ABSTRACT

CVA6 is one of Enteroviruses causing worldwide epidemics of HFMD with neurological and systemic complications. A suitable animal model is necessary for studying the pathogenesis of CVA6 and evaluating antiviral and vaccine efficacy. In this study, we generated a mouse-adapted CVA6 strain that successfully infected 10-day-old ICR mice via oral route. All infected mice were paralyzed and died within 11 dpi. Analysis of pathological changes and virus loads in fourteen tissues showed that CVA6 triggered systematic damage similar to i.p. inoculation route. Unlike i.p. route, we detected oral and gastrointestinal lesions with the presence of viral antigens. Both specific anti-CVA6 serum and inactivated vaccines successfully generated immune protection in mice. Meanwhile, we also established a successful infection of CVA6 via i.p. and i.m. route in 10-day-old mice. After infection, mice developed remarkably neurological signs and systemic manifestations such as emaciation, polypnea, quadriplegia, depilation and even death. Through i.p. inoculation, pathological examination showed brain and spinal cord damage caused by the virus infection with neuronal reduction, apoptosis, astrocyte activation, and recruitment of neutrophils and monocytes. Following neurological manifestation, the CVA6 infection became systemic, and high viral loads were detected in multiple organs along with morphological changes and inflammation. Moreover, analysis of spleen cells by FACS indicated that CVA6 led to immune system activation, which further contributed to systemic inflammation. Taken together, our novel murine model of CVA6 provides a useful tool for studying the pathogenesis and evaluating antiviral and vaccine efficacy.

摘要

CVA6 是导致全球手足口病流行的肠道病毒之一，并伴有神经和全身并发症。研究 CVA6 的发病机制和评估抗病毒和疫苗功效需要合适的动物模型。在这项研究中，我们产生了一种适应小鼠的 CVA6 菌株，该菌株通过口服途径成功感染了 10 天大的 ICR 小鼠。所有受感染的小鼠都在 11 dpi 内瘫痪并死亡。对十四个组织的病理变化和病毒载量分析表明，CVA6 引发了类似于 ip 接种途径的系统性损伤。与 ip 途径不同，我们检测到存在病毒抗原的口腔和胃肠道病变。特异性抗 CVA6 血清和灭活疫苗都成功地在小鼠中产生了免疫保护。同时我们还建立了通过ip和im成功感染CVA6 路线在 10 天大的老鼠身上。感染后，小鼠出现明显的神经症状和全身表现，如消瘦、多呼吸、四肢瘫痪、脱毛甚至死亡。通过腹腔内接种，病理检查显示病毒感染引起的脑和脊髓损伤，神经元减少、细胞凋亡、星形胶质细胞活化、中性粒细胞和单核细胞募集。在神经系统表现后，CVA6 感染成为全身性感染，在多个器官中检测到高病毒载量以及形态变化和炎症。此外，通过 FACS 对脾细胞的分析表明，CVA6 导致免疫系统激活，从而进一步导致全身炎症。综合起来，