Coxsackievirus A4 (CVA4) infection can cause hand, foot and mouth disease (HFMD), an epidemic illness affecting neonatal and paediatric cohorts, which can develop to severe neurological disease with high mortality. In this study, we established the first ICR mouse model of CVA4 infection for the evaluation of inactivated vaccines and antiviral drug screening. The CVA4 YT226R strain was selected to infect the neonatal mice and three infectious factors were optimized to establish the infection model. The 3-day-old neonatal mice exhibited clinical symptoms such as hind limb paralysis and death. The severe inflammatory reactions were closely related to the abnormal expression of the acute phase response proinflammatory cytokine IL-6 and an imbalance in the IFN-γ/IL-4 ratio. Importantly, the inactivated CVA4 whole-virus vaccine induced humoral immune responses in adult females and the maternal antibodies afforded mice complete protection against lethal dose challenges of homologous or heterologous CVA4 strains. Both IFN-α2a and antiserum inhibited the replication of CVA4 and increased the survival rates of neonatal mice during the early stages of infection. This neonatal murine model of CVA4 infection will be useful for the development of prophylactic and therapeutic vaccines and for screening of antiviral drugs targeting CVA4 to decrease morbidity and mortality.

中文翻译：

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柯萨奇病毒A4感染的新生鼠模型，用于评估疫苗和抗病毒药物。

柯萨奇病毒A4（CVA4）感染可引起手足口病（HFMD），这是一种流行病，影响新生儿和小儿队列研究，可发展为严重的神经系统疾病，死亡率很高。在这项研究中，我们建立了第一个CVA4感染的ICR小鼠模型，用于评估灭活疫苗和抗病毒药物筛选。选择CVA4 YT226R菌株感染新生小鼠，并优化了三种感染因子以建立感染模型。3天大的新生小鼠表现出诸如后肢瘫痪和死亡的临床症状。严重的炎症反应与急性期反应促炎细胞因子IL-6的异常表达和IFN-γ/ IL-4比的失衡密切相关。重要的，灭活的CVA4全病毒疫苗在成年雌性小鼠中引起体液免疫反应，而母源抗体为小鼠提供了完全保护，使其免受同源或异源CVA4菌株的致死剂量攻击。在感染的早期，IFN-α2a和抗血清都抑制了CVA4的复制并提高了新生小鼠的存活率。这种CVA4感染的新生鼠模型对于开发预防性和治疗性疫苗以及筛选靶向CVA4的抗病毒药物以降低发病率和死亡率将非常有用。在感染的早期，IFN-α2a和抗血清都抑制了CVA4的复制并提高了新生小鼠的存活率。这种CVA4感染的新生鼠模型对于开发预防性和治疗性疫苗以及筛选靶向CVA4的抗病毒药物以降低发病率和死亡率将非常有用。在感染的早期，IFN-α2a和抗血清都抑制了CVA4的复制并提高了新生小鼠的存活率。这种CVA4感染的新生鼠模型对于开发预防性和治疗性疫苗以及筛选靶向CVA4的抗病毒药物以降低发病率和死亡率将非常有用。