Biological Significance of Dual Mutations A494D and E495K of the Genotype III Newcastle Disease Virus Hemagglutinin-Neuraminidase In Vitro and In Vivo.
Biological Significance of Dual Mutations A494D and E495K of the Genotype III Newcastle Disease Virus Hemagglutinin-Neuraminidase In Vitro and In Vivo.
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基因型III新城疫病毒血凝素-神经氨酸酶双突变A494D和E495K的体外和体内生物学意义
DOI：
10.3390/v14112338
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发表时间：
2022-10-25
期刊：
影响因子：
--
通讯作者：
Liu X
中科院分区：
文献类型：
--
作者：
Lu X;Zhan T;Liu K;Chen Y;Hu Z;Hu J;Gu M;Hu S;Wang X;Liu X;Liu X
纽卡斯尔病毒（NDV）血凝素-神经氨酸酶（HN）蛋白是一种多功能蛋白，参与多种生物学功能。从中基因疫苗株Mukteswar进化而来的强基因型III NDV JS/7/05/Ch在HN蛋白中显示出主要氨基酸（aa）突变。然而，突变HN蛋白的确切生物学意义仍不清楚。本研究旨在研究突变HN蛋白对体外和体内生物学活性的影响。与原始HN蛋白（Mukteswar型HN）相比，突变HN蛋白（JS/7/05/Ch-type HN）显着增强了血细胞吸附（HAd）和融合促进活性，但削弱了神经氨酸酶（NA）活性。值得注意的是，HN中的A494 D和E495 K在调节生物活性方面表现出协同作用。此外，突变HN蛋白，特别是HN中的A494 D和E495 K，增强了F蛋白的切割水平，这可能有助于F蛋白的活化。体外感染试验进一步表明，携带A494 D和E495 K的NDV在HN中显著损害细胞活力。同时，HN中的A494 D和E495 K在感染早期增强病毒复制水平，但在感染后期减弱，这可能与NA活性和细胞活力减弱有关。动物实验表明，HN中的A494 D和E495 K增强了NDV感染鸡的病死率、散毒率、病毒循环和组织病理学损害。总之，这些发现突出了HN中的关键aa突变在调节NDV的生物学活性中的重要性，并扩展了对基因型III NDV的增强的致病性的理解。
As a multifunctional protein, the hemagglutinin-neuraminidase (HN) protein of Newcastle disease virus (NDV) is involved in various biological functions. A velogenic genotype III NDV JS/7/05/Ch evolving from the mesogenic vaccine strain Mukteswar showed major amino acid (aa) mutations in the HN protein. However, the precise biological significance of the mutant HN protein remains unclear. This study sought to investigate the effects of the mutant HN protein on biological activities in vitro and in vivo. The mutant HN protein (JS/7/05/Ch-type HN) significantly enhanced the hemadsorption (HAd) and fusion promotion activities but impaired the neuraminidase (NA) activity compared with the original HN protein (Mukteswar-type HN). Notably, A494D and E495K in HN exhibited a synergistic role in regulating biological activities. Moreover, the mutant HN protein, especially A494D and E495K in HN, enhanced the F protein cleavage level, which can contribute to the activation of the F protein. In vitro infection assays further showed that NDVs bearing A494D and E495K in HN markedly impaired the cell viability. Simultaneously, A494D and E495K in HN enhanced virus replication levels at the early stage of infection but weakened later in infection, which might be associated with the attenuated NA activity and cell viability. Furthermore, the animal experiments showed that A494D and E495K in HN enhanced case fatality rates, virus shedding, virus circulation, and histopathological damages in NDV-infected chickens. Overall, these findings highlight the importance of crucial aa mutations in HN in regulating biological activities of NDV and expand the understanding of the enhanced pathogenicity of the genotype III NDV.
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