H7N9 Influenza Virus Containing a Polybasic HA Cleavage Site Requires Minimal Host Adaptation to Obtain a Highly Pathogenic Disease Phenotype in Mice
H7N9 Influenza Virus Containing a Polybasic HA Cleavage Site Requires Minimal Host Adaptation to Obtain a Highly Pathogenic Disease Phenotype in Mice
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DOI：
10.3390/v12010065
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发表时间：
2020-01-01
期刊：
影响因子：
4.7
通讯作者：
Kobasa, Darwyn
中科院分区：
文献类型：
--
作者：
Chan, Mable;Leung, Anders;Kobasa, Darwyn
低致病性禽流感（LPAI）H7N9病毒最近已经进化以在血凝素（HA）蛋白中获得多碱基切割位点，从而产生在家禽中具有增加的致死性的变体，其满足高致病性禽流感（HPAI）病毒的标准。LPAI和HPAI变体均可导致人类严重疾病（病死率为40%）。在这里，我们研究了HPAI H7N9病毒在小鼠中的毒力，该病毒含有多碱HA切割位点（H7N9-PBC）。用H7N9-PBC接种小鼠没有导致可观察到的疾病;然而，用这种病毒的小鼠适应版本接种小鼠，通过在小鼠中单次传代产生，引起一致致命的疾病。除了PBC位点，我们还发现了另外三个对小鼠宿主适应和毒力很重要的突变：HA（A452 T）、PA（D347 G）和PB 2（M483 K）。使用反向遗传学，我们证实了HA突变是小鼠毒力增加的最关键因素。我们的研究确定了HPAI H7N9病毒的哺乳动物模型中的其他疾病决定因素。此外，病毒适应新宿主的容易性突出了H7N9-PBC病毒快速获得突变的潜力，这些突变可能会增加它们对人类或其他动物物种的风险。
Low pathogenic avian influenza (LPAI) H7N9 viruses have recently evolved to gain a polybasic cleavage site in the hemagglutinin (HA) protein, resulting in variants with increased lethality in poultry that meet the criteria for highly pathogenic avian influenza (HPAI) viruses. Both LPAI and HPAI variants can cause severe disease in humans (case fatality rate of 40%). Here, we investigated the virulence of HPAI H7N9 viruses containing a polybasic HA cleavage site (H7N9-PBC) in mice. Inoculation of mice with H7N9-PBC did not result in observable disease; however, mice inoculated with a mouse-adapted version of this virus, generated by a single passage in mice, caused uniformly lethal disease. In addition to the PBC site, we identified three other mutations that are important for host-adaptation and virulence in mice: HA (A452T), PA (D347G), and PB2 (M483K). Using reverse genetics, we confirmed that the HA mutation was the most critical for increased virulence in mice. Our study identifies additional disease determinants in a mammalian model for HPAI H7N9 virus. Furthermore, the ease displayed by the virus to adapt to a new host highlights the potential for H7N9-PBC viruses to rapidly acquire mutations that may enhance their risk to humans or other animal species.