H7N4低致病性禽流感病毒小鼠感染模型建立及感染致病特征研究

Pathogenic Characteristics of H7N4 Avian Influenza Virus in A Developed Mouse Infection Model

2018年,我国江苏省首次报告人感染H7N4禽流感病毒事件,提示H7N4禽流感病毒具有跨种传播和人畜共患的风险。为评估流行的H7N4禽流感病毒感染和适应哺乳动物的能力,预警未来禽流感病毒感染致病哺乳动物甚至人类的风险,提供疫苗及药物研发和评价的工具,本研究利用BALB/c小鼠建立了H7N4禽流感病毒感染模型并初步研究了病毒的感染致病特性。结果显示,随着病毒感染小鼠和连续传代次数的增加,病毒对小鼠的致病力逐渐增强。野生型病毒感染小鼠后(MA1),病毒可在肺脏中复制,但小鼠体重轻微且短暂性下降;自病毒在小鼠体内传至第2代(MA2)起,感染小鼠开始全部死亡且小鼠死亡时间逐渐缩短。MA2代感染小鼠7 d内全部死亡,MA5代感染小鼠4 d内全部死亡。对每代次病毒进行全基因组测序比对分析发现,随着感染代次的增加,病毒多个基因呈现出动态适应性突变,其中PB2-E627K和PA-T97I等突变很可能导致病毒对小鼠的致病力增强。研究结果提示:流行的H7N4禽流感病毒具有感染致病哺乳动物的能力和潜在风险,建立的小鼠感染模型为病毒的致病机制研究及疫苗和药物研发奠定了基础。

In 2018,the first human infection by the H7N4 avian influenza virus(AIV)was reported in Jiangsu Province,China,indicating the zoonotic risk and potential for cross-species transmission of H7N4 AIVs.To uncover the infectivity and adaption of the epidemic H7N4 AIV in mammals,further evaluate its zoonotic risk,and provide tools for future vaccine and drug development and evaluation,we established a mammalian infection model of H7N4 AIV using BALB/c mice.We discovered that viral pathogenicity increased gradually in mice during successive passaging.After infection with the wild type(WT)virus(mouse-adapted strains in the first passage,MA1),the virus could replicate in the lungs,and the bodyweight of mice decreased slightly.From MA2,all infected mice died and their survival time decreased continuously from MA2 to MA5.All mice infected with MA2 died within 7 days.All mice infected with the MA5 generation died within 4 days.The whole-virus genomes of WT and MA1–MA5 strains were sequenced.Comparative analysis displayed the dynamic adaptive mutations of H7N4 AIV during passaging in mice,including PB2-E627K and PA-T97I mutations,which were likely to increase the viral pathogenicity in mice.The mechanism underlying the infection and pathogenicity of H7N4 AIVs in mammals could be further studied in the developed mouse infection model,which will also support vaccine and drug development agianst AIVs.