Experimental Pneumococcal Meningitis in Mice: A Model of Intranasal Infection

Department of Pediatrics, University Hospital Vrije Universiteit, and Department of Experimental Internal Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ, Amsterdam, The Netherlands.
The Journal of Infectious Diseases (Impact Factor: 6). 05/2001; 183(7):1143-6. DOI: 10.1086/319271
Source: PubMed


Effective laboratory animal models of bacterial meningitis are needed to unravel the pathophysiology of this disease. Previous models have failed to simulate human meningitis by using a directly intracerebral route of infection. Hyaluronidase is a virulence factor of Streptococcus pneumoniae. In this study, a novel model of murine meningitis is described. Intranasal administration of S. pneumoniae with hyaluronidase induced meningitis in 50% of inoculated mice, as defined by a positive cerebrospinal fluid (CSF) culture and an inflammatory infiltrate in the meninges. None of the mice inoculated without hyaluronidase developed meningitis. Hyaluronidase was found to facilitate pneumococcal invasion of the bloodstream after colonization of the upper respiratory tract. Meningitis was characterized by pleocytosis of CSF and the induction of proinflammatory cytokines and CXC chemokines in brain tissue. These results indicate that this murine model mimics important features of human disease and allow for the use of this model for studying issues related to the pathophysiology and the treatment of pneumococcal meningitis.

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    • "A previous report demonstrated the upexpression of PTS-EIIA and ugl during infection of the lung, indicating that utilization of HA may also contribute to bacterial growth during disease [35]. Probably in in vivo the pneumococcal hyaluronate lyase aids bacterial invasion and this localized invasion contributes to bacterial colonization in addition to degrading HA for nutrition [14, 36]. "
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    ABSTRACT: We investigate the role of hyaluronic acid (HA) on S. pneumoniae in vitro biofilm formation and evaluate gene expressions of virulence and/or biofilm related genes. Biofilms were grown in medium supplied with HA derived from capsule of Streptococcus equi. The biomasses of biofilms were detected by crystal-violet (CV) microtiter plate assay, and the morphology was viewed under scanning electron microscope (SEM). The gene expressions were assessed by relative quantitative RT-PCR. The results showed that the HA support pneumococcal growth in planktonic form and within biofilms. The CV-microtiter plate assay detected significantly increased biofilm growth in medium containing HA. The SEM analysis revealed thick and organized biofilms in positive control and HA supplemented medium. The nanA, nanB, bgaA, strH, luxS, hysA, ugl, and PST-EIIA encoding genes were significantly upregulated in the planktonic cells grown in presence of HA, while the lytA and comA genes were downregulated. Similarly the luxS, hysA, ugl, and PST-EIIA encoding genes were significantly upregulated by more than 2-folds in HA biofilms. The results of this study indicate that the HA derived from capsule of S. equi supports pneumococcal growth in planktonic state and within biofilms and upregulated virulence and biofilm related genes.
    09/2013; 2013:690217. DOI:10.1155/2013/690217
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    • "Several murine models have been developed, using intracerebral [14,15], intraperitoneal [16], intravenous [16], intranasal [17] or intracisternal inoculation methods [18,19], and have recently been reviewed [12]. Problems with reproducibility, limited disease progression or iatrogenic structural damage, combined with a need for a single model in which most pathological features seen in human pneumococcal meningitis can be measured, has fueled the development of new animal models. "
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    ABSTRACT: S. pneumoniae is the most common causative agent of meningitis, and is associated with high morbidity and mortality. We aimed to develop an integrated and representative pneumococcal meningitis mouse model resembling the human situation. Adult mice (C57BL/6) were inoculated in the cisterna magna with increasing doses of S. pneumoniae serotype 3 colony forming units (CFU; n = 24, 104, 105, 106 and 107 CFU) and survival studies were performed. Cerebrospinal fluid (CSF), brain, blood, spleen, and lungs were collected. Subsequently, mice were inoculated with 104 CFU S. pneumoniae serotype 3 and sacrificed at 6 (n = 6) and 30 hours (n = 6). Outcome parameters were bacterial outgrowth, clinical score, and cytokine and chemokine levels (using Luminex®) in CSF, blood and brain. Meningeal inflammation, neutrophil infiltration, parenchymal and subarachnoidal hemorrhages, microglial activation and hippocampal apoptosis were assessed in histopathological studies. Lower doses of bacteria delayed onset of illness and time of death (median survival CFU 104, 56 hrs; 105, 38 hrs, 106, 28 hrs. 107, 24 hrs). Bacterial titers in brain and CSF were similar in all mice at the end-stage of disease independent of inoculation dose, though bacterial outgrowth in the systemic compartment was less at lower inoculation doses. At 30 hours after inoculation with 104 CFU of S. pneumoniae, blood levels of KC, IL6, MIP-2 and IFN- γ were elevated, as were brain homogenate levels of KC, MIP-2, IL-6, IL-1β and RANTES. Brain histology uniformly showed meningeal inflammation at 6 hours, and, neutrophil infiltration, microglial activation, and hippocampal apoptosis at 30 hours. Parenchymal and subarachnoidal and cortical hemorrhages were seen in 5 of 6 and 3 of 6 mice at 6 and 30 hours, respectively. We have developed and validated a murine model of pneumococcal meningitis.
    BMC Infectious Diseases 03/2012; 12(1):71. DOI:10.1186/1471-2334-12-71 · 2.61 Impact Factor
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    • "Experimental evidence suggests that the choroid plexus may be a site of invasion [Daum et al. 1978]. Meningococci are found in the choroid plexus as well as in the meninges [Pron et al. 1997] and pneumococci infiltrate the leptomeningeal blood vessels [Zwijnenburg et al. 2001; Rodriguez et al. 1991] in meningitis. These data suggest that several highly vascularized sites are potential entry locations. "
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    ABSTRACT: Bacterial meningitis is a medical emergency requiring immediate diagnosis and immediate treatment. Streptococcus pneumoniae and Neisseria meningitidis are the most common and most aggressive pathogens of meningitis. Emerging antibiotic resistance is an upcoming challenge. Clinical and experimental studies have established a more detailed understanding of the mechanisms resulting in brain damage, sequelae and neuropsychological deficits. We summarize the current pathophysiological concept of acute bacterial meningitis and present current treatment strategies.
    Therapeutic Advances in Neurological Disorders 11/2009; 2(6):1-7. DOI:10.1177/1756285609337975 · 3.14 Impact Factor
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