Background: The role played by pneumolysin and autolysin in pneumococcal meningitis is poorly understood.\ud Method: A rat model was used to investigate the disease, in which surgical implantation of a cisternal catheter allowed bacterial instillation and cerebrospinal fluid (CSF) sampling.\ud Results: CSF infection of rats with wild-type pneumococci caused meningitis within 26 h, whereas isogenic mutants that do not express pneumolysin (∆Ply) or autolysin (LytA ¯) caused very mild or no disease. Wild-type infections resulted in pneumococci in the CSF and cortical homogenates, but a minority of the rats infected with ∆Ply or LytA ¯had bacteria in these locations at 26 h. Leukocyte numbers in the CSF were similar after infection with all\ud pneumococci; however, neutrophils and monocytes predominated after wild-type infection, whereas lymphocytes and atypical lymphocytes predominated after infection with the mutants. Wild-type pneumococci caused disruption to the ependyma, but this was not observed in rats infected with ∆Ply or LytA ¯. Cells surrounding the ventricles in wild type–infected animals expressed caspase 3, and astrocytes had hypertrophy; both findings were absent in rats infected with the mutants.\ud Conclusions: This study provides strong in vivo evidence that pneumolysin and autolysin play crucial roles in the pathogenesis of pneumococcal meningitis
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