Abstract
BackgroundPneumococcal meningitis (PM) is a life-threatening disease with a high case-fatality rate and elevated risk for serious neurological sequelae. In this study, we investigated the contribution of three major virulence factors of Streptococcus pneumoniae, the capsule, pneumococcal surface protein A (PspA) and C (PspC), to the pathogenesis of experimental PM.MethodsMice were challenged by the intracranial route with the serotype 4 TIGR4 strain (wt) and three isogenic mutants devoid of PspA, PspC, and the capsule. Survival, bacterial counts, and brain histology were carried out. To study the interaction between S. pneumoniae mutants and microglia, phagocytosis and survival experiments were performed using the BV2 mouse microglial cell line.ResultsVirulence of the PspC mutant was comparable to that of TIGR4. In contrast, survival of animals challenged with the PspA mutant was significantly increased compared with the wt, and the mutant was also impaired at replicating in the brain and blood of infected mice. Brain histology indicated that all strains, except for the unencapsulated mutant, caused PM. Analysis of inflammation and damage in the brain of mice infected with TIGR4 or its unencapsulated mutant demonstrated that the rough strain was unable to induce inflammation and neuronal injury, even at high challenge doses. Results with BV2 cells showed no differences in phagocytic uptake between wt and mutants. In survival assays, however, the PspA mutant showed significantly reduced survival in microglia compared with the wt.ConclusionsPspA contributed to PM pathogenesis possibly by interacting with microglia at early infection stages, while PspC had limited importance in the disease. The rough mutant did not cause brain inflammation, neuronal damage or mouse death, strengthening the key role of the capsule in PM.
Highlights
Pneumococcal meningitis (PM) is a life-threatening disease with a high case-fatality rate and elevated risk for serious neurological sequelae
The pathogenesis of PM is highly complex and multifactorial, and it is difficult to ascribe a precise role to a bacterial virulence factor in the disease
The results obtained with our i.c. model indicate a limited role for Pneumococcal surface protein C (PspC), whereas pneumococcal surface protein A (PspA) participates in PM pathogenesis possibly by interacting with microglial cells at an early phase of infection
Summary
Pneumococcal meningitis (PM) is a life-threatening disease with a high case-fatality rate and elevated risk for serious neurological sequelae. We investigated the contribution of three major virulence factors of Streptococcus pneumoniae, the capsule, pneumococcal surface protein A (PspA) and C (PspC), to the pathogenesis of experimental PM. The microorganism produces a plethora of virulence factors, including the polysaccharide capsule, several surface-located proteins, and the toxin pneumolysin [1,2]. The capsule is a major virulence determinant due to its anti-phagocytic activity [3,4,5]. PspA interferes with complement activation and deposition mediated by both the classical and alternative pathways [6,7,8,9] and binds lactoferrin [10]. PspC shows anti-phagocytic properties due to its capability to bind to complement C3 [15] and factor H [11,16,17,18]
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