Program in Emerging Infectious Diseases, Duke-National University of Singapore Medical School, Singapore, 169857, Singapore.
Department of Pathology, Duke University Medical Center, Durham, 27710, NC, USA.
Nat Commun. 2019 Feb 11;10(1):706. doi: 10.1038/s41467-019-08641-z.
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.
日本脑炎病毒（JEV）是病毒性脑炎的主要病因。然而，JEV 穿透血脑屏障（BBB）的机制仍知之甚少。肥大细胞（MCs）是位于血管周围的颗粒状先天免疫哨兵，包括在 BBB 中。在这里，我们表明 JEV 激活 MCs，导致体内颗粒相关蛋白酶的释放。与同基因野生型（WT）小鼠相比，MC 缺陷小鼠在 JEV 感染期间显示出 BBB 通透性降低，表明 JEV 感染期间大脑中血管渗漏增加是 MC 依赖性的。此外，MCs 促进了中枢神经系统（CNS）中 JEV 感染的增加、神经功能缺损的加重和体内存活率的降低。从机制上讲，糜酶，一种 MC 特异性蛋白酶，增强了 JEV 诱导的 BBB 破裂和紧密连接蛋白的裂解。糜酶抑制逆转了 BBB 渗漏，减少了 JEV 感染期间的脑感染和神经功能缺损，并延长了存活时间，表明糜酶是预防 JEV 脑炎的新的治疗靶点。
