史卫峰课题组发表柯萨奇病毒CVA10抗病毒感染研究成果

rentianyixu

2017年4月19日，国际病毒学领域主流期刊《Journal of Virology》在线发表了泰山医学院史卫峰教授课题组最新研究成果“甲醛灭活柯萨奇病毒10型全病毒疫苗和抗病毒药物对新生乳鼠的保护效果”（Protective efficacy of formaldehyde-inactivated whole-virus vaccine and antivirals in a murine model of coxsackievirus A10 infection），基础医学院青年教师张振杰博士和公共卫生学院硕士生董兆鹏为本文共同第一作者，史卫峰教授和公共卫生学院李栋教授为共同通讯作者。这是课题组继3月1日在《Journal of Virology》发表CVA6乳鼠模型研究后，在该杂志发表的柯萨奇A组病毒又一研究成果。

柯萨奇A组10型病毒（Coxsackievirus A10，CVA10）是引起儿童手足口病（HFMD）的主要病原体之一，尤其是1-3岁的婴幼儿，能够引起重症，导致严重的无菌性脑膜炎和急性弛缓性麻痹等临床症状，病情进展快，使其成为一种严重危害婴幼儿健康的疾病。尽管都属于A组病毒，但CVA10与EV71、CVA16和CVA6的感染过程和致病机理的异同尚未知，且缺少有效的广谱抗肠道病毒药物。近两年CVA10感染率显著升高，在我国部分地区甚至超过EVA71和CVA16，因此有必要对CVA10进行抗病毒研究。

本研究采用CVA10细胞适应株TA151R建立了稳定且高致死率的ICR乳鼠感染模型，5日龄乳鼠感染后呈现与CVA6感染相似的病毒性肺炎和后肢瘫痪等临床症状。同时，病毒感染可诱导高水平炎性细胞因子IL-6和IFN-γ表达，使其成为导致乳鼠重症甚至死亡的重要因素。利用该模型筛选并验证广谱抗病毒药物利巴韦林能够显著缓解发病乳鼠临床症状，同样适用于抗CVA6的感染。该研究通过成年鼠的主动和被动免疫评价了甲醛灭活的CVA10全病毒灭活疫苗的免疫效果，高滴度的母源抗体也能够完全保护乳鼠对致死剂量CVA10的感染。通过抗体治疗实验，发现中和抗体能够逆转早期发病乳鼠的症状，为将来临床采用免疫球蛋白治疗重症患儿提供思路。基于ICR乳鼠感染模型，我们发现CVA10和CVA6有相似的致病过程，均能够模拟表现人类相似的临床症状，获得理想的全病毒灭活疫苗。同样的策略还可以应用于其它型肠道病毒的抗病毒研究。

Protective efficacy of formaldehyde-inactivated whole-virus vaccine and antivirals in a murine model of coxsackievirus A10 infection
ABSTRACT

Coxsackievirus A10 (CVA10) is one of the major pathogens associated with hand, foot and mouth disease (HFMD). CVA10 infection can cause herpangina and viral pneumonia, which can be complicated by severe neurological sequelae. Morbidity and mortality of CVA10-associated HFMD has been increasing in recent years, particularly in the pan-Pacific region. There are limited studies however on the pathogenesis and immunology of CVA10-associated HFMD infections, and few antiviral drugs or vaccines have been reported. In the present study, a cell-adapted CVA10 strain was employed to inoculate intramuscularly five-day-old ICR mice, which developed significant clinical signs including: reduced mobility, lower weight gain and quadriplegia, with significant pathology in the brain, hind limb skeletal muscles and lungs of infected mice in the moribund state. The severity of illness was associated with abnormally high expression of the proinflammatory cytokine IL-6. Antiviral assays demonstrated that ribavirin and gamma interferon administration could significantly inhibit CVA10 replication both in vitro and in vivo. In addition, formaldehyde-inactivated CVA10 whole-virus vaccines induced immune responses in adult mice and maternal neutralizing antibodies could be transmitted to neonatal mice providing protection against CVA10 clinical strains. Furthermore, high titer antisera were effective against CVA10 and could relieve early clinical symptoms and improve the survival rates of CVA10-challenged neonatal mice. In summary, we present a novel murine model to study CVA10 pathology which will be extremely useful to develop effective antivirals and vaccines to diminish the burden of HFMD-associated disease.

IMPORTANCE

Hand, foot and mouth disease cases in infancy, arising from coxsackievirus A10 (CVA10) infections, are typically benign, resolving without any significant adverse events. Severe disease and fatalities can however occur in some children, necessitating the development of vaccines and antiviral therapies. The present study has established a newborn mouse model of CVA10 which, importantly, recapitulates many aspects of human disease, with respect to the neuropathology and skeletal muscle pathology. We found that high levels of the proinflammatory cytokine interleukin 6 correlated with disease severity and that ribavirin and gamma interferon could decrease viral titers in vitro and in vivo. Whole-virus vaccines produced immune responses in adult mice and immunized mothers conferred protection to neonates against challenge from CVA10 clinical strains. Passive immunization with high titer antisera could also improve survival rates in newborn animals.

Ascovirus

老史，美美哒