Interferon-λ Attenuates Rabies Virus Infection by Inducing Interferon-Stimulated Genes and Alleviating Neurological Inflammation
Interferon-λ Attenuates Rabies Virus Infection by Inducing Interferon-Stimulated Genes and Alleviating Neurological Inflammation
复制标题
干扰素-α 通过诱导干扰素刺激基因并减轻神经炎症来减轻狂犬病病毒感染
DOI：
10.3390/v12040405
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发表时间：
2020-04-01
期刊：
影响因子：
4.7
通讯作者：
Zhou, Ming
中科院分区：
文献类型：
--
作者：
Li, Yingying;Zhao, Ling;Zhou, Ming
狂犬病由狂犬病病毒(RABV)引起，是一种致命的神经系统疾病，每年仍导致超过5.9万人死亡。S是一种具有I型干扰素样抗病毒活性的细胞因子。虽然干扰素-lambda可以抑制某些病毒，特别是肠道病毒的感染，但对RABV感染的抑制作用尚不清楚。本研究探讨了III型干扰素抗RABV感染的作用。最初，我们发现干扰素-lambda 2和干扰素-lambda 3能抑制RABV在细胞内的复制。为了研究干扰素-lambda在RABV感染小鼠模型中的作用，构建并回收了表达小鼠干扰素-lambda 2或干扰素-lambda 3的重组RABV，分别命名为rB2c-干扰素lambda 2或rB2c-干扰素lambda 3。研究发现，干扰素-lambda的表达可以降低RABV的致病性，并通过不同的感染途径限制病毒在脑内的传播。此外，干扰素-lambda的表达可以诱导JAK-STAT通路的激活，导致干扰素刺激基因(ISGs)的产生。研究还发现，表达干扰素-lambda的rRABV可以减少原代星形胶质细胞和微血管细胞中炎性细胞因子的产生，限制血脑屏障(BBB)的开放，防止炎性细胞过度渗透到脑内，这可能是RABV引起神经元损伤的原因之一。一致地，干扰素-lambda被发现维持血脑屏障紧密连接(TJ)蛋白ZO-1的完整性，以减轻Transwell模型中的神经炎症。我们的研究强调了干扰素-lambda在抑制RABV感染中的作用，从而增强了干扰素-lambda作为治疗RABV感染的可能的治疗剂的作用。
Rabies, caused by rabies virus (RABV), is a fatal neurological disease that still causes more than 59,000 human deaths each year. Type III interferon IFN-lambda s are cytokines with type I IFN-like antiviral activities. Although IFN-lambda can restrict the infection for some viruses, especially intestinal viruses, the inhibitory effect against RABV infection remains undefined. In this study, the function of type III IFN against RABV infection was investigated. Initially, we found that IFN-lambda 2 and IFN-lambda 3 could inhibit RABV replication in cells. To characterize the role of IFN-lambda in RABV infection in a mouse model, recombinant RABVs expressing murine IFN-lambda 2 or IFN-lambda 3, termed as rB2c-IFN lambda 2 or rB2c-IFN lambda 3, respectively, were constructed and rescued. It was found that expression of IFN-lambda could reduce the pathogenicity of RABV and limit viral spread in the brains by different infection routes. Furthermore, expression of IFN-lambda could induce the activation of the JAK-STAT pathway, resulting in the production of interferon-stimulated genes (ISGs). It was also found that rRABVs expressing IFN-lambda could reduce the production of inflammatory cytokines in primary astrocytes and microgila cells, restrict the opening of the blood-brain barrier (BBB), and prevent excessive infiltration of inflammatory cells into the brain, which could be responsible for the neuronal damage caused by RABV. Consistently, IFN-lambda was found to maintain the integrity of tight junction (TJ) protein ZO-1 of BBB to alleviate neuroinflammation in a transwell model. Our study underscores the role of IFN-lambda in inhibiting RABV infection, which potentiates IFN-lambda as a possible therapeutic agent for the treatment of RABV infection.