Clinical outcome in pneumococcal meningitis correlates with CSF lipoteichoic acid concentrations

Schneider, Olaf; Michel, Uwe; Zysk, Gregor; Dubuis, Olivier; Nau, Roland

doi:10.1212/wnl.53.7.1584

Cited by 70 publications

(58 citation statements)

References 11 publications

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“…Several studies have shown that LTA can be released from actively growing streptococci in vitro (48 -51), and it has also been shown that individuals infected with streptococci can have LTA levels that exceed the concentrations we have used in this study, in cerebrospinal fluid, for example (52). Because S. pyogenes produces two potent hemolysins, streptolysin S and streptolysin O, local concentrations of Hb during a typical course of infection could be even higher than normal levels of free Hb in plasma.…”

Section: Discussionmentioning

confidence: 76%

Monocyte and Macrophage Activation by Lipoteichoic Acid Is Independent of Alanine and Is Potentiated by Hemoglobin

Hasty

Meron-Sudai

Cox

et al. 2006

The Journal of Immunology

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Lipoteichoic acids (LTAs) are Gram-positive bacterial cell wall components that elicit mononuclear cell cytokine secretion. Cytokine-stimulating activity is thought to be dependent on retaining a high level of ester-linked d-alanine residues along the polyglycerol phosphate backbone. However, Streptococcus pyogenes LTA essentially devoid of d-alanine caused human and mouse cells to secrete as much IL-6 as LTA with a much higher d-alanine content. Furthermore, hemoglobin (Hb) markedly potentiates the stimulatory effect of various LTAs on mouse macrophages or human blood cells, regardless of their d-alanine content. LTA and Hb appear to form a molecular complex, based on the ability of each to affect the other’s migration on native acrylamide gels, their comigration on these gels, and the ability of LTA to alter the absorption spectra of Hb. Because S. pyogenes is known to release LTA and secrete at least two potent hemolytic toxins, LTA-Hb interactions could occur during streptococcal infections and might result in a profound alteration of the local inflammatory response.

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Section: Discussionmentioning

confidence: 76%

Monocyte and Macrophage Activation by Lipoteichoic Acid Is Independent of Alanine and Is Potentiated by Hemoglobin

Hasty

Meron-Sudai

Cox

et al. 2006

The Journal of Immunology

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“…The clinical relevance of this finding is underlined by the fact that pneumococcal cell wall components, a known TLR2 agonist (30,31), are excessively released after antibiotic-induced lysis of bacteria and that patient outcome is correlated to their concentration in the CSF (32). The ubiquitous presence of lipopeptides on bacterial surfaces, including other meningitis-inducing pathogens, further broadens the clinical importance.…”

Section: Discussionmentioning

confidence: 99%

TLR2 Mediates Neuroinflammation and Neuronal Damage

Hoffmann¹,

Braun²,

Becker³

et al. 2007

The Journal of Immunology

130

107

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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.

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“…During disease, BBB cells are exposed to pneumococci and PCW, with PCW persisting at the site of infection well beyond the period of bacterial viability (29). To assess direct cytotoxic effects of pneumococci and PCW, we exposed primary BMECs to living bacteria (D39; 10 6 , 10 7 and 10 8 CFU/ml) or PCW (equivalent of 10 6 , 10 7 , 10 8 and 10 9 CFU/ml) at concentrations relevant for human bacterial meningitis.…”

Section: Pneumococci and Pcw Induce Apoptosis In Bmecsmentioning

confidence: 99%

“…These components keep inflammation going, fuel tissue destruction in later stages of disease, and impede repair. In particular, the concentration of PCW in the CSF is directly correlated to a poor outcome of meningitis (29). TLR2, a critical receptor in innate immune response, is directly involved in cell wall-associated endothelial cell death.…”

Section: Figurementioning

confidence: 99%

“…Purified PCW induces meningeal inflammation in different animal models indistinguishable from meningitis caused by living bacteria in the early phase of the disease (23,28). The clinical outcome of pneumococcal meningitis correlates with the concentration of PCW in the CSF (29). Thus, it is of clinical importance to understand not only the ability of intact bacteria to interact with PCD pathways, but also the activities of cell walls that persist at the site of infection long after bacteria are killed.…”

Section: Introductionmentioning

confidence: 99%

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

Bermpohl¹,

Halle²,

Freyer³

et al. 2005

J. Clin. Invest.

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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.

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Clinical outcome in pneumococcal meningitis correlates with CSF lipoteichoic acid concentrations

Cited by 70 publications

References 11 publications

Monocyte and Macrophage Activation by Lipoteichoic Acid Is Independent of Alanine and Is Potentiated by Hemoglobin

Monocyte and Macrophage Activation by Lipoteichoic Acid Is Independent of Alanine and Is Potentiated by Hemoglobin

TLR2 Mediates Neuroinflammation and Neuronal Damage

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

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