Department of Molecular Genetics and Microbiology, Duke University School of Medicinegrid.471396.e, Durham, North Carolina, USA.
Duke Human Vaccine Institute, Duke University School of Medicinegrid.471396.e, Durham, North Carolina, USA.
J Virol. 2022 Jul 13;96(13):e0033022. doi: 10.1128/jvi.00330-22. Epub 2022 Jun 14.
Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae and death, particularly in neonates. However, the mechanisms by which these viruses induce meningeal inflammation are poorly understood, owing at least in part to the lack of models that recapitulate this aspect of echovirus pathogenesis. Here, we developed an neonatal mouse model that recapitulates key aspects of echovirus-induced meningitis. We show that expression of the human homologue of the primary echovirus receptor, the neonatal Fc receptor (FcRn), is not sufficient for infection of the brains of neonatal mice. However, ablation of type I, but not III, interferon (IFN) signaling in mice expressing human FcRn permitted high levels of echovirus replication in the brain, with corresponding clinical symptoms, including delayed motor skills and hind-limb weakness. Using this model, we defined the immunological response of the brain to echovirus infection and identified key cytokines, such as granulocyte colony-stimulating factor (G-CSF) and interleukin 6 (IL-6), that were induced by this infection. Lastly, we showed that echoviruses specifically replicate in the leptomeninges, where they induce profound inflammation and cell death. Together, this work establishes an model of aseptic meningitis associated with echovirus infections that delineates the differential roles of type I and type III IFNs in echovirus-associated neuronal disease and defines the specificity of echoviral infections within the meninges. Echoviruses are among the most common worldwide causes of aseptic meningitis, which can cause long-term sequelae or even death. The mechanisms by which echoviruses infect the brain are poorly understood, largely owing to the lack of robust models that recapitulate this aspect of echovirus pathogenesis. Here, we establish a neonatal mouse model of echovirus-induced aseptic meningitis and show that expression of the human homologue of the FcRn, the primary receptor for echoviruses, and ablation of type I IFN signaling are required to recapitulate echovirus-induced meningitis and clinical disease. These findings provide key insights into the host factors that control echovirus-induced meningitis and a model that could be used to test anti-echovirus therapeutics.
肠道病毒是全球引起无菌性脑膜炎的最常见原因之一，可导致长期后遗症甚至死亡，尤其是在新生儿中。然而，这些病毒引起脑膜炎症的机制还了解甚少，部分原因是缺乏能够重现肠道病毒发病机制这一方面的模型。在这里，我们建立了一种重现肠道病毒引起的无菌性脑膜炎的新生小鼠模型。我们表明，表达肠道病毒的主要受体——新生儿 Fc 受体（FcRn）的人同源物不足以感染新生小鼠的大脑。然而，在表达人 FcRn 的小鼠中敲除 I 型而非 III 型干扰素（IFN）信号通路可允许肠道病毒在大脑中高水平复制，并伴有相应的临床症状，包括运动技能延迟和后肢无力。使用该模型，我们定义了大脑对肠道病毒感染的免疫反应，并鉴定了关键细胞因子，如粒细胞集落刺激因子（G-CSF）和白细胞介素 6（IL-6），这些细胞因子是由这种感染诱导的。最后，我们表明肠道病毒专门在软脑膜中复制，在那里它们引起严重的炎症和细胞死亡。总之，这项工作建立了一种与肠道病毒感染相关的无菌性脑膜炎模型，该模型阐明了 I 型和 III 型 IFN 在肠道病毒相关神经疾病中的差异作用，并定义了肠道病毒在脑膜中的特异性感染。
