狂犬病毒感染引發(fā)人類(lèi)和動(dòng)物嚴(yán)重的中樞神經(jīng)系統(tǒng)功能障礙，具有極高的死亡率。盡管狂犬疫苗能有效預(yù)防病毒感染，但對(duì)于未注射疫苗的感染患者仍缺乏有效的治療手段，每年全球仍有55,000患者死于狂犬病。

在王紅艷研究員的指導(dǎo)下，實(shí)驗(yàn)室科研人員焦少灼與中國(guó)疾控中心黃瑩和陶曉燕博士合作，通過(guò)分析不同毒力狂犬病毒的毒株感染的乳鼠和成年鼠，發(fā)現(xiàn)在狂犬病毒感染后期(即瀕死前)的小鼠，中樞神經(jīng)系統(tǒng)出現(xiàn)巨噬細(xì)胞和淋巴細(xì)胞浸潤(rùn)及炎癥反應(yīng)，并與顯著升高的趨化因子CCL5緊密相關(guān)。通過(guò)向腦部注射外源性趨化因子CCL5，研究人員發(fā)現(xiàn)CCL5促進(jìn)免疫細(xì)胞通過(guò)FAK/AKT的信號(hào)通路，定向遷移至中樞神經(jīng)系統(tǒng)，提高促炎因子產(chǎn)生，并加重神經(jīng)細(xì)胞的凋亡。

更重要的是，該研究發(fā)現(xiàn)，在利用CCL5的拮抗劑即Met-CCL5處理狂犬病毒感染乳鼠或成年鼠后，顯著降低了中樞神經(jīng)系統(tǒng)的炎癥反應(yīng)，進(jìn)而延長(zhǎng)感染小鼠的生存時(shí)間。

本課題與中國(guó)疾控中心唐青研究組和梁國(guó)棟教授共同合作完成，并感謝軍事醫(yī)學(xué)科學(xué)院扈榮良、張守峰、趙敬慧教授和清華大學(xué)公衍道教授的大力支持。該項(xiàng)研究工作得到國(guó)家科技部、基金委、中科院百人計(jì)劃和上海浦江計(jì)劃等經(jīng)費(fèi)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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