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氨基酸突变 PB1-V719M 和 PA-N444D 与 PB2-627K 的联合作用导致了 H7N9 在小鼠中的致病性。

Amino acid mutations PB1-V719M and PA-N444D combined with PB2-627K contribute to the pathogenicity of H7N9 in mice.

机构信息

College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, China.

Joint International Research Laboratory of Agriculture and Agri-Product Safety, The Ministry of Education of China, Yangzhou University, Yangzhou, 225009, China.

出版信息

Vet Res. 2024 Jul 5;55(1):86. doi: 10.1186/s13567-024-01342-6.

DOI:10.1186/s13567-024-01342-6
PMID:38970119
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11227215/
Abstract

H7N9 subtype avian influenza viruses (AIVs) cause 1567 human infections and have high mortality, posing a significant threat to public health. Previously, we reported that two avian-derived H7N9 isolates (A/chicken/Eastern China/JTC4/2013 and A/chicken/Eastern China/JTC11/2013) exhibit different pathogenicities in mice. To understand the genetic basis for the differences in virulence, we constructed a series of mutant viruses based on reverse genetics. We found that the PB2-E627K mutation alone was not sufficient to increase the virulence of H7N9 in mice, despite its ability to enhance polymerase activity in mammalian cells. However, combinations with PB1-V719M and/or PA-N444D mutations significantly enhanced H7N9 virulence. Additionally, these combined mutations augmented polymerase activity, thereby intensifying virus replication, inflammatory cytokine expression, and lung injury, ultimately increasing pathogenicity in mice. Overall, this study revealed that virulence in H7N9 is a polygenic trait and identified novel virulence-related residues (PB2-627K combined with PB1-719M and/or PA-444D) in viral ribonucleoprotein (vRNP) complexes. These findings provide new insights into the molecular mechanisms underlying AIV pathogenesis in mammals, with implications for pandemic preparedness and intervention strategies.

摘要

H7N9 亚型禽流感病毒 (AIVs) 导致 1567 人感染，死亡率高，对公共卫生构成重大威胁。此前，我们报道了两种来源于禽类的 H7N9 分离株 (A/鸡/华东/ JTC4/2013 和 A/鸡/华东/ JTC11/2013) 在小鼠中表现出不同的致病性。为了了解毒力差异的遗传基础，我们基于反向遗传学构建了一系列突变病毒。我们发现，尽管 PB2-E627K 突变能够增强病毒在哺乳动物细胞中的聚合酶活性，但单独突变不足以增加 H7N9 在小鼠中的毒力。然而，与 PB1-V719M 和/或 PA-N444D 突变的组合显著增强了 H7N9 的毒力。此外，这些组合突变增强了聚合酶活性，从而加剧了病毒复制、炎症细胞因子表达和肺损伤，最终增加了小鼠的致病性。总体而言，这项研究揭示了 H7N9 的毒力是一种多基因特征，并确定了病毒核糖核蛋白 (vRNP) 复合物中与毒力相关的新残基 (PB2-627K 与 PB1-719M 和/或 PA-444D 结合)。这些发现为理解哺乳动物中 AIV 发病机制的分子机制提供了新的见解，对大流行的防范和干预策略具有重要意义。

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Human infection of avian influenza A H3N8 virus and the viral origins: a descriptive study.
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