Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085437 (bacterial meningitis)
 4,038 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The infant or child who presents to the Emergency Department with bacterial meningitis may have nonspecific vague symptoms with few signs of serious illness. However, the disease is often rapidly progressive and life-threatening, and may be associated with respiratory failure, circulatory failure, increased intracranial pressure, disseminated intravascular coagulation, or convulsions, any of which may lead to a fatal outcome. It is important for the triage technician in an Emergency Department to cautiously inspect each young patient who presents with illness, carefully considering whether the presenting syndrome of symptoms and signs might be consistent with early meningitis. If the young patient is triaged in a nonemergent category, then periodic assessments of the patients waiting to be seen may ensure that, when the infant or child with an obscure presentation develops evidence suggesting this diagnosis, the triage technician will promptly notify the appropriate definitive care providers who assume responsibility for immediate definitive evaluation and stabilization. Changes in delivery of lifesaving care to the life-threatened child are being impacted by current advances in the understanding of the biochemical basis of disease at the cellular and subcellular levels. Endotoxin release into the blood causes increased production of kinins, which results in vasodilatation and increased vascular permeability. Members of the leukotriene family may also enhance vascular permeability as well as produce augmented leukocyte aggregation to vascular endothelium, vasoconstriction, and bronchoconstriction. Endotoxin activates the complement cascade and induces platelets to form reversible aggregates that may be trapped in the pulmonary microcirculation; and endotoxemia-activated platelets release serotonin, which may be associated with pulmonary hypertension. Now that we have antibiotics that are effective against organisms whose degradation produces endotoxin, there is interest in lessening the host inflammatory response to endotoxin through use of dexamethasone as an anti-inflammatory agent. Clinical trials have revealed that patients who received dexamethasone became afebrile earlier and were less likely to acquire deafness after bacterial meningitis. Because administration of antibiotics is the current specific medical therapy for this life-threatening microbial invasion, it is reasonable to continue to strive to shorten the interval between recognition of disease and specific therapy. However, new studies suggest that consequences of the complex host inflammatory response (at the cellular and subcellular level) to microbial invasion and endotoxin release from bacterial degradation are increasingly important in determining survival or severity of morbidity. Therapeutic intervention with specific antibiotics and steroid anti-inflammatory agents for modulating host responses enhances outcome.
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PMID:Emergency department stabilization of pediatric patients with bacterial meningitis. Current advances. 189 92

Inflammatory recruitment of leukocytes into the cerebrospinal fluid (CSF) during bacterial meningitis has been shown to contribute significantly to the neurological damage commonly associated with this serious disease. In this study we tested whether or not inhibition of leukocyte rolling, a precondition for firm leukocyte adhesion to vascular endothelium in vivo, may reduce CSF leukocyte recruitment and associated inflammatory changes in rabbits with experimental meningitis. As documented by intravital microscopy of small venules in the rabbit mesentery and tenuissimus muscle, leukocyte rolling was rapidly and profoundly reduced by intravenous treatment with the polysaccharide fucoidin, a homopolymer of sulfated L-fucose known to block the function of the leukocytic "rolling receptor" L-selectin. Moreover, fucoidin treatment dramatically reduced the accumulation of both leukocytes and plasma protein in the CSF of rabbits challenged intrathecally with pneumococcal antigen. These main findings thus illustrate that inhibition of leukocyte rolling, an early and obligatory step in the process of leukocyte extravasation, may be an effective therapeutic approach to attenuate leukocyte-dependent central nervous system damage in bacterial meningitis.
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PMID:Inhibition of leukocyte rolling with polysaccharide fucoidin prevents pleocytosis in experimental meningitis in the rabbit. 751 Jul 19

Interleukin-8 (IL-8) elaborated by monocytes and endothelial cells is a cytokine which is responsible for adhesion of leucocytes to vascular endothelium and migration of neutrophils into the cerebrospinal fluid (CSF) from the intravascular space. The inflammation in meningitis is elicited by the cytokine release from leucocytes which encounter micro-organisms in the arachnoid or subarachnoid space. In bacterial meningitis, tumour necrosis factor (TNF), IL-1 and IL-6 are produced vigorously, and initiate and augment the inflammation in the central nervous system. In this study, utilizing a quantitative immunometric sandwich enzyme immunoassay, the concentration of IL-8 was investigated in the CSF of patients with bacterial meningitis, patients with aseptic meningitis, and patients with gastroenteritis who served as controls. The IL-8 concentration was markedly higher in the CSF of patients with bacterial meningitis (224 +/- 2.57 pg/ml; mean +/- SD) than in the CSF of patients with aseptic meningitis (less than 30 pg/ml). The IL-8 level in the CSF of patients with aseptic meningitis did not differ from that in the CSF of the patients with gastroenteritis (less than 30 pg/ml). The augmented production of IL-8 in CSF may account for the inflammation in bacterial meningitis being more severe than that in aseptic meningitis.
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PMID:Augmented production of interleukin-8 in cerebrospinal fluid in bacterial meningitis. 826 63

Brain injury in meningitis occurs in part as a consequence of leukocyte migration and activation. Leukocyte integrins are pivotal in the inflammatory response by mediating adhesion to vascular endothelium and extracellular matrix proteins. We have demonstrated that moderate hypothermia early in the course of meningitis decreases leukocyte sequestration within the brain parenchyma. This study examines whether hypothermia alters neutrophil integrin expression in a rabbit model of bacterial meningitis. Prior to the induction of meningitis, peripheral blood samples were obtained and the neutrophils isolated. Sixteen hours after inducing group B streptococcal meningitis, animals were treated with antibiotics, i.v. fluids, and mechanically ventilated. Animals were randomized to hypothermia (32-33 degrees C) or normothermia conditions. After 10 hours of hypothermia or normothermia, neutrophils were isolated from the blood and cerebral spinal fluid (CSF), stained for beta1 and beta2 integrins, and analyzed using flow cytometry. Cerebral spinal fluid neutrophil beta1 integrin expression was significantly decreased in hypothermic animals. Beta-1 integrins can assume a higher affinity or "activated" state following inflammatory stimulation. Expression of "activated" beta1 integrins was also significantly decreased in hypothermic animals. Beta2 CSF neutrophil integrin expression was decreased in hypothermic animals, but failed to reach significance. These data suggest hypothermia may attenuate extravasated leukocyte expression of both total and "activated" beta1 integrins.
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PMID:Hypothermia attenuates beta1 integrin expression on extravasated neutrophils in an animal model of meningitis. 1140 4

Inflammatory recruitment of leukocytes into the cerebrospinal fluid (CSF) during bacterial meningitis has been shown to contribute to the neurological damage commonly associated with this disease. In this study we tested whether inhibition of firm leukocyte adhesion to vascular endothelium could reduce leukocyte recruitment into the subarachnoid space (SAS) and into the skin in rabbits challenged with pneumococcal cell wall (PCW) antigen. PCW was given either as an intracisternal or an intradermal (i.d.) injection. Intravenous (i.v.) treatment with a monoclonal antibody (mAb), IB4, against the leukocytic adhesion molecule CD18 has previously been documented to attenuate leukocyte CSF accumulation in experimental bacterial meningitis. In the present study, i.v. treatment with anti-CD18 mAbs (IB4) only tended to inhibit CSF leukocyte influx in animals with PCW-induced meningitis. However, if the antigen was injected i.d., treatment i.v. with the same mAb (IB4) dramatically reduced leukocyte accumulation in the skin. Our findings indicate that the mechanisms responsible for PCW-induced inflammatory accumulation of leukocytes in skin and meninges are different.
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PMID:Treatment with an anti-CD18 monoclonal antibody in rabbits inhibits pneumococcal-induced leukocyte recruitment in the skin, but not in the meninges. 1241 Mar 48

A diverse array of infectious agents, including prions and certain neurotropic viruses, bind to the laminin receptor (LR), and this determines tropism to the CNS. Bacterial meningitis in childhood is almost exclusively caused by the respiratory tract pathogens Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae, but the mechanism by which they initiate contact with the vascular endothelium of the blood brain barrier (BBB) is unknown. We hypothesized that an interaction with LR might underlie their CNS tropism. Using affinity chromatography, coimmunoprecipitation, retagging, and in vivo imaging approaches, we identified 37/67-kDa LR as a common receptor for all 3 bacteria on the surface of rodent and human brain microvascular endothelial cells. Mutagenesis studies indicated that the corresponding bacterial LR-binding adhesins were pneumococcal CbpA, meningococcal PilQ and PorA, and OmpP2 of H. influenzae. The results of competitive binding experiments suggest that a common adhesin recognition site is present in the carboxyl terminus of LR. Together, these findings suggest that disruption or modulation of the interaction of bacterial adhesins with LR might engender unexpectedly broad protection against bacterial meningitis and may provide a therapeutic target for the prevention and treatment of disease.
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PMID:Laminin receptor initiates bacterial contact with the blood brain barrier in experimental meningitis models. 1982 88

Streptococcus pneumoniae (the pneumococcus) is a Gram-positive bacterium and the predominant cause of bacterial meningitis. Meningitis is thought to occur as the result of pneumococci crossing the blood-brain barrier to invade the Central Nervous System (CNS); yet little is known about the steps preceding immediate disease development. To study the interactions between pneumococci and the vascular endothelium of the blood-brain barrier prior to meningitis we used an established bacteremia-derived meningitis model in combination with immunofluorescent imaging. Brain tissue of mice infected with S. pneumoniae strain TIGR4, a clinical meningitis isolate, was investigated for the location of the bacteria in relation to the brain vasculature in various compartments. We observed that S. pneumoniae adhered preferentially to the subarachnoid vessels, and subsequently, over time, reached the more internal cerebral areas including the cerebral cortex, septum, and choroid plexus. Interestingly, pneumococci were not detected in the choroid plexus till 8 hours-post infection. In contrast to the lungs, little to no leukocyte recruitment to the brain was observed over time, though Iba-1 and GFAP staining showed that microglia and astrocytes were activated as soon as 1 hour post-infection. Our results imply that i) the local immune system of the brain is activated immediately upon entry of bacteria into the bloodstream and that ii) adhesion to the blood brain barrier is spatiotemporally controlled at different sites throughout the brain. These results provide new information on these two important steps towards the development of pneumococcal meningitis.
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PMID:Interactions between blood-borne Streptococcus pneumoniae and the blood-brain barrier preceding meningitis. 2387 13

The Gram-positive bacterium Streptococcus pneumoniae is the main causative agent of bacterial meningitis. S. pneumoniae is thought to invade the central nervous system via the bloodstream by crossing the vascular endothelium of the blood-brain barrier. The exact mechanism by which pneumococci cross endothelial cell barriers before meningitis develops is unknown. Here, we investigated the role of PECAM-1/CD31, one of the major endothelial cell adhesion molecules, in S. pneumoniae adhesion to vascular endothelium of the blood-brain barrier. Mice were intravenously infected with pneumococci and sacrificed at various time points to represent stages preceding meningitis. Immunofluorescent analysis of brain tissue of infected mice showed that pneumococci colocalized with PECAM-1. In human brain microvascular endothelial cells (HBMEC) incubated with S. pneumoniae, we observed a clear colocalization between PECAM-1 and pneumococci. Blocking of PECAM-1 reduced the adhesion of S. pneumoniae to endothelial cells in vitro, implying that PECAM-1 is involved in pneumococcal adhesion to the cells. Furthermore, using endothelial cell protein lysates, we demonstrated that S. pneumoniae physically binds to PECAM-1. Moreover, both in vitro and in vivo PECAM-1 colocalizes with the S. pneumoniae adhesion receptor pIgR. Lastly, immunoprecipitation experiments revealed that PECAM-1 can physically interact with pIgR. In summary, we show for the first time that blood-borne S. pneumoniae colocalizes with PECAM-1 expressed by brain microvascular endothelium and that, in addition, they colocalize with pIgR. We hypothesize that this interaction plays a role in pneumococcal binding to the blood-brain barrier vasculature prior to invasion into the brain.
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PMID:Platelet endothelial cell adhesion molecule-1, a putative receptor for the adhesion of Streptococcus pneumoniae to the vascular endothelium of the blood-brain barrier. 2491 19

Microglia have a pivotal role in the pathophysiology of bacterial meningitis. The goal of this review is to provide an overview on how microglia respond to bacterial pathogens targeting the brain, how the interplay between microglia and bacteria can be studied experimentally, and possible ways to use gained knowledge to identify novel preventive and therapeutic strategies. We discuss the dual role of microglia in disease development, the beneficial functions crucial for bacterial clearing, and the destructive properties through triggering neuroinflammation, characterized by cytokine and chemokine release which leads to leukocyte trafficking through the brain vascular endothelium and breakdown of the blood-brain barrier integrity. Due to intrinsic complexity of microglia and up until recently lack of specific markers, the study of microglial response to bacterial pathogens is challenging. New experimental models and techniques open up possibilities to accelerate progress in the field. We review existing models and discuss possibilities and limitations. Finally, we summarize recent findings where bacterial virulence factors are identified to be important for the microglial response, and how manipulation of evoked responses could be used for therapeutic or preventive purposes. Among promising approaches are: modulations of microglia phenotype switching toward anti-inflammatory and phagocytic functions, the use of non-bacterolytic antimicrobials, preventing release of bacterial components into the neural milieu and consequential amplification of immune activation, and protection of the blood-brain barrier integrity.
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PMID:The Role of Microglia in Bacterial Meningitis: Inflammatory Response, Experimental Models and New Neuroprotective Therapeutic Strategies. 3096 52