Rabies, caused by rabies virus (RABV), is a fatal encephalitis in humans and other mammals, which continues to present a public health threat in most parts of the world. Our previous study demonstrated that Toll-like receptor 7 (TLR7) is essential in the induction of anti-RABV antibodies via the facilitation of germinal center formation. In the present study, we investigated the role of TLR7 in the pathogenicity of RABV in a mouse model. Using isolated plasmacytoid dendritic cells (pDCs), we demonstrated that TLR7 is an innate recognition receptor for RABV. When RABV invaded from the periphery, TLR7 detected viral single-stranded RNA and triggered immune responses that limited the virus's entry into the central nervous system (CNS). When RABV had invaded the CNS, its detection by TLR7 led to the production of cytokines and chemokines and an increase the permeability of the blood-brain barrier. Consequently, peripheral immune cells, including pDCs, macrophages, neutrophils, and B cells infiltrated the CNS. While this immune response, triggered by TLR7, helped to clear viruses, it also increased neuroinflammation and caused immunopathology in the mouse brain. Our results demonstrate that TLR7 is an innate recognition receptor for RABV, which restricts RABV invasion into the CNS in the early stage of viral infection but also contributes to immunopathology by inducing neuroinflammation.IMPORTANCE Developing targeted treatment for RABV requires understanding the innate immune response to the virus because early virus clearance is essential for preventing the fatality when the infection has progressed to the CNS. Previous studies have revealed that TLR7 is involved in the immune response to RABV. Here, we establish that TLR7 recognizes RABV and facilitates the production of some interferon-stimulated genes. We also demonstrated that when RABV invades into the CNS, TLR7 enhances the production of inflammatory cytokines which contribute to immunopathology in the mouse brain. Taken together, our findings suggest that treatments for RABV must consider the balance between the beneficial and harmful effects of TLR7-triggered immune responses.

中文翻译：

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Toll 样受体 7 在小鼠模型狂犬病病毒发病机制中的双重作用。

狂犬病由狂犬病病毒（RABV）引起，是人类和其他哺乳动物的致命脑炎，持续对世界大部分地区的公共卫生构成威胁。我们之前的研究表明，Toll 样受体 7 (TLR7) 对于通过促进生发中心形成来诱导抗 RABV 抗体至关重要。在本研究中，我们在小鼠模型中研究了 TLR7 在 RABV 致病性中的作用。使用分离的浆细胞样树突状细胞 (pDC)，我们证明 TLR7 是 RABV 的先天识别受体。当RABV从外周入侵时，TLR7检测到病毒单链RNA并触发免疫反应，限制病毒进入中枢神经系统（CNS）。当RABV侵入中枢神经系统时，TLR7检测到它会导致细胞因子和趋化因子的产生，并增加血脑屏障的通透性。因此，外周免疫细胞，包括 pDC、巨噬细胞、中性粒细胞和 B 细胞浸润到中枢神经系统。虽然这种由 TLR7 触发的免疫反应有助于清除病毒，但它也增加了神经炎症并引起小鼠大脑的免疫病理学。我们的研究结果表明，TLR7 是 RABV 的先天识别受体，它在病毒感染的早期阶段限制 RABV 侵入 CNS，但也通过诱导神经炎症来促进免疫病理学。 重要性 开发针对 RABV 的靶向治疗需要了解对 RABV 的先天免疫反应。因为当感染进展到中枢神经系统时，早期病毒清除对于防止死亡至关重要。先前的研究表明TLR7参与RABV的免疫反应。在这里，我们确定 TLR7 识别 RABV 并促进一些干扰素刺激基因的产生。我们还证明，当 RABV 侵入 CNS 时，TLR7 会增强炎症细胞因子的产生，从而促进小鼠大脑的免疫病理学。综上所述，我们的研究结果表明，RABV 的治疗必须考虑 TLR7 触发的免疫反应的有益和有害影响之间的平衡。