上海巴斯德所手足口病免疫致病机理研究取得新进展

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8月19日，国际知名学术杂志Journal of Virology在线发表了中科院上海巴斯德研究所冷启彬课题组的研究论文“Type I interferons triggered through the TLR3-TRIF pathway control Coxsackievirus A16 infection in young mice” 。

　　手足口病主要感染对象为1-5岁儿童，2015年我国手足口病的感染病例已经高达278万。CVA16和EV71是手足口病的主要病原体，其中重症手足口病基本由EV71感染引起，CVA16病毒感染引起的疾病严重程度相对较轻。但至今尚无研究揭示，该两种病毒感染引发疾病的严重程度不同的原因。

　　上海巴斯德所博士研究生杨钜皓、杨春富等在冷启彬研究员的指导下，发现了CVA16感染小鼠后并不激活iNKT细胞，而且iNKT细胞对CVA16感染幼鼠也没有保护作用；这一研究发现有别于与研究组前期发表在PLoS Pathogens对EV71感染的研究结果，说明机体控制这两种手足口病主要病原体的免疫机制完全不同。此外，利用基因敲除小鼠研究发现，Ⅰ型干扰素在控制CVA16感染致病方面起关键作用：先天性免疫细胞可通过TLR3-TRIF信号通路诱导Ⅰ型干扰素的产生，TRIF信号通路诱导的免疫应答可以通过抑制CVA16在神经系统的复制而防止疾病发生。此外，Ⅰ型干扰素治疗可以降低被CVA16感染并经TRIF基因敲除后小鼠的疾病程度和死亡率，说明I型干扰素在TLR3-TRIF通路诱导的宿主抗CVA16免疫反应中起重要作用。

　　研究结果表明，EV71和CVA16感染所引起的不同临床病理和疾病严重程度可能与各自诱导的机体免疫应答机制有关，这一发现为手足口病的治疗策略提供了新的参考依据。

    该项研究得到了第二军医大学王红阳院士、军事医学科学院秦成峰教授，同济大学戈宝学教授和北京大学顾军教授的支持和帮助，获得了国家自然科学基金和国家重大科学研究计划（973）等项目资助。


图1、Ⅰ型干扰素在控制幼鼠CVA16病毒感染中起关键作用


图2、EV71和CVA16病毒感染所诱导的机体免疫应答截然不同可能与其各自导致的手足口病不同临床结果有关

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J Virol. 2015 Aug 19. pii: JVI.01627-15. [Epub ahead of print]
Type I interferons triggered through the TLR3-TRIF pathway control Coxsackievirus A16 infection in young mice.
Yang J1, Yang C1, Guo N1, Zhu K1, Kaiming L1, Zhang N1, Zhao H2, Cui Y1, Chen L3, Wang H3, Gu J4, Ge B5, Cheng-Feng Q2, Leng Q6.
Author information
1Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, China.
2State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, China.
3International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China National Center for Liver Cancer, Shanghai, China.
4State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China.
5Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China.
6Key Laboratory of Molecular Virology and Immunology, Institut Pasteur of Shanghai, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai, China qbleng@sibs.ac.cn.
Abstract
Coxsackievirus A16 (CVA16) is one of the major etiological agents that cause hand, foot and mouth disease (HFMD) in children. The host defense mechanisms against CVA16 infection remain almost entirely unknown. Unlike previous observations with EV71 infection, here we show that IFN-γ or iNKT cell deficiency did not affect the disease development and survival of CVA16-infected mice. In contrast, type I interferon receptor deficiency resulted in mice developing more severe disease, and they had a lower survival rate than wild-type mice. Similarly, deficiency of TLR3 and TRIF, but not other pattern recognition receptors, led to decreased survival of CVA16-infected mice. TLR3-TRIF signaling was indispensable for the induction of type I interferons during CVA16 infection in mice and protected young mice from disease caused by the infection. In particular, TRIF-mediated immunity was critical for preventing CVA16 replication in the neuronal system before disease occurred. IFN-β treatment was also found to compensate for TRIF deficiency in mice and decreased disease severity and mortality of CVA16-infected mice. Altogether, type I interferons induced by TLR3-TRIF signaling mediate protective immunity against CVA16 infection. These findings may shed light on therapeutic strategies to combat HFMD caused by CVA16 infection.
IMPORTANCE:
Hand, foot and mouth disease (HFMD) is a major threat to public health in the Asia-Pacific region. Both CVA16 and EV71 are major pathogens that are responsible for HFMD. The majority of research efforts have focused on the more virulent EV71 but little has been done with CVA16. Thus far, host immune responses to CVA16 infection have not yet be elucidated. The present study discovered an initial molecular mechanism underlying host protective immunity against CVA16 infection, providing the first explanation for why CVA16 and EV71 cause different clinical outcomes upon infection of humans. Therefore, different therapeutic strategies should be developed to treat HFMD cases caused by these two viruses.