Abstract
Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis. 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. Here we show that JEV activates MCs, leading to the release of granule-associated proteases in vivo. MC-deficient mice display reduced BBB permeability during JEV infection compared to congenic wild-type (WT) mice, indicating that enhanced vascular leakage in the brain during JEV infection is MC-dependent. Moreover, MCs promoted increased JEV infection in the central nervous system (CNS), enhanced neurological deficits, and reduced survival in vivo. Mechanistically, chymase, a MC-specific protease, enhances JEV-induced breakdown of the BBB and cleavage of tight-junction proteins. Chymase inhibition reversed BBB leakage, reduced brain infection and neurological deficits during JEV infection, and prolonged survival, suggesting chymase is a novel therapeutic target to prevent JEV encephalitis.
Highlights
Japanese encephalitis virus (JEV) is a leading cause of viral encephalitis
We examined the brains of JEVinfected animals for evidence of Mast cells (MCs) degranulation
Mice were infected with 2 × 107 plaque forming units (PFU) of JEV, strain
Summary
The mechanisms of JEV penetration of the blood-brain-barrier (BBB) remain poorly understood. MCs promoted increased JEV infection in the central nervous system (CNS), enhanced neurological deficits, and reduced survival in vivo. Chymase, a MC-specific protease, enhances JEV-induced breakdown of the BBB and cleavage of tight-junction proteins. BBB leakage, reduced brain infection and neurological deficits during JEV infection, and prolonged survival, suggesting chymase is a novel therapeutic target to prevent JEV encephalitis. Breakdown of tight junctions (TJs) between brain endothelial cells has been shown to occur and can potentially facilitate JEV entry into the brain, as supported by JEV-induced breakdown of TJ proteins in vivo in mice[12]. Suspected to have an immune component, the factors initiating BBB breakdown during JEV infection remain elusive
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