Abstract
BackgroundThe prognosis of bacterial meningitis largely depends on the severity of the inflammatory response. The transcription factor CAAT/enhancer-binding protein δ (C/EBPδ) plays a key role in the regulation of the inflammatory response during bacterial infections. Consequently, we assessed the role of C/EBPδ during experimental meningitis.MethodsWild-type and C/EBPδ-deficient mice (C/EBPδ−/−) were intracisternally infected with Streptococcus pneumoniae and sacrificed after 6 or 30 h, or followed in a survival study.ResultsIn comparison to wild-type mice, C/EBPδ−/− mice showed decreased bacterial loads at the primary site of infection and decreased bacterial dissemination to lung and spleen 30 h after inoculation. Expression levels of the inflammatory mediators IL-10 and KC were lower in C/EBPδ−/− brain homogenates, whereas IL-6, TNF-α, IL-1β, and MIP-2 levels were not significantly different between the two genotypes. Moreover, C/EBPδ−/− mice demonstrated an attenuated systemic response as reflected by lower IL-10, IL-6, KC, and MIP-2 plasma levels. No differences in clinical symptoms or in survival were observed between wild-type and C/EBPδ−/− mice.ConclusionC/EBPδ in the brain drives the inflammatory response and contributes to bacterial dissemination during pneumococcal meningitis. C/EBPδ does, however, not affect clinical parameters of the disease and does not confer a survival benefit.
Highlights
Bacterial meningitis remains an important cause of mortality and morbidity worldwide, despite the implementation of vaccination strategies, effective antibiotic therapy and adjunctive dexamethasone treatment [1,2]
CAAT/enhancer-binding protein δ (C/EBPδ) expression is increased during pneumococcal meningitis To obtain insight into the expression of C/EBPδ during meningitis caused by S. pneumoniae, we measured c/ebpδ mRNA levels in brain tissue from wild-type mice intracisternally inoculated with 1 × 104 CFU. c/ebpδ mRNA expression was low in uninfected brain, slightly increased at 6 h after S. pneumoniae inoculation, this did not reach statistical difference, whereas c/ebpδ levels were about tenfold increased at 30 h after infection (Figure 1A)
C/EBPδ was strongly expressed in the endothelium, ependymal and choroid plexus, and, to a lesser extent, in glia and arachnoidal cells
Summary
Bacterial meningitis remains an important cause of mortality and morbidity worldwide, despite the implementation of vaccination strategies, effective antibiotic therapy and adjunctive dexamethasone treatment [1,2]. C/EBPδ was shown to limit bacterial dissemination and prolong survival during a lethal model of Escherichia coli-induced peritonitis and during Klebsiella pneumoniae-induced pulmonary infection [12,13]. During Streptococcus pneumoniae-induced pulmonary infection, C/EBPδ exaggerated bacterial dissemination and wild-type mice succumbed earlier to the disease as compared to C/EBPδ−/− mice [14]. C/EBPδ seems to play a complex and potential dual role during infectious disease most likely depending on the causing pathogen, the severity of the infection and the infection site. The prognosis of bacterial meningitis largely depends on the severity of the inflammatory response. The transcription factor CAAT/enhancer-binding protein δ (C/EBPδ) plays a key role in the regulation of the inflammatory response during bacterial infections. Methods: Wild-type and C/EBPδ-deficient mice (C/EBPδ−/−) were intracisternally infected with Streptococcus pneumoniae and sacrificed after 6 or 30 h, or followed in a survival study. No differences in clinical symptoms or in survival were observed between wild-type and C/EBPδ−/− mice
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