Mutations in PB2 and HA enhanced pathogenicity of H4N6 avian influenza virus in mice
Mutations in PB2 and HA enhanced pathogenicity of H4N6 avian influenza virus in mice
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PB2和HA突变增强H4N6禽流感病毒对小鼠的致病性
DOI：
10.1099/jgv.0.001192
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发表时间：
2020-01-01
影响因子：
3.8
通讯作者：
Ding，Jiabo
中科院分区：
文献类型：
--
作者：
Xu，Guanlong;Wang，Fang;Ding，Jiabo
H4亚型禽流感病毒（AIV）继续在野生鸟类和家禽中传播，偶尔感染哺乳动物（如猪）。在家禽养殖场工人中也检测到H4特异性抗体，这表明H4 AIV对公共卫生构成潜在威胁。然而，H4 aiv能够适应哺乳动物的分子机制以及这种机制是否已经发生，在很大程度上仍然未知。为了更好地了解这一机制，我们将一株H4N6无毒毒株（A/mallard/Beijing/21/2011, BJ21）在小鼠体内连续传代，并在传代后对其突变进行了表征。经过12次传代，产生一株毒力强的小鼠适应株，暂定为BJ21-MA。BJ21- ma菌株在体内和体外的复制效率都高于亲本BJ21。BJ21-MA的分子分析鉴定出4个突变，分别位于蛋白PB2 （E158K和E627K）和HA （L331I和G453R， H3编号）。进一步的研究表明，在PB2中引入E158K和/或E627K取代，可显著提高聚合酶活性，从而增强BJ21-MA的复制能力和毒力。虽然HA中单个L331I或G453R的替换没有改变BJ21在小鼠中的致病性，但这两种突变都显著增强了毒力。总之，我们在本研究中提供的数据表明，禽H4病毒可以通过PB2或HA的点突变适应哺乳动物，从而对公共卫生构成潜在威胁。
The H4 subtype avian influenza virus (AIV) continues to circulate in both wild birds and poultry, and occasionally infects mammals (e.g. pigs). H4-specific antibodies have also been detected in poultry farm workers, which suggests that H4 AIV poses a potential threat to public health. However, the molecular mechanism by which H4 AIVs could gain adaptation to mammals and whether this has occurred remain largely unknown. To better understand this mechanism, an avirulent H4N6 strain (A/mallard/Beijing/21/2011, BJ21) was serially passaged in mice and mutations were characterized after passaging. A virulent mouse-adapted strain was generated after 12 passages, which was tentatively designated BJ21-MA. The BJ21-MA strain replicated more efficiently than the parental BJ21, bothin vivoandin vitro. Molecular analysis of BJ21-MA identified four mutations, located in proteins PB2 (E158K and E627K) and HA (L331I and G453R, H3 numbering). Further studies showed that the introduction of E158K and/or E627K substitutions into PB2 significantly increased polymerase activity, which led to the enhanced replication and virulence of BJ21-MA. Although individual L331I or G453R substitutions in HA did not change the pathogenicity of BJ21 in mice, both mutations significantly enhanced virulence. In conclusion, our data presented in this study demonstrate that avian H4 virus can adapt to mammals by point mutations in PB2 or HA, which consequently poses a potential threat to public health.