Bacterial Cytolysin during Meningitis Disrupts the Regulation of Glutamate in the Brain, Leading to Synaptic Damage

Abstract

Streptococcus pneumoniae (pneumococcal) meningitis is a common bacterial infection of the brain. The cholesterol-dependent cytolysin pneumolysin represents a key factor, determining the neuropathogenic potential of the pneumococci. Here, we demonstrate selective synaptic loss within the superficial layers of the frontal neocortex of post-mortem brain samples from individuals with pneumococcal meningitis. A similar effect was observed in mice with pneumococcal meningitis only when the bacteria expressed the pore-forming cholesterol-dependent cytolysin pneumolysin. Exposure of acute mouse brain slices to only pore-competent pneumolysin at disease-relevant, non-lytic concentrations caused permanent dendritic swelling, dendritic spine elimination and synaptic loss. The NMDA glutamate receptor antagonists MK801 and D-AP5 reduced this pathology. Pneumolysin increased glutamate levels within the mouse brain slices. In mouse astrocytes, pneumolysin initiated the release of glutamate in a calcium-dependent manner. We propose that pneumolysin plays a significant synapto- and dendritotoxic role in pneumococcal meningitis by initiating glutamate release from astrocytes, leading to subsequent glutamate-dependent synaptic damage. We outline for the first time the occurrence of synaptic pathology in pneumococcal meningitis and demonstrate that a bacterial cytolysin can dysregulate the control of glutamate in the brain, inducing excitotoxic damage.

Infectious immunity in the central nervous system and brain function

“…Although baseline surveillance of the meninges and choroid plexus by interleukin 4 (IL-4)-expressing CD4 + type 2 helper T (T H 2) cells is critical for the performance of cognitive tasks 38 , high concentrations of T H 1 cytokines such as IL-1β, tumor necrosis factor (TNF) and interferon-γ (IFN-γ) may result in continued cognitive impairment after bacterial meningitis, as suggested by studies in animal models using agents that target these molecules 3 . Although the mechanisms that cause cognitive impairment during acute meningitis are incompletely understood, studies suggest involvement of global and regional disruptions in neurogenesis 39 , synaptic coupling 40 and neuronal circuitry 41 , all of which underlie various aspects of perception, mood, learning and memory formation.…”

Cerebrospinal fluid transcriptional analyses reveals upregulation of IL-17, Type 1 interferon transcriptional pathways and neutrophil persistence genes associated with increased mortality from pneumococcal meningitis in adults

“…The inflammatory cascade and cytotoxic effects of host pro-inflammatory mediators 11,12 together with bacterial toxins drive tissue damage characterised by apoptotic neuronal cell injury, raised intracranial pressure (ICP), thrombosis, cerebral oedema, and cerebral ischaemia. 13,14 These findings supported the use of anti-inflammatory agents, such as dexamethasone as adjunct therapies for PM. Dexamethasone has demonstrated efficacy in controlled trials in industrialised countries in HIV-negative adults with PM, with an estimated relative risk reduction in mortality of 0.5 (95% CI 0.3 -0.83).…”

“…53 Pneumolysin has been shown in PM to kill neutrophils, attenuate CNS leukocyte counts and cause direct neuronal cell death through synaptic dysfunction. 14,54,55 Our data show that the presence of increased pneumococci in the CSF is a significant driver of the observed CSF pro-inflammatory cascade, overexpression of the IL-17 pathway, attenuated neutrophil activity and increased host cell damage in may be due to correspondingly increased production of pneumolysin in the CSF. 56 High bacterial loads in the CSF of non-survivors in our study suggest bacterial control by neutrophils may be ineffective in these patients, we hypothesised that the neutrophil transcriptome would be down-regulated in non-survivors.…”

MicroRNAs expression changes in acute Streptococcus pneumoniae meningitis

“…Despite the significant advances in treatment, S. pneumoniae meningitis autopsy cases and in an animal model [22]. The observed long-term cognitive decline in survivors of pneumococcal meningitis may relate to synaptic damage and loss.…”