Department of Microbiology, and the Institute for Viral Diseases, College of Medicine, Korea University, Seoul, 02841, Republic of Korea.
Sci Rep. 2017 Sep 7;7(1):10928. doi: 10.1038/s41598-017-11348-0.
It has been noticed that neuraminidase (NA) stalk truncation has arisen from evolutionary adaptation of avian influenza A viruses (IAVs) from wild aquatic birds to domestic poultry. We identified this molecular alteration after the adaptation of a 2009 pandemic H1N1 virus (pH1N1) in BALB/c mice. The mouse-adapted pH1N1 lost its eight consecutive amino acids including one potential N-linked glycosite from the NA stalk region. To explore the relationship of NA stalk truncation or deglycosylation with viral pathogenicity changes, we generated NA stalk mutant viruses on the pH1N1 backbone by reverse genetics. Intriguingly, either NA stalk truncation or deglycosylation changed pH1N1 into a lethal virus to mice by resulting in extensive pathologic transformation in the mouse lungs and systemic infection affecting beyond the respiratory organs in mice. The increased pathogenicity of these NA stalk mutants was also reproduced in ferrets. In further investigation using a human-infecting H7N9 avian IAV strain, NA stalk truncation or deglycosylation enhanced the replication property and pathogenicity of H7N9 NA stalk mutant viruses in the same mouse model. Taken together, our results suggest that NA stalk truncation or deglycosylation can be the pathogenic determinants of seasonal influenza viruses associated with the evolutionary adaptation of IAVs.
已经注意到，神经氨酸酶（NA）茎突截短是流感病毒从野生水禽到家禽的进化适应的结果。我们在 BALB/c 小鼠中适应 2009 年大流行 H1N1 病毒（pH1N1）后发现了这种分子改变。适应后的 pH1N1 失去了其 NA 茎突区域的连续八个氨基酸，包括一个潜在的 N 连接糖基化位点。为了探索 NA 茎突截短或去糖基化与病毒致病性变化的关系，我们通过反向遗传学在 pH1N1 骨架上生成了 NA 茎突突变病毒。有趣的是，NA 茎突截短或去糖基化通过导致小鼠肺部广泛的病理转化和系统性感染，使 pH1N1 成为对小鼠致命的病毒，感染范围超出了呼吸道。这些 NA 茎突突变体的致病性增加也在雪貂中得到了重现。在使用感染人类的 H7N9 禽流感病毒的进一步研究中，NA 茎突截短或去糖基化增强了 H7N9 NA 茎突突变病毒在相同小鼠模型中的复制特性和致病性。总之，我们的结果表明，NA 茎突截短或去糖基化可能是季节性流感病毒的致病决定因素，与流感病毒的进化适应有关。
