State Key Laboratory of Agricultural Microbiology, Huazhong Agricultural University, Wuhan 430070, China.
College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
Viruses. 2020 Apr 6;12(4):405. doi: 10.3390/v12040405.
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-λs are cytokines with type I IFN-like antiviral activities. Although IFN-λ 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-λ2 and IFN-λ3 could inhibit RABV replication in cells. To characterize the role of IFN-λ in RABV infection in a mouse model, recombinant RABVs expressing murine IFN-λ2 or IFN-λ3, termed as rB2c-IFNλ2 or rB2c-IFNλ3, respectively, were constructed and rescued. It was found that expression of IFN-λ could reduce the pathogenicity of RABV and limit viral spread in the brains by different infection routes. Furthermore, expression of IFN-λ 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-λ 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-λ 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-λ in inhibiting RABV infection, which potentiates IFN-λ as a possible therapeutic agent for the treatment of RABV infection.
狂犬病是由狂犬病病毒（RABV）引起的一种致命的神经疾病，每年仍导致超过 59000 人死亡。III 型干扰素 IFN-λ 是具有 I 型 IFN 样抗病毒活性的细胞因子。虽然 IFN-λ 可以限制某些病毒（特别是肠道病毒）的感染，但对 RABV 感染的抑制作用仍未确定。在本研究中，研究了 III 型 IFN 对 RABV 感染的作用。最初，我们发现 IFN-λ2 和 IFN-λ3 可以抑制细胞中的 RABV 复制。为了表征 IFN-λ 在 RABV 感染中的作用，在小鼠模型中构建并拯救了表达鼠 IFN-λ2 或 IFN-λ3 的重组 RABV，分别命名为 rB2c-IFNλ2 或 rB2c-IFNλ3。结果发现，IFN-λ 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大脑中的传播。此外，IFN-λ 的表达可以诱导 JAK-STAT 途径的激活，从而产生干扰素刺激基因（ISGs）。还发现，表达 IFN-λ 的 rRABV 可以减少原代星形胶质细胞和小胶质细胞中炎症细胞因子的产生，限制血脑屏障（BBB）的开放，并防止炎症细胞过度浸润大脑，这可能是 RABV 引起的神经元损伤的原因。一致地，IFN-λ 被发现可以维持 BBB 的紧密连接（TJ）蛋白 ZO-1 的完整性，以减轻转染模型中的神经炎症。我们的研究强调了 IFN-λ 在抑制 RABV 感染中的作用，这使得 IFN-λ 成为治疗 RABV 感染的潜在治疗剂。
