Neuronal injury in bacterial meningitis: mechanisms and implications for therapy

Nau, Roland; Brück, Wolfgang

doi:10.1016/s0166-2236(00)02024-5

Cited by 268 publications

(216 citation statements)

References 77 publications

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“…In fact, although we have not yet examined the extent of apoptosis in brain abscesses, work by others has demonstrated that apoptosis represents a relatively minor component of parenchymal cell death in the brain abscess model (7). The necrotic cell death characteristic of brain abscesses differs from that described for bacterial meningitis, where apoptosis is implicated as one of the main pathophysiological effector mechanisms (54,55). Another possibility to account for the accelerated mortality rate of MyD88 KO mice is that the animals may become septic due to the dramatic destruction of brain parenchyma and failure to contain lesions; however, this remains speculative at the present time.…”

Section: Discussionmentioning

confidence: 88%

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

Kielian

Phulwani

Esen

et al. 2007

The Journal of Immunology

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Brain abscesses form in response to a parenchymal infection by pyogenic bacteria, with Staphylococcus aureus representing a common etiologic agent of human disease. Numerous receptors that participate in immune responses to bacteria, including the majority of TLRs, the IL-1R, and the IL-18R, use a common adaptor molecule, MyD88, for transducing activation signals leading to proinflammatory mediator expression and immune effector functions. To delineate the importance of MyD88-dependent signals in brain abscesses, we compared disease pathogenesis using MyD88 knockout (KO) and wild-type (WT) mice. Mortality rates were significantly higher in MyD88 KO mice, which correlated with a significant reduction in the expression of several proinflammatory mediators, including but not limited to IL-1β, TNF-α, and MIP-2/CXCL2. These changes were associated with a significant reduction in neutrophil and macrophage recruitment into brain abscesses of MyD88 KO animals. In addition, microglia, macrophages, and neutrophils isolated from the brain abscesses of MyD88 KO mice produced significantly less TNF-α, IL-6, MIP-1α/CCL3, and IFN-γ-induced protein 10/CXCL10 compared with WT cells. The lack of MyD88-dependent signals had a dramatic effect on the extent of tissue injury, with significantly larger brain abscesses typified by exaggerated edema and necrosis in MyD88 KO animals. Interestingly, despite these striking changes in MyD88 KO mice, bacterial burdens did not significantly differ between the two strains at the early time points examined. Collectively, these findings indicate that MyD88 plays an essential role in establishing a protective CNS host response during the early stages of brain abscess development, whereas MyD88-independent pathway(s) are responsible for pathogen containment.

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Section: Discussionmentioning

confidence: 88%

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

Kielian

Phulwani

Esen

et al. 2007

The Journal of Immunology

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“…The effect of T cells in the central nervous system (CNS) appears to be context-dependent, as their presence has been shown to promote neuronal survival following certain types of injuries or, conversely, contribute to CNS pathology, such as in experimental autoimmune encephalomyelitis (EAE) and infection (Byram et al, 2004;Martino and Hartung, 1999;Nau and Bruck, 2002;Schwartz, 2001;Serpe et al, 1999). Peripheral transection of the facial nerve in adult mice induces retrograde neuronal cell loss in the facial motor nucleus (FMN) that is accompanied by a site-specific infiltration of T cells across an intact blood-brain-barrier to the injured motor neurons (Moran and Graeber, 2004;Raivich et al, 1998).…”

Section: Introductionmentioning

confidence: 99%

Influence of injury severity on the rate and magnitude of the T lymphocyte and neuronal response to facial nerve axotomy

Ha¹,

Parikh²,

Huang³

et al. 2008

Journal of Neuroimmunology

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The temporal relationship between severity of peripheral axonal injury and T lymphocyte trafficking to the neuronal cell bodies of origin in the brain has been unclear. We sought to test the hypothesis that greater neuronal death induced by disparate forms of peripheral nerve injury would result in differential patterns of T cell infiltration and duration at the cell bodies of origin in the brain and that these measures would correlate with the magnitude of neuronal death over time and cumulative neuronal loss. To test this hypothesis, we compared the time course of CD3 + T cell infiltration and neuronal death (assessed by CD11b + perineuronal microglial phagocytic clusters) following axonal crush versus axonal resection injuries, two extreme variations of facial nerve axotomy that result in mild versus severe neuronal loss, respectively, in the facial motor nucleus. We also quantified the number of facial motor neurons present at 49 days post-injury to determine whether differences in the levels of neuronal death between nerve crush and resection correlated with differences in cumulative neuronal loss. Between 1-7 days post-injury when levels of neuronal death were minimal, we found that the rate of accumulation and magnitude of the T cell response was similar following nerve crush and resection. Differences in the T cell response were apparent by 14 days post-injury when the level of neuronal death following resection was substantially greater than that seen in crush injury. For nerve resection, the peak of neuronal death at 14 days post-resection was followed by a maximal T cell response one week later at 21 days. Differences in the level of neuronal death between the two injuries across the time course tested reflected differences in cumulative neuronal loss at 49 days post-injury. Altogether, these data suggest that the trafficking of T cells to the injured FMN is dependent upon the intensity of peripheral nerve injury and associated neuronal death.

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“…However, the functional consequences resulting from changes in the extent of astrocyte coupling remain an area of debate and are likely influenced by the context of CNS damage (Farahani et al, 2005;Perez Velazquez et al, 2003). Neuroinflammation is a hallmark of various CNS pathologies such as trauma, bacterial meningitis, brain abscess, Alzheimer's disease, and multiple sclerosis, which share a general feature of reactive gliosis characterized, to varying degrees, by the proliferation and hypertrophy of activated astrocytes (Eikelenboom et al, 2002;Griffin and Mrak, 2002;Kielian, 2004;Koedel et al, 2002;McGeer and McGeer, 2002;Nau and Bruck, 2002;Scheld et al, 2002). When activated by an appropriate stimulus, astrocytes have the capacity to produce robust amounts of proinflammatory mediators which may have profound effects on GJC (Dong and Benveniste, 2001;Esen et al, 2004;Kim et al, 2005;Smits et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

Esen

Shuffield

Syed

et al. 2006

Glia

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Gap junctions establish direct intercellular conduits between adjacent cells and are formed by the hexameric organization of protein subunits called connexins (Cx). It is unknown whether the proinflammatory milieu that ensues during CNS infection with S. aureus, one of the main etiologic agents of brain abscess in humans, is capable of eliciting regional changes in astrocyte homocellular gap junction communication (GJC) and, by extension, influencing neuron homeostasis at sites distant from the primary focus of infection. Here we investigated the effects of S. aureus and its cell wall product peptidoglycan (PGN) on Cx43, Cx30, and Cx26 expression, the main Cx isoforms found in astrocytes. Both bacterial stimuli led to a time-dependent decrease in Cx43 and Cx30 expression; however, Cx26 levels were elevated following bacterial exposure. Functional examination of dye coupling, as revealed by single-cell microinjections of Lucifer yellow, demonstrated that both S. aureus and PGN inhibited astrocyte GJC. Inhibition of protein synthesis with cyclohexamide (CHX) revealed that S. aureus directly modulates, in part, Cx43 and Cx30 expression, whereas Cx26 levels appear to be regulated by a factor(s) that requires de novo protein production; however, CHX did not alter the inhibitory effects of S. aureus on astrocyte GJC. The p38 MAPK inhibitor SB202190 was capable of partially restoring the S. aureus-mediated decrease in astrocyte GJC to that of unstimulated cells, suggesting the involvement of p38 MAPK-dependent pathway(s). These findings could have important implications for limiting the long-term detrimental effects of abscess formation in the brain which may include seizures and cognitive deficits.

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Neuronal injury in bacterial meningitis: mechanisms and implications for therapy

Cited by 268 publications

References 77 publications

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

MyD88-Dependent Signals Are Essential for the Host Immune Response in Experimental Brain Abscess

Influence of injury severity on the rate and magnitude of the T lymphocyte and neuronal response to facial nerve axotomy

Modulation of connexin expression and gap junction communication in astrocytes by the gram‐positive bacterium S. aureus

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