Spatio-temporal brain invasion pattern of Streptococcus pneumoniae and dynamic changes of the cellular environment in meningitis pathogenesis.

Abstract

Streptococcus pneumoniae (the pneumococcus) is the major cause of bacterial meningitis globally, and pneumococcal meningitis is associated with increased risk of long-term neurological sequelae. These include several sensorimotor functions that are controlled by specific brain regions which, during bacterial meningitis, are damaged by the vast neuroinflammation and bacterial toxins. Little is known about the invasion pattern of the pneumococcus into the brain. Using a bacteremia-derived meningitis mouse model, we combined 3D whole brain imaging with brain microdissection to show that all brain regions were equally affected during disease progression, with pneumococci in close association to the microvasculature. In the hippocampus, the invasion provoked a dynamic microglial response, while the dentate gyrus showed a significant loss of neuroblasts. Our results indicate that, even before symptom occur, the bacterial load throughout the brain causes neuroinflammation and cell death, a pathological scenario which ultimately leads to a failing regeneration of new neurons.