Streptococcus pneumoniae Interacts with pIgR Expressed by the Brain Microvascular Endothelium but Does Not Co-Localize with PAF Receptor

The microvasculature of the human brain plays an important role in the development and maintenance of the central nervous system and in the pathogenesis of brain diseases, and is the site of differential gene expression within the brain. However, human brain microvascular-specific genes may not be detected in whole-brain gene microarray because the volume of the brain microvascular endothelium is relatively small (0.1%) compared with the whole brain. Therefore, the differential gene expression within the human brain microvasculature was evaluated using suppression subtractive hybridization with RNA isolated from human brain microvessels. Gene identification was restricted to the first 71 clones that were differentially expressed at the brain microvasculature. Twenty of these were genes encoding proteins with known function that were involved in angiogenesis, neurogenesis, molecular transport, and maintenance of endothelial tight junctions or the cytoskeleton. Eighteen genes coding for proteins of an unknown function were identified, including five genes containing satellite DNA sequences. The results provide the initial outline of the genomics of the human brain microvasculature, and have implications for the identification of both targets for brain-specific drug transport and changes in microvascular gene expression in brain diseases.

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Streptococcus pneumoniae Meningoencephalitis With Bilateral Basal Ganglia Necrosis

Journal of Child Neurology ◽

10.1177/0883073811409223 ◽

2011 ◽

Vol 26 (11) ◽

pp. 1438-1443 ◽

Cited By ~ 4

Author(s):

Jessy Magnus ◽

Paul M. Parizel ◽

Berten Ceulemans ◽

Patrick Cras ◽

Marloes Luijks ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Basal Ganglia ◽

Neurological Impairment ◽

Hemorrhagic Transformation ◽

Exceptional Case ◽

Mr Images ◽

Caudate Nuclei ◽

Magnetic Resonance Imaging Mri ◽

The Brain ◽

Severe Neurological Impairment

Streptococcus pneumoniae ( S pneumoniae) is a common cause of bacterial meningitis, frequently leading to death or severe neurological impairment. We report an exceptional case of a 4-month-old boy with meningitis caused by S pneumoniae. Computed tomography (CT) and magnetic resonance imaging (MRI) examinations of the brain showed bilateral symmetrical necrosis involving the lentiform and caudate nuclei, as well as the thalamus. T1-weighted MR images showed patchy areas of increased signal intensity, consistent with hemorrhagic transformation of the lesions. Autopsy revealed widespread necrosis of the basal ganglia with clear signs of vasculitis. Severe complications of S pneumoniae meningoencephalitis are known in infants but to our knowledge, such lesions in the basal ganglia have only been reported thrice in adults and never in children.

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Streptococcus pneumoniae-Induced Inhibition of Rat Ependymal Cilia Is Attenuated by Antipneumolysin Antibody

Infection and Immunity ◽

10.1128/iai.72.11.6694-6698.2004 ◽

2004 ◽

Vol 72 (11) ◽

pp. 6694-6698 ◽

Cited By ~ 19

Author(s):

Robert A. Hirst ◽

Bashir J. Mohammed ◽

Timothy J. Mitchell ◽

Peter W. Andrew ◽

Christopher O'Callaghan

Keyword(s):

Streptococcus Pneumoniae ◽

Therapeutic Potential ◽

Ependymal Cell ◽

Ex Vivo ◽

Beat Frequency ◽

Ciliary Beat Frequency ◽

Ependymal Cells ◽

Wild Type ◽

Ependymal Cilia ◽

The Brain

ABSTRACT Ciliated ependymal cells line the ventricular surfaces and aqueducts of the brain. In ex vivo experiments, pneumolysin caused rapid inhibition of the ependymal ciliary beat frequency and caused ependymal cell disruption. Wild-type pneumococci and pneumococci deficient in pneumolysin caused ciliary slowing, but penicillin lysis of wild-type, not pneumolysin-deficient, pneumococci increased the extent of ciliary inhibition. This effect was abolished by antipneumolysin antibody. Ependymal ciliary stasis by purified pneumolysin was also blocked by the addition of antipneumolysin monoclonal antibodies. These data show that antibiotic lysis of Streptococcus pneumoniae can be detrimental to the ciliated ependyma and that antipneumolysin antibody may have a therapeutic potential.

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Mechanisms of Brain Aging Regulation by Insulin: Implications for Neurodegeneration in Late-Onset Alzheimer's Disease

ISRN Neurology ◽

10.5402/2011/306905 ◽

2011 ◽

Vol 2011 ◽

pp. 1-9 ◽

Cited By ~ 21

Author(s):

Artur F. Schuh ◽

Carlos M. Rieder ◽

Liara Rizzi ◽

Márcia Chaves ◽

Matheus Roriz-Cruz

Keyword(s):

Alzheimer’S Disease ◽

Insulin Resistance ◽

Alzheimer's Disease ◽

Brain Aging ◽

Late Onset ◽

Energy Deficit ◽

Insulin Degrading Enzyme ◽

Microvascular Endothelium ◽

Chronic Hyperglycemia ◽

The Brain

Insulin and IGF seem to be important players in modulating brain aging. Neurons share more similarities with islet cells than any other human cell type. Insulin and insulin receptors are diffusely found in the brain, especially so in the hippocampus. Caloric restriction decreases insulin resistance, and it is the only proven mechanism to expand lifespan. Conversely, insulin resistance increases with age, obesity, and sedentarism, all of which have been shown to be risk factors for late-onset Alzheimer's disease (AD). Hyperphagia and obesity potentiate the production of oxidative reactive species (ROS), and chronic hyperglycemia accelerates the formation of advanced glucose end products (AGEs) in (pre)diabetes—both mechanisms favoring a neurodegenerative milieu. Prolonged high cerebral insulin concentrations cause microvascular endothelium proliferation, chronic hypoperfusion, and energy deficit, triggering β-amyloid oligomerization and tau hyperphosphorylation. Insulin-degrading enzyme (IDE) seems to be the main mechanism in clearing β-amyloid from the brain. Hyperinsulinemic states may deviate IDE utilization towards insulin processing, decreasing β-amyloid degradation.

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Effect of Focused Ultrasound Applied With an Ultrasound Contrast Agent on the Tight Junctional Integrity of the Brain Microvascular Endothelium

Ultrasound in Medicine & Biology ◽

10.1016/j.ultrasmedbio.2007.12.015 ◽

2008 ◽

Vol 34 (7) ◽

pp. 1093-1104 ◽

Cited By ~ 238

Author(s):

Nickolai Sheikov ◽

Nathan McDannold ◽

Shipra Sharma ◽

Kullervo Hynynen

Keyword(s):

Contrast Agent ◽

Focused Ultrasound ◽

Ultrasound Contrast Agent ◽

Microvascular Endothelium ◽

Ultrasound Contrast ◽

The Brain

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Cerebral microvascular endothelium and the pathogenesis of neurodegenerative diseases

Expert Reviews in Molecular Medicine ◽

10.1017/s1462399411001918 ◽

2011 ◽

Vol 13 ◽

Cited By ~ 114

Author(s):

Paula Grammas ◽

Joseph Martinez ◽

Bradley Miller

Keyword(s):

Endothelial Cells ◽

Dynamic Properties ◽

Early Event ◽

High Concentration ◽

Microvascular Endothelium ◽

Leukocyte Transmigration ◽

New Therapeutic Approaches ◽

The Central Nervous System ◽

Cerebrovascular Endothelial Cells ◽

The Brain

Diseases of the central nervous system (CNS) pose a significant health challenge, but despite their diversity, they share many common features and mechanisms. For example, endothelial dysfunction has been implicated as a crucial event in the development of several CNS disorders, such as Alzheimer disease, Parkinson disease, amyotrophic lateral sclerosis, multiple sclerosis, human immunodeficiency virus (HIV)-1-associated neurocognitive disorder and traumatic brain injury. Breakdown of the blood–brain barrier (BBB) as a result of disruption of tight junctions and transporters, leads to increased leukocyte transmigration and is an early event in the pathology of these disorders. The brain endothelium is highly reactive because it serves as both a source of, and a target for, inflammatory proteins and reactive oxygen species. BBB breakdown thus leads to neuroinflammation and oxidative stress, which are implicated in the pathogenesis of CNS disease. Furthermore, the physiology and pathophysiology of endothelial cells are closely linked to the functioning of their mitochondria, and mitochondrial dysfunction is another important mediator of disease pathology in the brain. The high concentration of mitochondria in cerebrovascular endothelial cells might account for the sensitivity of the BBB to oxidant stressors. Here, we discuss how greater understanding of the role of BBB function could lead to new therapeutic approaches for diseases of the CNS that target the dynamic properties of brain endothelial cells.

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Shear-Dependent Attenuation of Cellular ROS Levels can Suppress Proinflammatory Cytokine Injury to Human Brain Microvascular Endothelial Barrier Properties

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.2015.102 ◽

2015 ◽

Vol 35 (10) ◽

pp. 1648-1656 ◽

Cited By ~ 14

Author(s):

Keith D Rochfort ◽

Laura E Collins ◽

Alisha McLoughlin ◽

Philip M Cummins

Keyword(s):

Human Brain ◽

Barrier Properties ◽

Microvascular Endothelial Cell ◽

Brain Microvascular Endothelial Cell ◽

Microvascular Endothelium ◽

Cellular Redox ◽

Tnf Α ◽

Microvascular Endothelial ◽

Laminar Shear ◽

The Brain

The regulatory interplay between laminar shear stress and proinflammatory cytokines during homeostatic maintenance of the brain microvascular endothelium is largely undefined. We hypothesized that laminar shear could counteract the injurious actions of proinflammatory cytokines on human brain microvascular endothelial cell (HBMvEC) barrier properties, in-part through suppression of cellular redox signaling. For these investigations, HBMvECs were exposed to either shear stress (8 dynes/cm2, 24 hours) or cytokines (tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6), 0 to 100 ng/mL, 6 or 18 hours). Human brain microvascular endothelial cell ‘preshearing’ ± cytokine exposure was also performed. Either cytokine dose–dependently decreased expression and increased phosphorylation (pTyr/pThr) of interendothelial occludin, claudin-5, and vascular endothelial-cadherin; observations directly correlating to endothelial barrier reduction, and in precise contrast to effects seen with shear. We further observed that, relative to unsheared cells, HBMvECs presheared for 24 hours exhibited significantly reduced reactive oxygen species production and barrier permeabilization in response to either TNF-α or IL-6 treatment. Shear also downregulated NADPH oxidase (nicotinamide adenine dinucleotide phosphate-oxidase) activation in HBMvECs, as manifested in the reduced expression and coassociation of gp91phox and p47phox. These findings lead us to conclude that physiologic shear can protect the brain microvascular endothelium from injurious cytokine effects on interendothelial junctions and barrier function by regulating the cellular redox state in-part through NADPH oxidase inhibition.

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Streptococcus pneumoniae Causes Experimental Meningitis following Intranasal and Otitis Media Infections via a Nonhematogenous Route

Infection and Immunity ◽

10.1128/iai.69.12.7318-7325.2001 ◽

2001 ◽

Vol 69 (12) ◽

pp. 7318-7325 ◽

Cited By ~ 38

Author(s):

Andrea Marra ◽

Daniel Brigham

Keyword(s):

Central Nervous System ◽

Cerebrospinal Fluid ◽

Nervous System ◽

Streptococcus Pneumoniae ◽

Otitis Media ◽

Intranasal Inoculation ◽

The Central Nervous System ◽

Human Infections ◽

The Brain ◽

Do So

ABSTRACT Using two different animal models of Streptococcus pneumoniae infection, we have demonstrated that this organism is able to spread to the central nervous system and cause meningitis by bypassing the bloodstream. Following respiratory tract infection induced via intranasal inoculation, bacteria were rapidly found in the bloodstream and brains in the majority of infected mice. A similar pattern of dissemination occurred following otitis media infection via transbullar injection of gerbils. However, a small percentage of animals infected by either route showed no bacteria in the blood and yet did have significant numbers of bacteria in brain tissue. Subsequent experiments using a galU mutant of S. pneumoniae, which is impaired in its ability to disseminate to the bloodstream following infection, showed that this organism is able to spread to the brain and cerebrospinal fluid. These results demonstrate that, unlike many bacterial pathogens that cause meningitis, S. pneumoniae is able to do so independent of bloodstream involvement upon different routes of infection. This may address the difficulty in treating human infections caused by this organism.

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