Yang Sheng, Huang Yufei, Shi Yonghong, Bai Xuebing, Yang Ping, Chen Qiusheng
MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, Jiangsu Province, 210095, China.
Shanghai Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Shanghai, 200241, China.
J Virol. 2021 Mar 10;95(7). doi: 10.1128/JVI.02191-20. Epub 2021 Jan 20.
Tembusu Virus (TMUV) is an emerging and re-emerging zoonotic pathogen that adversely affects poultry industry in recent years. TMUV disease is characterized by nonsuppurative encephalitis in ducklings. The duckling infection model was established to study the mechanism of TMUV crossing the blood-brain barrier (BBB) into the central nervous system (CNS). Here, we showed that no obvious clinical symptoms and enhancement of BBB permeability occurred at the early stage of infection (3∼5 dpi). While simultaneously virus particles were observed by transmission electron microscopy in the brain, inducing the accumulation of inflammatory cytokines. Neurological symptoms and disruption of BBB appeared at the intermediate stage of infection (7∼9 dpi). It was confirmed that TMUV could survive and propagate in brain microvascular endothelial cells (BMECs), but did not affect the permeability of BBB and at an early date. In conclusion, TMUV enters the CNS then causes encephalitis, and finally destruct the BBB, which may be due to the direct effect of TMUV on BMECs and the subsequent response of "inflammatory storm". The TMUV disease has caused huge losses to the poultry industry in Asia, which is potentially harmful to public health. Neurological symptoms and their sequelae are the main characters of this disease. However, the mechanism of how this virus enters the brain and causes encephalitis is unclear. In this study, we confirmed that the virus entered the CNS and then massively destroyed BBB and the BBB damage was closely associated with the subsequent outbreak of inflammation. TMUV may enter the CNS through the transcellular and "Trojan horse" pathways. These findings can fill the knowledge gap in the pathogenesis of TMUV-infected poultry and be benefit for the treatment of TMUV disease. What's more, TMUV is a representative to study the infection of avian flavivirus. Therefore, our studies have significances both for understanding of the full scope of mechanisms of TMUV and other flavivirus infection, and conceivably, for therapeutics.
坦布苏病毒（TMUV）是一种近年来对家禽业产生不利影响的新发和再发人畜共患病原体。TMUV疾病的特征是雏鸭发生非化脓性脑炎。建立了雏鸭感染模型以研究TMUV穿过血脑屏障（BBB）进入中枢神经系统（CNS）的机制。在此，我们发现感染早期（感染后3至5天）未出现明显临床症状，BBB通透性也未增强。同时，通过透射电子显微镜在脑中观察到病毒颗粒，诱导炎症细胞因子的积累。感染中期（感染后7至9天）出现神经症状和BBB破坏。证实TMUV可在脑微血管内皮细胞（BMECs）中存活和繁殖，但早期不影响BBB的通透性。总之，TMUV进入中枢神经系统然后导致脑炎，最终破坏BBB，这可能是由于TMUV对BMECs的直接作用以及随后的“炎症风暴”反应。TMUV疾病给亚洲家禽业造成了巨大损失，对公众健康具有潜在危害。神经症状及其后遗症是该疾病的主要特征。然而，这种病毒如何进入大脑并引起脑炎的机制尚不清楚。在本研究中，我们证实病毒进入中枢神经系统然后大量破坏BBB，并且BBB损伤与随后的炎症爆发密切相关。TMUV可能通过跨细胞和“特洛伊木马”途径进入中枢神经系统。这些发现可以填补TMUV感染家禽发病机制方面的知识空白，并有助于治疗TMUV疾病。此外，TMUV是研究禽黄病毒感染的一个代表。因此，我们的研究对于理解TMUV和其他黄病毒感染的全面机制具有重要意义，并且可以想象，对于治疗学也具有重要意义。
