狂犬病毒感染引发人类和动物严重的中枢神经系统功能障碍，具有极高的死亡率。尽管狂犬疫苗能有效预防病毒感染，但对于未注射疫苗的感染患者仍缺乏有效的治疗手段，每年全球仍有55,000患者死于狂犬病。

在王红艳研究员的指导下，实验室科研人员焦少灼与中国疾控中心黄莹和陶晓燕博士合作，通过分析不同毒力狂犬病毒的毒株感染的乳鼠和成年鼠，发现在狂犬病毒感染后期(即濒死前)的小鼠，中枢神经系统出现巨噬细胞和淋巴细胞浸润及炎症反应，并与显著升高的趋化因子CCL5紧密相关。通过向脑部注射外源性趋化因子CCL5，研究人员发现CCL5促进免疫细胞通过FAK/AKT的信号通路，定向迁移至中枢神经系统，提高促炎因子产生，并加重神经细胞的凋亡。

更重要的是，该研究发现，在利用CCL5的拮抗剂即Met-CCL5处理狂犬病毒感染乳鼠或成年鼠后，显著降低了中枢神经系统的炎症反应，进而延长感染小鼠的生存时间。

本课题与中国疾控中心唐青研究组和梁国栋教授共同合作完成，并感谢军事医学科学院扈荣良、张守峰、赵敬慧教授和清华大学公衍道教授的大力支持。该项研究工作得到国家科技部、基金委、中科院百人计划和上海浦江计划等经费的支持。

原文摘要：

Met-CCL5 represents an immunotherapy strategy to ameliorate rabies virus infection

Ying Huang, Shaozhuo Jiao, Xiaoyan Tao, Qing Tang, Wentao Jiao, Jun Xiao, Xiaoyan Xu, Yanbo Zhang, Guodong Liang and Hongyan Wang

Background

Infection of rabies virus (RABV) causes central nervous system (CNS) dysfunction and results in high mortality in human and animals. However, it is still unclear whether and how CNS inflammation and immune response contribute to RABV infection.

Methods

Suckling mice were intracerebrally infected with attenuated RABV aG and CTN strains, followed by examination of chemokine or cytokine production, inflammatory cell infiltration and neuron apoptosis in the brain. Furthermore, the suckling mice and adult mice that were intracerebrally infected with aG and the adult mice that were intramuscularly infected with street RABV HN10 were treated with CCL5 antagonist (Met-CCL5) daily beginning on day 2 postinfection. The survival rates and inflammation responses in the CNS of these mice were analyzed.

Results

Excessive CCL5 in the CNS was associated with CNS dysfunction, inflammation, and macrophage or lymphocyte infiltration after attenuated or street RABV infection. Administration of exogenous CCL5 induced excessive infiltration of immune cells into the CNS and enhanced inflammatory chemokine and cytokine production. Met-CCL5 treatment significantly prolonged survival time of the suckling mice inoculated with aG and adult mice infected with aG and HN10.

Conclusions

These results suggest that CCL5 in the CNS is a key regulator involved in inducing rabies encephalomyelitis. Furthermore, treatment with the CCL5 antagonist Met-CCL5 prolongs survival time of the mice infected with attenuated or street RABVs, which might represent a novel therapeutic strategy to ameliorate RABV infection.

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