Listeria monocytogenes-infected phagocytes are present in the bloodstream of experimentally infected mice, but whether they play a role in central nervous system (CNS) invasion is unclear. To test whether bacteria within infected leukocytes could establish CNS infection, experimentally infected mice were treated with gentamicin delivered by surgically implanted osmotic pumps. Bacterial inhibitory titers in serum and plasma ranged from 1:16 to 1:256, and essentially all viable bacteria in the bloodstream of treated mice were leukocyte associated. Nevertheless, CNS infection developed in gentamicin-treated animals infected intraperitoneally or by gastric lavage, suggesting that intracellular bacteria could be responsible for neuroinvasion. This was supported by data showing that 43.5% of bacteria found with blood leukocytes were intracellular and some colocalized with F-actin, indicating productive intracellular parasitism. Experiments using an L. monocytogenes strain containing a chromosomal actA-gfpuv-plcB transcriptional fusion showed that blood leukocytes were associated with intracellular and extracellularly bound green fluorescent protein-expressing (GFP ؉ ) bacteria. Treatment with gentamicin decreased the numbers of extracellularly bound GFP ؉ bacteria significantly but did not affect the numbers of intracellular GFP ؉ bacteria, suggesting that the latter were the result of intercellular spread of GFP ؉ bacteria to leukocytes. These data demonstrate that infected leukocytes and the intracellular L. monocytogenes harbored within them play key roles in neuroinvasion. Moreover, they suggest that phagocytes recruited to infected organs such as the liver or spleen are themselves parasitized by intercellular spread of L. monocytogenes and then reenter the bloodstream and contribute to the systemic dissemination of bacteria.Listeria monocytogenes is a facultative intracellular bacterium that infects the central nervous system (CNS) of humans and domesticated animals (21, 22). Most human infections result from ingestion of contaminated food and typically manifest as febrile gastroenteritis (25). Immunosuppressed hosts, however, are much more likely to develop invasive listeriosis marked by bacteremia, CNS infection, and death (24,27). Although the precise mechanism(s) used by L. monocytogenes for entering the CNS are not clear, current theory indicates that neuroinvasive bacteria in general can enter the CNS by several different routes (37). These include invasion of microvascular endothelial cells, invasion of epithelial cells of the choroid plexus, and passage of bacteria through intercellular junctions. In addition, bacteria that are capable of intracellular survival can enter the CNS via phagocyte-facilitated infection, the major steps of which are adhesion of infected phagocytes to endothelium followed by cell-to cell spread of bacteria to endothelial cells and/or migration of infected phagocytes into the CNS (10).Experimental L. monocytogenes infection of mice shows that bacteria enter the CNS following prol...
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