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Published on: September 23, 2022
Japanese encephalitis virus neuropenetrance is driven by mast cell chymase
Justin T Hsieh1, Abhay P S Rathore1,2, Gayathri Soundarajan1
1Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, 169857, Singapore.
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.
Insights
Japanese encephalitis virus (JEV) infection increases blood-brain barrier (BBB) permeability via mast cells (MCs). Inhibiting MC protease chymase reduces JEV brain entry and improves survival, revealing a therapeutic target for encephalitis.
Area of Science:
- Neuroscience
- Immunology
- Virology
Background:
- Japanese encephalitis virus (JEV) causes significant viral encephalitis globally.
- Mechanisms of JEV crossing the blood-brain barrier (BBB) are not fully understood.
- Mast cells (MCs), immune sentinels near the BBB, are implicated in neuroinflammation.
Purpose of the Study:
- To investigate the role of mast cells in JEV penetration of the BBB.
- To elucidate the molecular mechanisms by which MCs contribute to JEV encephalitis.
- To evaluate chymase as a potential therapeutic target against JEV-induced neuroinflammation.
Main Methods:
- Utilized MC-deficient and wild-type (WT) mice models for JEV infection.
- Assessed BBB permeability, viral load in the central nervous system (CNS), neurological deficits, and survival rates.
- Investigated the effect of chymase inhibition on JEV encephalitis.
Main Results:
- MC-deficient mice showed significantly reduced BBB permeability and CNS infection during JEV infection compared to WT mice.
- JEV activated MCs, leading to protease release and enhanced BBB breakdown.
- Chymase inhibition ameliorated BBB leakage, decreased neuroinflammation, and improved survival in JEV-infected mice.
Conclusions:
- Mast cells play a critical, MC-dependent role in JEV-induced blood-brain barrier disruption.
- MC-derived chymase is a key mediator of BBB damage and JEV neuroinvasion.
- Targeting chymase offers a promising therapeutic strategy to combat Japanese encephalitis.
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