Characterization of a pneumococcal meningitis mouse model

<p>Abstract</p> <p>Background</p> <p><it>S. pneumoniae </it>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.</p> <p>Methods</p> <p>Adult mice (C57BL/6) were inoculated in the cisterna magna with increasing doses of <it>S. pneumoniae </it>serotype 3 colony forming units (CFU; n = 24, 10⁴, 10⁵, 10⁶and 10⁷CFU) and survival studies were performed. Cerebrospinal fluid (CSF), brain, blood, spleen, and lungs were collected. Subsequently, mice were inoculated with 10⁴CFU <it>S. pneumoniae </it>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.</p> <p>Results</p> <p>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 10⁴CFU of <it>S. pneumoniae</it>, 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.</p> <p>Conclusion</p> <p>We have developed and validated a murine model of pneumococcal meningitis.</p

Pathogenesis and Pathophysiology of Pneumococcal Meningitis

Summary: Pneumococcal meningitis continues to be associated with high rates of mortality and long-term neurological sequelae. The most common route of infection starts by nasopharyngeal colonization by Streptococcus pneumoniae, which must avoid mucosal entrapment and evade the host immune system after local activation. During invasive disease, pneumococcal epithelial adhesion is followed by bloodstream invasion and activation of the complement and coagulation systems. The release of inflammatory mediators facilitates pneumococcal crossing of the blood-brain barrier into the brain, where the bacteria multiply freely and trigger activation of circulating antigen-presenting cells and resident microglial cells. The resulting massive inflammation leads to further neutrophil recruitment and inflammation, resulting in the well-known features of bacterial meningitis, including cerebrospinal fluid pleocytosis, cochlear damage, cerebral edema, hydrocephalus, and cerebrovascular complications. Experimental animal models continue to further our understanding of the pathophysiology of pneumococcal meningitis and provide the platform for the development of new adjuvant treatments and antimicrobial therapy. This review discusses the most recent views on the pathophysiology of pneumococcal meningitis, as well as potential targets for (adjunctive) therapy