The role of mast cells in Japanese encephalitis virus penetration of the blood-brain barrier Justin Hsieh1*, Abhay Rathore1, Gayathri Soundarajan1, Ashley St. John1 1Duke-NUS Medical School, Singapore *Corresponding author
Japanese encephalitis virus (JEV) is the leading cause of viral encephalitis in Asia. However, the mechanisms of JEV penetration of the blood-brain-barrier (BBB) remain poorly understood. Mast cells (MCs) are granulated innate immune sentinels located perivascularly, including at the BBB. They pre-store inflammatory mediators, including proteases that are capable of regulating vascular permeability. A similar flavivirus to JEV, dengue virus, has been shown to activate MCs and contribute to the pathologic vascular leakage that is characteristic of severe dengue infection. Therefore, we hypothesized that JEV could activate MCs, leading to the release of granule-associated products that could promote breakdown of the BBB. Our data using WT (C57BL/6) and congenic MC-deficient (Sash) mice show that JEV infection induces mast cell degranulation in vivo and causes enhanced vascular leakage in the brain in a MC-dependent manner. Moreover, WT mice displayed increased JEV infection in the central nervous system (CNS), enhanced neurological deficit, and reduced survival compared to Sash mice. Mechanistically, we show that chymase, a MC-specific protease, is a key mediator that enhances JEV-induced breakdown of the BBB. Our findings also point to chymase as a factor in worsening JEV infection and associated pathologies in the brain. Chymase inhibition reversed JEV-induced vascular leakage in the brain as well as neurological deficits, suggesting chymase as a novel therapeutic target to prevent JEV encephalitis.