Domain in Fiber-2 interacted with KPNA3/4 significantly affects the replication and pathogenicity of the highly pathogenic FAdV-4.
Domain in Fiber-2 interacted with KPNA3/4 significantly affects the replication and pathogenicity of the highly pathogenic FAdV-4.
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DOI：
10.1080/21505594.2021.1888458
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发表时间：
2021-12
期刊：
影响因子：
5.2
通讯作者：
Ye J
中科院分区：
文献类型：
--
作者：
Xie Q;Wang W;Li L;Kan Q;Fu H;Geng T;Li T;Wan Z;Gao W;Shao H;Qin A;Ye J
自2013年以来，由高致病性4型禽腺病毒(FAdV-4)引起的肝炎-心包积液综合征(HPS)的暴发给全球养禽业造成了巨大的经济损失。虽然Fibre-2基因已被确定为FAdV-4的关键毒力相关因子，但对其分子基础知之甚少。在这项研究中，我们通过1-40aa的N末端鉴定了Fibre-2与核粘附素α3/4(KPNA3/4)蛋白的有效相互作用。对KPNA3/4的过表达和敲除分析表明，KPNA3/4能有效地辅助FAdV-4的复制。此外，通过CRISPR-Cas9技术挽救了一株缺失7-40aa的Fib2编辑病毒fav-4_Del。与野生型FAdV-4相比，FAV-4_Del在体内外均有较强的减毒作用。值得注意的是，在鸡体内接种FAV-4_Del可以对野生型FAdV-4的致死攻击提供充分的保护。所有这些发现不仅为了解Fibre-2致病的分子基础提供了新的见解，也为开发抗病毒策略和针对高致病性FAdV-4的减毒活疫苗候选提供了有效的靶点。
The outbreaks of hepatitis-hydropericardium syndrome (HPS) caused by the highly pathogenic serotype 4 fowl adenovirus (FAdV-4) have caused a huge economic loss to the poultry industry globally since 2013. Although the Fiber-2 has been identified as a key virulent related factor for FAdV-4, little is known about its molecular basis. In this study, we identified the efficient interaction of the Fiber-2 with the karyopherin alpha 3/4 (KPNA3/4) protein via its N-terminus of 1–40aa. The analysis of the overexpression and knockout of KPNA3/4 showed that KPNA3/4 could efficiently assist the replication of FAdV-4. Moreover, a fiber-2-edited virus FAV-4_Del with a deletion of 7–40aa in Fiber-2 was rescued through the CRISPR-Cas9 technique. In comparison with the wild type FAdV-4, FAV-4_Del was highly attenuated in vitro and in vivo. Notably, the inoculation of FAV-4_Del in chickens could provide full protection against the lethal challenge with the wild type FAdV-4. All these findings not only give novel insights into the molecular basis for the pathogenesis of Fiber-2 but also provide efficient targets for developing antiviral strategies and live-attenuated vaccine candidates against the highly pathogenic FAdV-4.
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