Dual Phases of Apoptosis in Pneumococcal Meningitis

Mitchell, Lauren; Smith, S.A.; Braun, Johann; Herzog, Karl-Heinz; Weber, Joerg R.; Tuomanen, Elaine

doi:10.1086/425520

Cited by 81 publications

(73 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Studies of neuronal apoptosis induction in vivo by bacterial cell wall components have not previously been published. Earlier studies using viable pneumococci have argued that neuronal damage during meningitis is the combined effect of bacterial toxins and the inflammatory host response (13,28,29). Our present findings show that stimulation of the TLR2 pathway alone induces neuronal apoptosis in vivo.…”

Section: Discussionsupporting

confidence: 62%

“…In pneumococcal meningitis, at least two distinct pathways leading to neuronal loss have been demonstrated: live pneumococci induce an early caspase-3-independent, AIF-dependent wave of apoptosis, while later, the release of bacterial cell wall components leads to a different type of cell death involving release of cytochrome c, formation of the apoptosome, and ultimately activation of caspase-3 (21,24,28,29,41). It has been argued that induction of apoptosis by bacterial cell wall components occurs secondary to the activation of immune competent host cells (28). In vitro, bacterial cell wall components induce cell death in organotypical slices and in neuronal/glial coculture, but not in primary neurons cultured alone, and NO release from activated glia has been suggested as the relevant cytotoxic principle (42).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

TLR2 Mediates Neuroinflammation and Neuronal Damage

Hoffmann¹,

Braun²,

Becker³

et al. 2007

The Journal of Immunology

127

107

View full text Add to dashboard Cite

Innate immunity relies on pattern recognition receptors to detect the presence of infectious pathogens. In the case of Gram-positive bacteria, binding of bacterial lipopeptides to TLR2 is currently regarded as an important mechanism. In the present study, we used the synthetic bacterial lipopeptide Pam3CysSK4, a selective TLR2 agonist, to induce meningeal inflammation in rodents. In a 6-h rat model, intrathecal application of Pam3CysSK4 caused influx of leukocytes into the cerebrospinal fluid (CSF) and induced a marked increase of regional cerebral blood flow and intracranial pressure. In wild-type mice, we observed CSF pleocytosis and an increased number of apoptotic neurons in the dentate gyrus 24 h after intrathecal challenge. Inflammation and associated neuronal loss were absent in TLR2 knockout mice. In purified neurons, cytotoxicity of Pam3CysSK4 itself was not observed. Exposure of microglia to Pam3CysSK4 induced neurotoxic properties in the supernatant of wild-type, but not TLR2-deficient microglia. We conclude that TLR2-mediated signaling is sufficient to induce the host-dependent key features of acute bacterial meningitis. Therefore, synthetic lipopeptides are a highly specific tool to study mechanisms of TLR2-driven neurodegeneration in vivo.

show abstract

Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

TLR2 Mediates Neuroinflammation and Neuronal Damage

Hoffmann¹,

Braun²,

Becker³

et al. 2007

The Journal of Immunology

127

107

View full text Add to dashboard Cite

show abstract

“…Significant injury during bacterial meningitis arises from mechanisms of neuronal apoptosis, particularly in the hippocampus; in autopsies cases of bacterial meningitis were found apoptosis of neurons in the dentate gyrus 58 . Apoptosis can involve both the caspasedependent and the caspase-independent pathway 59 . The caspase-independent pathway is triggered by the pneumolysin and H 2 O 2 that are produced by S. pneumoniae.…”

Section: Neuronal Damage and Targets For Adjunctive Therapymentioning

confidence: 99%

“…The caspase-independent pathway is triggered by the pneumolysin and H 2 O 2 that are produced by S. pneumoniae. The actions of these toxins result in an increase in ROS and calcium, resulting in mitochondrial dysfunction that leads to the release of apoptosis-inducing factor into the cytosol 56,59 . However, the caspase-dependent pathway occurs later, and pneumococcal cell-wall components trigger the required host inflammatory response from the leukocytes.…”

Section: Neuronal Damage and Targets For Adjunctive Therapymentioning

confidence: 99%

Pathophysiology of acute meningitis caused by Streptococcus pneumoniae and adjunctive therapy approaches

Barichello

Generoso

Collodel

et al. 2012

Arq. Neuro-Psiquiatr.

View full text Add to dashboard Cite

Pneumococcal meningitis is a life-threatening disease characterized by an acute purulent infection affecting piamater, arachnoid and the subarachnoid space. The intense inflammatory host's response is potentially fatal and contributes to the neurological sequelae. Streptococcus pneumoniae colonizes the nasopharynx, followed by bacteremia, microbial invasion and blood-brain barrier traversal. S. pneumoniae is recognized by antigen-presenting cells through the binding of Toll-like receptors inducing the activation of factor nuclear kappa B or mitogen-activated protein kinase pathways and subsequent up-regulation of lymphocyte populations and expression of numerous proteins involved in inflammation and immune response. Many brain cells can produce cytokines, chemokines and others pro-inflammatory molecules in response to bacteria stimuli, as consequence, polymorphonuclear are attracted, activated and released in large amounts of superoxide anion and nitric oxide, leading to the peroxynitrite formation, generating oxidative stress. This cascade leads to lipid peroxidation, mitochondrial damage, blood-brain barrier breakdown contributing to cell injury during pneumococcal meningitis.

show abstract

“…Evidence in animal models of meningitis suggests that significant neuronal injury arises from more than classical apoptosis alone (15). In experimental meningitis, inhibition of caspase activity only reduces the number of apoptotic neurons in the dentate gyrus of the hippocampus by about 50% (16).…”

Section: Introductionmentioning

confidence: 99%

Bacterial programmed cell death of cerebral endothelial cells involves dual death pathways

Bermpohl¹,

Halle²,

Freyer³

et al. 2005

J. Clin. Invest.

View full text Add to dashboard Cite

Major barriers separating the blood from tissue compartments in the body are composed of endothelial cells. Interaction of bacteria with such barriers defines the course of invasive infections, and meningitis has served as a model system to study endothelial cell injury. Here we report the impressive ability of Streptococcus pneumoniae, clinically one of the most important pathogens, to induce 2 morphologically distinct forms of programmed cell death (PCD) in brain-derived endothelial cells. Pneumococci and the major cytotoxins H 2 0 2 and pneumolysin induce apoptosis-like PCD independent of TLR2 and TLR4. On the other hand, pneumococcal cell wall, a major proinflammatory component, causes caspase-driven classical apoptosis that is mediated through TLR2. These findings broaden the scope of bacterial-induced PCD, link these effects to innate immune TLRs, and provide insight into the acute and persistent phases of damage during meningitis.

show abstract

Dual Phases of Apoptosis in Pneumococcal Meningitis

Cited by 81 publications

References 34 publications

TLR2 Mediates Neuroinflammation and Neuronal Damage

TLR2 Mediates Neuroinflammation and Neuronal Damage

Pathophysiology of acute meningitis caused by Streptococcus pneumoniae and adjunctive therapy approaches

Bacterial programmed cell death of cerebral endothelial cells involves dual death pathways

Contact Info

Product

Resources

About