Virology Division, United States Army Medical Research Institute of Infectious Diseases , Fort Detrick, Maryland, USA.
REGENXBIO, Inc ., Rockville, Maryland, USA.
Virulence. 2021 Dec;12(1):430-443. doi: 10.1080/21505594.2020.1870834.
Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus that can cause debilitating, acute febrile illness and potentially result in encephalitis. Currently, there are no FDA-licensed vaccines or specific therapeutics for VEEV. Previous studies have demonstrated that VEEV infection results in increased blood-brain barrier (BBB) permeability that is mediated by matrix metalloproteinases (MMPs). Furthermore, after subarachnoid hemorrhage in mice, MMP-9 is upregulated in the brain and mediates BBB permeability in a toll-like receptor 4 (TLR4)-dependent manner. Here, we demonstrate that disease in C3H mice during VEEV TC-83 infection is dependent on TLR4 because intranasal infection of C3H/HeN (TLR4 ) mice with VEEV TC-83 resulted in mortality as opposed to survival of TLR4-defective C3H/HeJ (TLR4 ) mice. In addition, BBB permeability was induced to a lesser extent in TLR4 mice compared with TLR4 mice during VEEV TC-83 infection as determined by sodium fluorescein and fluorescently-conjugated dextran extravasation. Moreover, MMP-9, MMP-2, ICAM-1, CCL2 and IFN-γ were all induced to significantly lower levels in the brains of infected TLR4 mice compared with infected TLR4 mice despite the absence of significantly different viral titers or immune cell populations in the brains of infected TLR4 and TLR4 mice. These data demonstrate the critical role of TLR4 in mediating BBB permeability and disease in C3H mice during VEEV TC-83 infection, which suggests that TLR4 is a potential target for the development of therapeutics for VEEV.
委内瑞拉马脑炎病毒（VEEV）是一种致脑炎的甲病毒，可引起使人虚弱的急性发热性疾病，并可能导致脑炎。目前，尚无 FDA 批准的 VEEV 疫苗或特定疗法。先前的研究表明，VEEV 感染会导致血脑屏障（BBB）通透性增加，这是由基质金属蛋白酶（MMPs）介导的。此外，在小鼠蛛网膜下腔出血后，MMP-9 在脑中上调，并以 Toll 样受体 4（TLR4）依赖性方式介导 BBB 通透性。在这里，我们证明 C3H 小鼠在 VEEV TC-83 感染期间的疾病依赖于 TLR4，因为 C3H/HeN（TLR4 ）小鼠经鼻腔感染 VEEV TC-83 会导致死亡，而 TLR4 缺陷型 C3H/HeJ（TLR4 ）小鼠则存活。此外，与 TLR4 小鼠相比，TLR4 小鼠在 VEEV TC-83 感染期间 BBB 通透性的诱导程度较低，这是通过荧光素钠和荧光标记的葡聚糖外渗来确定的。此外，尽管感染 TLR4 和 TLR4 小鼠的脑中病毒滴度或免疫细胞群没有明显差异，但感染 TLR4 小鼠脑中的 MMP-9、MMP-2、ICAM-1、CCL2 和 IFN-γ 的诱导水平均明显较低。这些数据表明 TLR4 在介导 C3H 小鼠在 VEEV TC-83 感染期间的 BBB 通透性和疾病方面发挥着关键作用，这表明 TLR4 是开发 VEEV 治疗方法的潜在靶点。
