Toxicity of Streptococcus pneumoniae in Neurons, Astrocytes, and Microglia In Vitro

Kim, Young S.; Kennedy, Stephen L.; Täuber, Martin G.

doi:10.1093/infdis/171.5.1363

Cited by 35 publications

(24 citation statements)

References 12 publications

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“…However, inasmuch as intraperitoneal injection of LPS at a dosage of 4 mg/kg kills newborn guinea pigs within 6 h, such mechanisms seem to be of minor importance in the present study. Nevertheless, delayed cell injury may explain some 534 discrepancies between our results and studies in adult animals and completely differentiated cell cultures in which LPSinduced injury was observed (25)(26)(27)(28)(29)(30). In addition, if LPS is exclusively toxic to a certain cell type, e.g.…”

Section: Lipopolysaccharides and Fetal Brain Damagecontrasting

confidence: 58%

Lipopolysaccharides Do Not Alter Metabolic Disturbances in Hippocampal Slices of Fetal Guinea Pigs after Oxygen-Glucose Deprivation

et al. 2000

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The aim of the present study was to clarify whether endotoxins [lipopolysaccharides (LPS)] have a toxic effect on fetal brain tissue after cerebral ischemia, while excluding their effect on the cardiovascular system. Experiments were therefore performed on hippocampal slices prepared from mature fetal guinea pigs. In particular, we studied the influence of LPS on nitric oxide production, energy metabolism, and protein synthesis after oxygen-glucose deprivation (OGD). Incubating hippocampal slices in LPS (4 mg/L) for as long as 12 h did not alter cGMP tissue concentrations significantly. However, 10 min after OGD of 40-min duration, cGMP tissue concentrations were substantially increased in relation to controls, and this increase was almost completely blocked by the application of 100 M N -nitro-Larginine, indicating that nitric oxide synthase was activated after OGD in fetal brain tissue. Again, LPS did not have any effect on cGMP tissue concentrations after OGD. Furthermore, addition of LPS altered neither protein synthesis nor energy metabolism measured 12 h after OGD. We therefore conclude that, apart from their well-known influence on the cardiovascular system, LPS do not alter metabolic disturbances in hippocampal slices of fetal guinea pigs 12 h after OGD. A direct toxic effect of LPS on immature brain tissue within this interval does not therefore seem to be very likely. However, delayed activation of LPS-sensitive pathways that may be involved in cell death, or damage limited to a small subgroup of cells such as oligodendrocyte progenitors, cannot be fully excluded. Hypoxic-ischemic cerebral damage is an important contributor to perinatal mortality and morbidity, including long-term neurologic sequelae in term and preterm fetuses. On the other hand, there is increasing evidence that perinatal brain damage is caused not only by hypoxic-ischemic insults, but also by ascending intrauterine infection before or during birth (1). Infants whose amnion is acutely inflamed are at a much greater risk of developing brain injury than control subjects (2, 3). However, it remains unclear whether fetal brain damage is the result of cerebral hypoperfusion caused by circulatory decentralization owing to severe endotoxemia or is caused by a direct effect of endotoxins on cerebral tissue (4). The present study was therefore set up to clarify whether endotoxins (LPS) have a direct toxic effect on fetal brain tissue after cerebral ischemia, while excluding their effects on the cardiovascular system. For this purpose we used the in-vitro system of OGD in hippocampal slices prepared from mature guinea pig fetuses (5, 6). In particular, we studied the influence of LPS on NO production, energy metabolism, and protein synthesis after OGD. Prolonged inhibition of protein synthesis after OGD seems to be an especially sensitive early marker of ischemic cell injury (7). METHODSThe present study was performed on guinea pigs, a precocious species, at 0.9 gestation (term, 68 d). The dams were anesthetized with halothane and decapitated,...

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Section: Lipopolysaccharides and Fetal Brain Damagecontrasting

confidence: 58%

Lipopolysaccharides Do Not Alter Metabolic Disturbances in Hippocampal Slices of Fetal Guinea Pigs after Oxygen-Glucose Deprivation

et al. 2000

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“…In vitro, lipopolysaccharides cause ultrastractural changes (35) and selectively depolarize (36) rodent astroglia, whereas pneumococcal cell walls selectively kill human astroglia (37). In rodents in vivo, the invading neutrophils become intimately associated with astroglia (38) and Haemophilus influenzae causes massive astroglial swelling (39).…”

Section: Discussionmentioning

confidence: 99%

Aquaporin-4 Gene Disruption in Mice Reduces Brain Swelling and Mortality in Pneumococcal Meningitis

Papadopoulos

Verkman

2005

Journal of Biological Chemistry

276

193

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The astroglial water channel aquaporin-4 (AQP4) facilitates water movement into and out of brain parenchyma. To investigate the role of AQP4 in meningitisinduced brain edema, Streptococcus pneumoniae was injected into cerebrospinal fluid (CSF) in wild type and AQP4 null mice. AQP4-deficient mice had remarkably lower intracranial pressure (9 ؎ 1 versus 25 ؎ 5 cm H 2 O) and brain water accumulation (2 ؎ 1 versus 9 ؎ 1 l) at 30 h, and improved survival (80 versus 0% survival) at 60 h, through comparable CSF bacterial and white cell counts. Meningitis produced marked astrocyte foot process swelling in wild type but not AQP4 null mice, and slowed diffusion of an inert macromolecule in brain extracellular space. AQP4 protein was strongly up-regulated in meningitis, resulting in a ϳ5-fold higher water permeability (P f ) across the blood-brain barrier compared with non-infected wild type mice. Mathematical modeling using measured P f and CSF dynamics accurately simulated the elevated lower intracranial pressure and brain water produced by meningitis and predicted a beneficial effect of prevention of AQP4 upregulation. Our findings provide a novel molecular mechanism for the pathogenesis of brain edema in acute bacterial meningitis, and suggest that inhibition of AQP4 function or up-regulation may dramatically improve clinical outcome.Streptococcus pneumoniae (pneumococcus) is the most common and aggressive meningeal pathogen (1-3). The overall incidence of pneumococcal meningitis is rising (4, 5) and the emergence of penicillin-resistant S. pneumoniae makes treatment harder (6, 7). Even with effective antibiotic treatment, mortality from pneumococcal meningitis is 10 -30%, with 30 -50% of patients acquiring permanent neurological deficits (1-3). A major complication associated with unfavorable outcome in bacterial meningitis is brain edema, which causes a rise in intracranial pressure potentially leading to brain ischemia, herniation, and death (8, 9). The molecular mechanisms responsible for the formation and absorption of excess fluid in brain edema associated with meningitis are poorly understood.The two main types of brain edema are cytotoxic and vasogenic (10). Cytotoxic edema, as occurs in ischemic stroke, refers to cell swelling that primarily affects astroglial cells. Vasogenic edema, as occurs in brain tumors, involves accumulation of excess fluid in the extracellular space of the brain parenchyma because of a leaky blood-brain barrier (BBB). 1 Although both types of brain edema are thought to co-exist in meningitis (8, 9), their relative contributions to brain swelling are not known.Recently, the bidirectional water channel aquaporin-4 (AQP4) has been found to play an important role in brain-water homeostasis (11-16). AQP4 protein is expressed strongly in astroglia at the BBB and CSF-brain interfaces (17, 18), suggesting involvement in water movement between fluid compartments (blood and CSF) and brain parenchyma. AQP4 deletion markedly reduced brain swelling in mouse models of cytotoxic brain edema, includin...

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“…Previous findings indeed demonstrated that treatment of bacterial meningitis with ␤-lactam antibiotics liberates harmful bacterial products (peptidoglycans, teichoic and lipoteichoic acids, pneumolysin) in the subarachnoid space, which results in an immediate increase in the number of active molecules that are capable of causing a rapid increase in the inflammatory response (7,10,21,28,32). In fact, the release of bacterial components, as well as host proinflammatory components and mediators, has been shown to be neurotoxic, causing apoptosis in neurons, predominantly in the dentate gyrus of the hippocampus (13,21,37). Interestingly, treatment with antibiotics such as rifampin and clindamycin, which induce (26).…”

Section: Discussionmentioning

confidence: 99%

Reduction of Astrogliosis by Early Treatment of Pneumococcal Meningitis Measured by Simultaneous Imaging, In Vivo, of the Pathogen and Host Response

Kadurugamuwa¹,

Modi²,

Coquoz³

et al. 2005

Infect Immun

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We developed a method for simultaneous in vivo biophotonic monitoring of pneumococcal meningitis and the accompanying neuronal injury in live transgenic mice. Streptococcus pneumoniae engineered for bioluminescence (lux) was used for direct visualization of disease progression and antibiotic treatment in a mouse model of meningitis. The host response was monitored in transgenic mice containing an inducible firefly luciferase (luc) reporter gene under transcriptional control of the mouse glial fibrillary acidic protein (GFAP) promoter. Based on the different spectra of light emission and substrate requirements for lux and luc, we were able to separately monitor the two reporters using a highly sensitive in vivo imaging system. The level of neuronal damage and recovery following antibiotic treatment was dependent on the time of treatment. This model has potential for simultaneous multiparameter monitoring and testing of therapies that target the pathogen or host response to prevent neuronal injury and recovery.

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Toxicity of Streptococcus pneumoniae in Neurons, Astrocytes, and Microglia In Vitro

Cited by 35 publications

References 12 publications

Lipopolysaccharides Do Not Alter Metabolic Disturbances in Hippocampal Slices of Fetal Guinea Pigs after Oxygen-Glucose Deprivation

Lipopolysaccharides Do Not Alter Metabolic Disturbances in Hippocampal Slices of Fetal Guinea Pigs after Oxygen-Glucose Deprivation

Aquaporin-4 Gene Disruption in Mice Reduces Brain Swelling and Mortality in Pneumococcal Meningitis

Reduction of Astrogliosis by Early Treatment of Pneumococcal Meningitis Measured by Simultaneous Imaging, In Vivo, of the Pathogen and Host Response

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