Cytotoxic Effects on Hair Cells of Guinea Pig Cochlea Produced by Pneumolysin, the Thiol Activated Toxin of<i>Streptococcus pneumoniae</i>

Comis, S. D.; Osborne, Michael P.; Stephen, J.; Tarlow, M J; Hayward, Tamasen; Mitchell, Timothy J.; Andrew, Peter W.; Boulnois, Graham J.

doi:10.3109/00016489309135784

Cited by 50 publications

(38 citation statements)

References 12 publications

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“…Use of adjunctive doxycycline also resulted in a moderate but significant decrease in the ABR thresholds of infected animals compared to the ABR thresholds of the animals that received only saline. This partial protection may reflect previous damage to the hair cells during the acute disease, probably caused by factors that adjunctive doxycycline could not attenuate, such as the release of bacterial pneumolysin in the perilymphatic and endolymphatic spaces (10,46). If this is the case, the withdrawal of neurotrophins normally produced by the hair cells might further aggravate neuron loss in the spiral ganglion (30).…”

Section: Discussionmentioning

confidence: 99%

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

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Bacterial meningitis is characterized by an inflammatory reaction to the invading pathogens that can ultimately lead to sensorineural hearing loss, permanent brain injury, or death. The matrix metalloproteinases (MMPs) and tumor necrosis factor alpha-converting enzyme (TACE) are key mediators that promote inflammation, blood-brain barrier disruption, and brain injury in bacterial meningitis. Doxycycline is a clinically used antibiotic with anti-inflammatory effects that lead to reduced cytokine release and the inhibition of MMPs. Here, doxycycline inhibited TACE with a 50% inhibitory dose of 74 M in vitro and reduced the amount of tumor necrosis factor alpha released into the cerebrospinal fluid by 90% in vivo. In an infant rat model of pneumococcal meningitis, a single dose of doxycycline (30 mg/kg) given as adjuvant therapy in addition to ceftriaxone 18 h after infection significantly reduced the mortality, the blood-brain barrier disruption, and the extent of cortical brain injury. Adjuvant doxycycline (30 mg/kg given subcutaneously once daily for 4 days) also attenuated hearing loss, as assessed by auditory brainstem response audiometry, and neuronal death in the cochlear spiral ganglion at 3 weeks after infection. Thus, doxycycline, probably as a result of its anti-inflammatory properties, had broad beneficial effects in the brain and the cochlea and improved survival in this model of pneumococcal meningitis in infant rats. Pneumococcal meningitis has a high level of mortality (up to 30%), and brain and/or cochlear damage occurs in up to 50% of the survivors (2). Inflammatory mediators, such as tumor necrosis factor alpha (TNF-␣) and matrix metalloproteinases (MMPs), are produced during the host response to bacteria and contribute to the pathophysiology that can ultimately lead to death, brain damage, and hearing impairment (23,26,29,36). The role of cytokines and MMPs in the pathophysiology of the cochlear damage associated with pneumococcal meningitis is still unknown. However, it has been demonstrated that MMPs are constitutively expressed at high levels in the cochlea (8) and that in meningitis pneumococci and polymorphonuclear leukocytes (PMNs) extend from the cerebrospinal fluid (CSF) to the perilymph via the cochlear aqueduct (5).Tetracyclines are bacteriostatic agents with broad-spectrum antimicrobial activity (3). Doxycycline is a semisynthetic, longacting, second-generation tetracycline which is absorbed rapidly and penetrates well into the brain and CSF (48). Doxycycline has been shown to have anti-inflammatory effects that are separate and distinct from its antimicrobial action (13,16,35,43). These effects include the reduction of cytokine release and the inhibition of MMPs (7, 38). Experimental and clinical studies have indicated that treatment with doxycycline may be beneficial in inflammatory diseases associated with excessive MMP activity (7,13,35).In pneumococcal meningitis massive subarachnoid and ventricular space inflammation is triggered by the presence of bacteria in the CSF space (7,1...

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Section: Discussionmentioning

confidence: 99%

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

et al. 2006

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“…In pneumococcal meningitis, pneumolysin causes the death of cochlear cells and subsequent hearing loss (12,40). Independently of the inflammatory response, pneumolysin also mediates neuronal loss in the dentate gyrus, where it is colocalized with neurons undergoing apoptosis (4).…”

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confidence: 99%

Pneumolysin Causes Neuronal Cell Death through Mitochondrial Damage

Braun

Hoffmann²,

Schickhaus³

et al. 2007

Infect Immun

106

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Bacterial toxins such as pneumolysin are key mediators of cytotoxicity in infections. Pneumolysin is a pore-forming toxin released by Streptococcus pneumoniae, the major cause of bacterial meningitis. We found that pneumolysin is the pneumococcal factor that accounts for the cell death pathways induced by live bacteria in primary neurons. The pore-forming activity of pneumolysin is essential for the induction of mitochondrial damage and apoptosis. Pneumolysin colocalized with mitochondrial membranes, altered the mitochondrial membrane potential, and caused the release of apoptosis-inducing factor and cell death. Pneumolysin induced neuronal apoptosis without activating caspase-1, -3, or -8. Wild-type pneumococci also induced apoptosis without activation of caspase-3, whereas pneumolysin-negative pneumococci activated caspase-3 through the release of bacterial hydrogen peroxide. Pneumolysin caused upregulation of X-chromosome-linked inhibitor of apoptosis protein and inhibited staurosporine-induced caspase activation, suggesting the presence of actively suppressive mechanisms on caspases. In conclusion, our results indicate additional functions of pneumolysin as a mitochondrial toxin and as a determinant of caspase-independent apoptosis. Considering this, blocking of pneumolysin may be a promising cytoprotective strategy in pneumococcal meningitis and other infections.

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“…This work and that of others (5,24) has led us to believe that blocking the toxic effects of pneumolysin may be advantageous, and the aim of the present study was to determine the ability of antipneumolysin antibodies to reduce damage to the ependymal layer. The rapid release of pneumolysin on antibiotic-induced bacterial lysis (23) is thought to contribute to toxic shock and local tissue damage and may partially be responsible for causing deafness (7). Recently we have shown that pneumococci and pneumolysin cause rapid ependymal ciliary stasis in ependymal brain slices and cultured primary ependymal cells (12), an effect that is mirrored in experimental meningitis in rats (11).…”

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confidence: 95%

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

et al. 2004

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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.Ependymal cells lining the ventricular surfaces and aqueducts of the brain form a barrier between the infected cerebrospinal fluid (CSF) of patients with meningitis and their neuronal tissue. Each ependymal cell is covered with around 40 cilia, which beat continuously (1) at a frequency between 35 and 40 Hz. We established an ex vivo model that allowed measurement of the ependymal ciliary beat frequency (CBF), by high-speed video photography, during exposure to bacteria and bacterial toxins. Our initial studies using this model targeted pneumococcal meningitis, for which new, improved therapeutic strategies are urgently required to reduce mortality and neurological damage (11,12,13,16). Currently, only dexamethasone has widely been used as an adjunctive therapy to antibiotic treatment (8). Although its use has shown benefit in a recent European trial (8), no benefit was demonstrated in a clinical trial in Africa (17).Our recent research has focused on the role of the pneumococcal toxin, pneumolysin, in the pathological process associated with pneumococcal meningitis (12,13). This work and that of others (5, 24) has led us to believe that blocking the toxic effects of pneumolysin may be advantageous, and the aim of the present study was to determine the ability of antipneumolysin antibodies to reduce damage to the ependymal layer. The rapid release of pneumolysin on antibiotic-induced bacterial lysis (23) is thought to contribute to toxic shock and local tissue damage and may partially be responsible for causing deafness (7). Recently we have shown that pneumococci and pneumolysin cause rapid ependymal ciliary stasis in ependymal brain slices and cultured primary ependymal cells (12), an effect that is mirrored in experimental meningitis in rats (11).The role of pneumolysin in pneumococcal meningitis has been further elucidated by results from recent in vivo studies (5,24,25). The use of ␤-lactam antibiotics leads to the rapid release of proinflammatory toxic bacterial compounds (18). Therefore, alternative strategies might seek to prevent the release of inflammatory compounds or to block them after they are released. Indeed, a recent study has shown reduced mortality and neuronal injury following treatment of pneumococcal meningitis with inhibit...

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Cytotoxic Effects on Hair Cells of Guinea Pig Cochlea Produced by Pneumolysin, the Thiol Activated Toxin ofStreptococcus pneumoniae

Cited by 50 publications

References 12 publications

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Doxycycline Reduces Mortality and Injury to the Brain and Cochlea in Experimental Pneumococcal Meningitis

Pneumolysin Causes Neuronal Cell Death through Mitochondrial Damage

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

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