控制肠道病毒71型感染的先天性免疫保护机制及其应用

Enterovirus 71 (EV71) has emerged as a significant pathogen causing large outbreaks of hand, foot and mouth disease (HFMD) and related child death in China for the past 4 years. Neither vaccine for prophylaxis nor antiviral medicine is currently available. The persistant epidemics of EV71 give rise to public health concern and threaten the lives of children. Understanding the pathogenic process of EV71 infection may shed light on developing novel therapy or effective vaccine against HFMD. Our preliminary study has revealed that the paucity of NKT cells in the early life caused suckling mice vulnerable to EV71 infection. EV71 infection in vitro and in vivo led to activation of NKT cells. Transfer of purified NKT cell into suckling mice dramatically inhibited EV71 replication and prevented disease development. In addition, the mice deficient for type I interferon receptors are very vulnerable to EV71 infection. Altogether, our preliminary studies in the mouse model of EV71 infection has revealed that both NKT cells and type I interferon play important roles in controlling EV71 infection in mice. Based on our primary animal study, we plan to study: 1)the protective role of type I interferons in controlling EV71 infection in mice and the mechanisms underlying induction of type I interferon; 2) the protective role of NKT cells in controlling EV71 infection and the mechanisms underlying synergistic protection of NKT cells and type I interferons in EV71-infected mice; and 3)the efficacy of treatment of EV71-infected mice with type I interferons and immunomodulators of NKT cell activation. We hope to provide a basis for developing the diagnostic tools for early detection of disease severity, new therapeutic and prophylactic approaches to cope with HFMD.

手足口病已经成为危害我国儿童健康的重要传染病，目前不仅没有有效的抗病毒药物用于治疗，也还没有疫苗用于预防。 因此,疾病流行形势非常严峻。至今为止影响EV71病毒易感性和手足口病疾病严重程度的原因仍然不清楚，极大地影响了对手足口病的预防和临床病人的治疗。我们的EV71小鼠感染模型研究表明，I型干扰素和NKT细胞都对控制EV71感染小鼠的发病和疾病严重程度至关重要。本课题将在我们已有的研究基础上开展如下几个方面的研究：（1）揭示EV71感染小鼠诱导I型干扰素的分子机制及其在控制EV71感染中的作用；（2）深入探讨EV71感染小鼠NKT细胞激活的机制以及I型干扰素和NKT细胞在控制小鼠EV71感染的协同作用；（3）研究针对I型干扰素和NKT细胞作为靶点的手足口病免疫治疗的可行性。我们希望为手足口病的早期诊断和免疫治疗提供理论支持。

自2008年3月起手足口病在我国持续大流行，给公共卫生带来严峻的挑战。EV71感染是导致重症手足口病发生和死亡的的重要原因，迄今尚未有效防治措施。手足口病的免疫致病机制仍不完全清楚，在共发表了6篇通讯作者SCI论文，其中包括国际著名期刊PLoS Pathogens和J Virol杂志上发表的两篇文章,应邀作国际会议报告两次。我们发现了巨噬细胞通过TLR3 通路激活iNKT细胞从而控制EV71病毒感染的分子机制，以及TLR3-TRIF通路激活诱导I型干扰素产生从而控制CVA16病毒感染的分子机制，系统性地阐明了控制手足口病主要病原体EV71和CVA16易感性的免疫致病机理。