Enterovirus A71 (EV-A71) is one of the main causative agents of hand-foot-and-mouth disease and is occasionally associated with severe neurological complications. EV-A71 pathophysiology is poorly understood due to the lack of small animal models that robustly support viral replication in relevant organs/tissues. Here, we show that adult severe combined immune-deficient (SCID) mice can serve as an EV-A71 infection model to study neurotropic determinants and viral tropism. Mice inoculated intraperitoneally with an EV-A71 clinical isolate had an initial infection of the lung compartment, followed by neuroinvasion and infection of (motor)neurons, resulting in slowly progressing paralysis of the limbs. We identified a substitution (V135I) in the capsid protein VP2 as a key requirement for neurotropism. This substitution was also present in a mouse-adapted variant, obtained by passaging the clinical isolate in the brain of one-day-old mice, and induced exclusive neuropathology and rapid paralysis, confirming its role in neurotropism. Finally, we showed that this residue enhances the capacity of EV-A71 to use mouse PSGL1 for viral entry. Our data reveal that EV-A71 initially disseminates to the lung and identify viral and host determinants that define the neurotropic character of EV-A71, pointing to a hitherto understudied role of PSGL1 in EV-A71 tropism and neuropathology.

中文翻译：

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带有PSGL1使用和神经毒力增强的肠道病毒A71变体在宿主内的出现。

肠病毒A71（EV-A71）是手足口病的主要病原体之一，偶有严重的神经系统并发症。EV-A71的病理生理学认识不佳，原因是缺少能够在相关器官/组织中强有力地支持病毒复制的小型动物模型。在这里，我们表明成年严重的联合免疫缺陷（SCID）严重小鼠可以用作EV-A71感染模型，以研究神经营养决定簇和病毒嗜性。腹膜内接种EV-A71临床分离株的小鼠最初感染了肺室，随后发生了神经浸润和（运动）神经元感染，导致四肢缓慢进展性麻痹。我们确定了衣壳蛋白VP2中的取代（V135I）是向神经性的关键要求。这种替代也存在于小鼠适应的变体中，该变体是通过对一天龄小鼠脑中的临床分离物进行传代而获得的，并诱导了排他性神经病理学和快速瘫痪，证实了其在嗜神经性中的作用。最后，我们表明该残基增强了EV-A71使用小鼠PSGL1进行病毒进入的能力。我们的数据表明，EV-A71最初会散布到肺部，并确定定义EV-A71的神经性特征的病毒和宿主决定簇，这表明PSGL1在EV-A71的向性性和神经病理学方面迄今尚未被研究。我们显示该残基增强了EV-A71使用小鼠PSGL1进行病毒进入的能力。我们的数据表明，EV-A71最初会散布到肺部，并确定定义EV-A71的神经性特征的病毒和宿主决定簇，这表明PSGL1在EV-A71的向性性和神经病理学方面迄今尚未被研究。我们显示该残基增强了EV-A71使用小鼠PSGL1进行病毒进入的能力。我们的数据表明，EV-A71最初会散布到肺部，并确定定义EV-A71的神经性特征的病毒和宿主决定簇，这表明PSGL1在EV-A71的向性性和神经病理学方面迄今尚未被研究。