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

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.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...

Role of Pore-Forming Toxins in Bacterial Infectious Diseases

“…Additionally, the introduction of a novel class of antimicrobial prophylactic or therapeutic agents would open up possibilities for adjunctive therapy (e.g., coadministration with existing antibiotics), which may result in synergistic effects. The use of existing bactericidal antibiotics can lead to increased release of PFTs from bacteria (as observed, for example, during treatment of S. pneumoniae infection [392]), and adjunctive therapy could also limit the damage caused by the released PFTs (e.g., in line with the S. pneumoniae example, anti-PLY antibodies can limit PLY effects [483], and administration of antibodies that inhibit B. anthracis ALO's cytotoxic properties have a protective effect in B. anthracis-infected mice [484]). …”

Hydrogen peroxide at a concentration used during neurosurgery disrupts ciliary function and causes extensive damage to the ciliated ependyma of the brain

“…Small animals with primary ciliary dyskinesia (PCD) commonly develop hydrocephalus and hydrocephalus is also occasionally seen in humans with PCD [9,10]. It is known that bacteria and their toxins adversely affect ciliary function [4,5,11] and it has been shown that viral or bacterial infection of the CSF, in animal models, may cause ependymal damage and hydrocephalus [7,8].…”

Controversies in the Treatment of Pneumococcal Community-Acquired Pneumonia

“…Although it is not our intention to detract from the value of β-lactam therapy in CAP, we believe that strategies exist through which the efficacy of β-lactams can be improved. This contention is based on observations that cellwall-targeted antibiotics such as ceftriaxone [72] and penicillin [73] are much less effective inhibitors of pneumolysin synthesis than agents that target protein synthesis [72], and may even increase pneumolysin release due to lysis of bacteria [73]. These apparent limitations of bactericidal, cell-wall-directed antibiotics, albeit derived from experimental systems, are supported by clinical failure rates of 10-15% in CAP in the setting of seemingly appropriate cephalosporin/penicillin monotherapy, and even higher (22-54%) in the intensive care unit setting.…”