Bacterial meningitis: current therapy and possible future treatment options

Woehrl, Bianca; Klein, Matthias; Grandgirard, Denis; Koedel, Uwe; Leib, Stephen L.

doi:10.1586/eri.11.129

Cited by 23 publications

(15 citation statements)

References 123 publications

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“…Interestingly, some of these factors (TNF- α , MMPs, and nitric oxide) have already been described in experimental models using knockout animals [41] and/or intervention strategies [42] which reduced mortality and ameliorated the outcome of infected animals. The most promising strategies derived from these experimental models include the reduction of the inflammatory reaction by targeting different steps in the inflammatory process [43], from the release of proinflammatory bacterial products to the activation of the innate immune system and the production/release of cytokines or chemokines, as well as the inhibition of metalloproteinases or treatments with antioxidants [44].…”

Section: Discussionmentioning

confidence: 99%

The Causative Pathogen Determines the Inflammatory Profile in Cerebrospinal Fluid and Outcome in Patients with Bacterial Meningitis

Grandgirard

Gäumann

Coulibaly

et al. 2013

Mediators of Inflammation

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Background. The brain's inflammatory response to the infecting pathogen determines the outcome of bacterial meningitis (BM), for example, the associated mortality and the extent of brain injury. The inflammatory cascade is initiated by the presence of bacteria in the cerebrospinal fluid (CSF) activating resident immune cells and leading to the influx of blood derived leukocytes. To elucidate the pathomechanisms behind the observed difference in outcome between different pathogens, we compared the inflammatory profile in the CSF of patients with BM caused by Streptococcus pneumonia (n = 14), Neisseria meningitidis (n = 22), and Haemophilus influenza (n = 9). Methods. CSF inflammatory parameters, including cytokines and chemokines, MMP-9, and nitric oxide synthase activity, were assessed in a cohort of patients with BM from Burkina Faso. Results. Pneumococcal meningitis was associated with significantly higher CSF concentrations of IFN-γ, MCP-1, and the matrix-metalloproteinase (MMP-) 9. In patients with a fatal outcome, levels of TNF-α, IL-1β, IL-1RA, IL-6, and TGF-α were significantly higher. Conclusion. The signature of pro- and anti-inflammatory mediators and the intensity of inflammatory processes in CSF are determined by the bacterial pathogen causing bacterial meningitis with pneumococcal meningitis being associated with a higher case fatality rate than meningitis caused by N. meningitidis or H. influenzae.

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Section: Discussionmentioning

confidence: 99%

The Causative Pathogen Determines the Inflammatory Profile in Cerebrospinal Fluid and Outcome in Patients with Bacterial Meningitis

Grandgirard

Gäumann

Coulibaly

et al. 2013

Mediators of Inflammation

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“…Moreover, S. pneumoniae is now the most common etiological agent of bacterial meningitis in the United States and Europe [1]. Meningitis is an infection of the Central Nervous System (CNS), which is characterized by inflammation of the protective membranes covering the brain and spinal cord, collectively known as the meninges [2], [3]. One entry route for S. pneumoniae into the CNS is thought to be via the bloodstream by crossing the blood vessels of the blood-brain barrier.…”

Section: Introductionmentioning

confidence: 99%

“…One entry route for S. pneumoniae into the CNS is thought to be via the bloodstream by crossing the blood vessels of the blood-brain barrier. The blood-brain barrier is composed of a specialized vasculature covered by endothelial cells that protects the brain from harmful substances that are present in the blood stream and supplies the brain with the required nutrients for its proper functions, making the brain an immune privileged organ [2], [3]. The entry of pathogens into the CNS leads to inflammation, local production of pro-inflammatory cytokines and activation of the endothelium.…”

Section: Introductionmentioning

confidence: 99%

Interactions between Blood-Borne Streptococcus pneumoniae and the Blood-Brain Barrier Preceding Meningitis

et al. 2013

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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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“…Streptococcus pneumoniae (the pneumococcus) is the main causative agent of bacterial meningitis in Europe and in the USA [1], [2] and is thought to invade into the brain via the bloodstream by crossing the vasculature of the blood-brain barrier (BBB) [3], [4]. The platelet-activating factor receptor (PAFR) is implicated in pneumococcal adhesion to endothelial cells [5], [6], [7].…”

Section: Introductionmentioning

confidence: 99%

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

2014

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Streptococcus pneumoniae is thought to adhere to the blood-brain barrier (BBB) endothelium prior to causing meningitis. The platelet activating factor receptor (PAFR) has been implicated in this adhesion but there is a paucity of data demonstrating direct binding of the bacteria to PAFR. Additionally, studies that inhibit PAFR strongly suggest that alternative receptors for pneumococci are present on the endothelium. Therefore, we studied the roles of PAFR and pIgR, an established epithelial pneumococcal receptor, in pneumococcal adhesion to brain endothelial cells in vivo. Mice were intravenously infected with pneumococci and sacrificed at various time points before meningitis onset. Co-localization of bacteria with PAFR and pIgR was investigated using immunofluorescent analysis of the brain tissue. In vitro blocking with antibodies and incubation of pneumococci with endothelial cell lysates were used to further probe bacteria-receptor interaction. In vivo as well as in vitro pneumococci did not co-localize with PAFR. On the other hand the majority of S. pneumoniae co-localized with endothelial pIgR and pIgR blocking reduced pneumococcal adhesion to endothelial cells. Pneumococci physically interacted with pIgR in endothelial cell lysates. In conclusion, bacteria did not associate with PAFR, indicating an indirect role of PAFR in pneumococcal adhesion to endothelial cells. In contrast, pIgR on the BBB endothelium may represent a novel pneumococcal adhesion receptor.

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Bacterial meningitis: current therapy and possible future treatment options

Cited by 23 publications

References 123 publications

The Causative Pathogen Determines the Inflammatory Profile in Cerebrospinal Fluid and Outcome in Patients with Bacterial Meningitis

The Causative Pathogen Determines the Inflammatory Profile in Cerebrospinal Fluid and Outcome in Patients with Bacterial Meningitis

Interactions between Blood-Borne Streptococcus pneumoniae and the Blood-Brain Barrier Preceding Meningitis

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

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