Establishment of a lethal aged mouse model of human respiratory syncytial virus infection
Establishment of a lethal aged mouse model of human respiratory syncytial virus infection
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人呼吸道合胞病毒感染致死老年小鼠模型的建立
DOI：
10.1016/j.antiviral.2018.11.015
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发表时间：
2019-01-01
影响因子：
7.6
通讯作者：
Zhou, Jie
中科院分区：
文献类型：
--
作者：
Zhang, Ke;Li, Cun;Zhou, Jie
人类呼吸道合胞病毒（HRSV）感染是发病率和死亡率的重要原因，特别是在儿童和老年人中。尽管进行了广泛的努力，但目前还没有正式批准的疫苗，针对HRSV感染的有效抗病毒选择也很有限。由于缺乏有效的致死小鼠模型来评估候选疫苗或抗病毒药物的效力，HRSV疫苗和抗病毒策略的开发在一定程度上受到了阻碍。本研究通过连续传代临床HRSV分离株GZ08-0，建立致死性HRSV小鼠模型。GZ08-18从小鼠细支气管肺泡灌洗液中分离得到。重要的是，所有接种gz08 -18的小鼠在感染后第7天死亡，而所有接种gz08 -0的小鼠都从感染中恢复。随后的研究表明，与GZ08-0相比，GZ08-18在小鼠肺中复制到更高的滴度，诱导更突出的肺病理，并导致许多关键的促炎细胞因子，包括ifn - γ、MIP-1 α和tnf - α的表达水平更高。环磷酰胺预处理使小鼠更容易受到致命的结果与较少轮病毒接种。全基因组测序显示，GZ08-18有17个突变，其中一些突变可能导致致病性显著高于GZ08-0。此外，通过使用利巴韦林作为阳性对照，我们证明了这种致命小鼠模型作为HRSV调查工具的潜在应用。总之，我们已经成功建立了一种具有小鼠适应性的HRSV致死性小鼠模型，为今后HRSV候选疫苗和药物的体内研究提供了基础。
Human respiratory syncytial virus (HRSV) infection is a significant cause of morbidity and mortality, particularly among the children and the elderly. Despite extensive efforts, there is currently no formally approved vaccine and effective antiviral options against HRSV infection are limited. The development of vaccines and antiviral strategies for HRSV was partly hampered by the lack of an efficient lethal mouse model to evaluate the efficacy of the candidate vaccines or antivirals. In this study, we established a lethal HRSV mouse model by consecutively passaging a clinical HRSV isolate, GZ08-0. GZ08-18 was isolated from mouse bronchioalveolar lavage fluids at the 50th passage of GZ08-0. Importantly, all GZ08-18-inoculated mice succumbed to the infection by day 7 post infection, whereas all GZ08-0-inoculated mice recovered from the infection. Subsequent investigations demonstrated that GZ08-18 replicated to a higher titer in mouse lungs, induced more prominent lung pathology, and resulted in higher expression levels of a number of key pro-inflammatory cytokines including IFN-gamma, MIP-1 alpha, and TNF-alpha in comparison to that of GZ08-0. The cyclophosphamide pretreatment rendered the mice more susceptible to a lethal outcome with less rounds of virus inoculation. Full genome sequencing revealed 17 mutations in GZ08-18, some of which might account for the dramatically increased pathogenicity over GZ08-0. In addition, by using ribavirin as a positive control, we demonstrated the potential application of this lethal mouse model as a tool in HRSV investigations. Overall, we have successfully established a practical lethal mouse model for HRSV with a mouse-adapted virus, which may facilitate future in vivo studies on the evaluation of candidate vaccines and drugs against HRSV.