Increased permeability of blood–brain barrier is mediated by serine protease during Cryptococcus meningitis

Abstract

Objectives To determine the role of serine protease in the disruption of the blood–brain barrier (BBB) during Cryptococcus neoformans meningitis. Methods Reverse transcription–polymerase chain reaction and immunohistochemistry were used to determine the production of serine protease by different strains of C. neoformans. BBB permeability in immunosuppressed rats inoculated with C. neoformans or C. neoformans plus aprotinin was examined via Evans blue staining. In vitro BBB permeability (transwell passage of horseradish peroxidase) was determined in human brain microvascular endothelial cells (BMECs) cultured with serine protease or serine protease plus aprotinin. Electron microscopy of rat brain tissue was used to visualise C. neoformans infection. Results Serine protease mRNA and protein were detected in all C. neoformans serotypes. C. neoformans infection increased BBB permeability in vivo, but this effect was ameliorated by aprotinin. Treatment of BMECs with serine protease increased permeability in vitro. This effect was reversed by aprotinin. Conclusion Serine protease secreted by C. neoformans leads to BBB disruption during Cryptococcus meningitis. Serine protease may be a novel treatment target for Cryptococcus meningitis .