Mutations in influenza virus M1 CCHH, the putative zinc finger motif, cause attenuation in mice and protect mice against lethal influenza virus infection
Mutations in influenza virus M1 CCHH, the putative zinc finger motif, cause attenuation in mice and protect mice against lethal influenza virus infection
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DOI：
10.1128/jvi.02729-05
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发表时间：
2006-06-01
影响因子：
5.4
通讯作者：
Nayak, Debi P.
中科院分区：
文献类型：
--
作者：
Hui, Eric Ka-Wai;Smee, Donald F.;Nayak, Debi P.
CCHH的突变，假定的锌指基序，显然在培养的MDCK细胞中对病毒复制没有起到重要作用(E.K.-W.Huu，K.Ralston，A.K.Judd和D.P.Nayak，J.Gen.Virol)。84：3105-3113,2003)。然而，在这份报告中，我们证明了CCHH基序在小鼠的毒力中起着关键作用，并且一些CCHH突变体在BALB/c小鼠中高度减弱。一些变异病毒在小鼠的肺部复制最少，几乎没有引起肺部损害，并导致发病率和死亡率大大降低。此外，突变病毒在不同细胞系(MDCK、MLE12、3LL、A549和293T)中的生长模式也不同。在小鼠身上减毒的突变病毒在培养的小鼠和人类细胞中也生长得很差。然而，野生型(WT)病毒和所有突变病毒在MDCK(犬)细胞或胚胎鸡蛋中复制到相同的滴度。小鼠的衰减与小鼠细胞在培养中的生长减少相关，这表明可以从来自同一物种的培养细胞(最好是肺细胞)中病毒的生长特征来预测给定宿主的潜在衰减。在攻击实验中，用减毒突变病毒免疫的小鼠完全免受WT病毒的致死攻击。总之，这些突变体的复制和减毒特性表明，CCHH基序为小鼠的毒力提供了一个关键的决定因素，CCHH基序的突变产生了潜在的疫苗候选，可用于开发活的针对物种的减毒流感病毒疫苗。
Mutations in CCHH, the putative zinc finger motif, apparently do not play an important role in virus replication in MDCK cells in culture (E. K.-W. Hui, K. Ralston, A. K. Judd, and D. P. Nayak, J. Gen. Virol. 84:3105-3113, 2003). In this report, however, we demonstrate that the CCHH motif plays a critical role in virulence in mice and that some CCHH mutants are highly attenuated in BALB/c mice. Some of the mutant viruses replicated the least in mice lungs, induced little or no lung lesions, and caused highly reduced morbidity and mortality. Furthermore, growth patterns of mutant viruses in different cell lines (MDCK, MLE12, 3LL, A549, and 293T) varied. Mutant viruses that were attenuated in mice also grew poorly in mouse and human cells in culture. However, wild-type (WT) and all mutant viruses replicated to the same titer in MDCK (canine) cells or embryonated chicken eggs. Attenuation in mice correlated with reduced growth in mouse cells in culture, suggesting that potential attenuation in a given host can be predicted from the growth characteristics of the virus in cultured cells (preferably lung cells) from the same species. In challenge experiments, mice immunized by infection with attenuated mutant viruses were fully protected from lethal challenge with WT virus. In summary, the replication and attenuating properties of these mutants suggest that the CCHH motif provides a critical determinant for virulence in mouse and that mutations in the CCHH motif yield potential vaccine candidates for the development of live species-specific attenuated influenza virus vaccines.