Improved pathogenicity of H9N2 subtype of avian influenza virus induced by mutations occurred after serial adaptations in mice
Improved pathogenicity of H9N2 subtype of avian influenza virus induced by mutations occurred after serial adaptations in mice
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通过突变诱导的 H9N2 亚型禽流感病毒在小鼠体内进行一系列适应后，致病性提高。
DOI：
10.1016/j.micpath.2021.105204
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发表时间：
2021-09-24
影响因子：
3.8
通讯作者：
Wang, Chun-Feng
中科院分区：
文献类型：
--
作者：
Zhang, Rong-Rong;Yang, Xin;Wang, Chun-Feng
H9 N2亚型是一种低致病性禽流感病毒，正在成为中国和其他亚洲国家家禽工作场所传播的主要病原体。最近报告的哺乳动物种间传播病例数不断增加，引起了人们对其引发全球大流行风险的极大关注。试图了解H9 N2病毒如何破坏种间隔离传播给哺乳动物的潜在机制。通过在BALB/c小鼠中将野生型H9 N2 A/chicken/Hong Kong/G9/1997从肺到肺传代8次获得突变型H9 N2毒株。我们的发现显示，小鼠表现出严重的临床症状，包括体重减轻，肺部部位的病理损伤，并且在感染H9 N2突变株后两周内全部死亡，而相比之下，所有小鼠在感染野生型毒株后均存活，这表明突变株的致病性增加。此外，与野生型病毒感染的小鼠相比，小鼠血清中促炎细胞因子水平升高，包括IL-6、TNF-α和IL-1 β。序列分析结果表明，在PB 2627、HA 87、HA 234、NP 387和M156处发生了5个氨基酸替换，在M基因处发生了1个缺失突变（M157）。在这些突变中，PB 2 E627 K在调节小鼠致死率中起关键作用。结果表明，野生型H9 N2突变株在小鼠体内连续传代后毒力显著增强，导致小鼠死亡，这可能与其基因组发生累积突变有关。
H9N2 subtype, a low pathogenic avian influenza virus, is emerging as a major causative agent circulating poultry workplaces across China and other Asian countries. Increasing case number of interspecies transmissions to mammals reported recently provoked a great concern about its risks inducing global pandemics. In an attempt to understand the underlying mechanism of how the H9N2 virus disrupts the interspecies segregation to transmit to mammals. A mutant H9N2 strain was obtained by passaging the wildtype H9N2 A/chicken/Hong Kong/G9/1997 eight times from lung to lung in BALB/c mice. Our finding revealed that mice manifested severe clinical symptoms including losses of body weight, pathological damages in pulmonary sites and all died within two weeks after infected with the mutated H9N2, whereas all mice survived upon infected with wildtype strain in comparison, which suggested increased pathogenicity of the mutant strain. In addition, mice showed enhanced levels of proinflammatory cytokines in sera, including IL-6, TNF-alpha and IL-1 beta compared to those subjected to wildtype viral infections. Sequence analysis showed that five amino acid substitutions occurred at PB2627, HA87, HA234, NP387 and M156, and a deletion mutation happened in the M gene (M157). Of these mutations, PB2 E627K played key roles in modulating lethality in mice. Taken together, the mutant H9N2 strain obtained by serial passaging of its wildtype in mice significantly increased its virulence leading to death of mice, which might be associated the accumulated mutations occurred on its genome.