Japanese encephalitis virus neuropenetrance is driven by mast cell chymase.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Hsieh, JT; Rathore, APS; Soundarajan, G; St John, AL

Published Date

  • February 11, 2019

Published In

Volume / Issue

  • 10 / 1

Start / End Page

  • 706 -

PubMed ID

  • 30742008

Pubmed Central ID

  • PMC6370868

Electronic International Standard Serial Number (EISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/s41467-019-08641-z

Language

  • eng

Conference Location

  • England