (and/or its LOS) is able to induce apoptosis and activation of PBMEC. Results showed that adhesion of H. parasuis to PBMEC was partially mediated by LOS. Moreover, H. parasuis induces caspase-3-mediated apoptosis of PBMEC in a time -and dosedependent manner, but its LOS did not seem to be involved in such a process. Furthermore, H. parasuis and, to a lesser extent, its LOS, was able to induce the release of IL-8 and IL-6 by PBMEC. Field strains of H. parasuis serotypes 4 and 5 induced similar levels of these inflammatory mediators. Our data suggest that H. parasuis uses cellular adhesion, induction of apoptosis and up-regulation of inflammatory mediators as mechanisms to invade the CNS via the BBB, and that LOS would play a certain but limited role in such pathological process. Haemophilus parasuis / LOS / endothelial cells / BBB / meningitis

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Section: Discussionmentioning

confidence: 53%

Interactions ofHaemophilus parasuisand its LOS with porcine brain microvascular endothelial cells

et al. 2008

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“…In this regard, the propensity of certain viruses, such as respiratory syncytial virus, to induce an anti-apoptotic program in mammalian cells (15,40,54) may explain the association between certain respiratory viral infections and pneumococcal disease in humans. Finally, our results raise the possibility that interference with the action of certain TLRs or the inhibition of apoptosis by specific caspase inhibitors may increase susceptibility to specific bacterial infections and thus have deleterious effects on the host (59).…”

Section: Discussionmentioning

confidence: 99%

The Apoptotic Response to Pneumolysin Is Toll-Like Receptor 4 Dependent and Protects against Pneumococcal Disease

et al. 2005

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Pneumolysin, the cholesterol-dependent cytolysin of Streptococcus pneumoniae, induces inflammatory and apoptotic events in mammalian cells. Toll-like receptor 4 (TLR4) confers resistance to pneumococcal infection via its interaction with pneumolysin, but the underlying mechanisms remain to be identified. In the present study, we found that pneumolysin-induced apoptosis is also mediated by TLR4 and confers protection against invasive disease. The interaction between TLR4 and pneumolysin is direct and specific; ligand-binding studies demonstrated that pneumolysin binds to TLR4 but not to TLR2. Involvement of TLR4 in pneumolysin-induced apoptosis was demonstrated in several complementary experiments. First, macrophages from wild-type mice were significantly more prone to pneumolysin-induced apoptosis than cells from TLR4-defective mice. In gain-of-function experiments, we found that epithelial cells expressing TLR4 and stimulated with pneumolysin were more likely to undergo apoptosis than cells expressing TLR2. A specific TLR4 antagonist, B1287, reduced pneumolysin-mediated apoptosis in wild-type cells. This apoptotic response was also partially caspase dependent as preincubation of cells with the pan-caspase inhibitor zVAD-fmk reduced pneumolysin-induced apoptosis. Finally, in a mouse model of pneumococcal infection, pneumolysin-producing pneumococci elicited significantly more upper respiratory tract cell apoptosis in wild-type mice than in TLR4-defective mice, and blocking apoptosis by administration of zVAD-fmk to wild-type mice resulted in a significant increase in mortality following nasopharyngeal pneumococcal exposure. Overall, our results strongly suggest that protection against pneumococcal disease is dependent on the TLR4-mediated enhancement of pneumolysin-induced apoptosis.

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“…Experimental data in meningitis caused by Streptococcus pneumoniae -the most frequent and disastrous pathogen in meningitis -suggest that bacterial toxins, such as the pore-forming pneumolysin or hydrogen peroxide, mediate approximately 50% of the neuronal cell loss while the remaining neuronal damage is driven by host immune responses (25)(26)(27). In the context of antibiotic therapy, it is highly desirable to limit the inflammatory process in order to prevent such acute and chronic complications (28).…”

Section: Introductionmentioning

confidence: 99%

TRAIL limits excessive host immune responses in bacterial meningitis

Hoffmann

Priller²,

Prozorovski³

et al. 2007

J. Clin. Invest.

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Apart from potential roles in anti-tumor surveillance, the TNF-related apoptosis-inducing ligand (TRAIL) has important regulatory functions in the host immune response. We studied antiinflammatory effects of endogenous and recombinant TRAIL (rTRAIL) in experimental meningitis. Following intrathecal application of pneumococcal cell wall, a TLR2 ligand, we found prolonged inflammation, augmented clinical impairment, and increased apoptosis in the hippocampus of TRAIL -/-mice. Administration of rTRAIL into the subarachnoid space of TRAIL -/-mice or reconstitution of hematopoiesis with wild-type bone marrow cells reversed these effects, suggesting an autoregulatory role of TRAIL within the infiltrating leukocyte population. Importantly, intrathecal application of rTRAIL in wild-type mice with meningitis also decreased inflammation and apoptosis. Moreover, patients suffering from bacterial meningitis showed increased intrathecal synthesis of TRAIL.Our findings provide what we believe is the first evidence that TRAIL may act as a negative regulator of acute CNS inflammation. The ability of TRAIL to modify inflammatory responses and to reduce neuronal cell death in meningitis suggests that it may be used as a novel antiinflammatory agent in invasive infections.

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Reprogramming the Host Response in Bacterial Meningitis: How Best To Improve Outcome?

Cited by 75 publications

References 180 publications

Interactions ofHaemophilus parasuisand its LOS with porcine brain microvascular endothelial cells

Interactions ofHaemophilus parasuisand its LOS with porcine brain microvascular endothelial cells

The Apoptotic Response to Pneumolysin Is Toll-Like Receptor 4 Dependent and Protects against Pneumococcal Disease

TRAIL limits excessive host immune responses in bacterial meningitis

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