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2019-2022年中国H6N1亚型禽流感病毒的生物学特性分析OA北大核心CSTPCD

Biological Characteristics of H6N1 Subtype Avian Influenza Virus from 2019 to 2022 in China

中文摘要英文摘要

[背景]H6 亚型禽流感病毒(avian influenza virus,AIV)广泛流行于我国南方地区,是我国家禽中最常见AIV之一.H6N1 亚型AIV频繁地与其他野鸟源毒株重配,并且可以作为供体为高致病性AIV提供内部基因片段,产生新型重组病毒,进而威胁人类健康.[目的]通过对我国 H6N1 亚型 AIV 的演化动态及其相关生物学特性分析研究,为我国禽流感的综合防控提供数据支持.[方法]采集 2019-2022 年我国 25 个省(直辖市、自治区)的活禽交易市场及养殖场家禽喉和泄殖腔拭子,通过接种鸡胚分离到 7 株 H6N1 亚型AIVs并对其进行全基因组测序,分析其遗传演化特征、受体结合特性及其对SPF鸡和BALB/c小鼠的感染性.[结果]遗传演化分析表明,7 株病毒的基因与分离于北美及东南亚地区的野鸟源病毒基因同源性较高,基因来源复杂,具有明显的遗传多样性.贝叶斯演化分析表明,H6 亚型AIV HA基因曾发生过多次的跨洲际传播,欧亚谱系病毒在北美地区也有着较长时间流行.1 株病毒HA基因与北美地区毒株基因高度同源,根据贝叶斯演化分析结果,推测该病毒在野鸟体内经历了复杂的基因重配后形成,后经野鸟传入我国.特殊氨基酸位点分析结果显示,病毒 HA 蛋白裂解位点序列均为 PQIETR↓GLF,符合低致病性 AIV 特征;此外,另有 1株病毒的NP蛋白发生Y52H突变,据报道,该突变对AIV获得抵抗人干扰素刺激基因BTN3A3 的能力起到关键作用.受体结合特性分析表明,部分毒株具有双受体结合特性,但结合人源受体能力弱于结合禽源受体能力.病毒对 SPF 鸡的感染性试验表明,鸡感染A/chicken/Jiangxi/S40445/2019(H6N1)后能通过呼吸道及消化道排毒,并且病毒可在鸡群内通过接触传播.鸡感染A/duck/Jiangxi/S10941/2019(H6N1)后仅有少数鸡通过呼吸道排毒,病毒无法在鸡群间通过接触传播.BALB/c小鼠的感染性试验表明,H6N1 亚型AIV无需提前适应便可在小鼠呼吸道内有效复制,但对小鼠仍呈低致病力.[结论]2019-2022 年分离于我国的H6N1 亚型AIV基因大部分来源于野鸟源病毒,候鸟可经东亚-澳大利亚迁徙路线将病毒传入我国;部分病毒能够结合人源唾液酸受体并在小鼠呼吸道内有效复制,表明该亚型病毒对公共卫生安全构成潜在威胁.

[Background]H6 avian influenza virus(AIV)is widely prevalent in southern China,which is one of the most common subtypes of AIVs circulating in poultry in China.H6N1 AIVs frequently undergo gene reassortment events with other wild bird-origin virus,which can be a donor to provide internal gene segments to highly pathogenic AIVs,which may lead to the emergence of novel virus and threaten human health.[Objective]The aim of this study was to investigate the evolution and biological characteristics of H6N1 AIVs in China,so as to provide valuable data for the prevention and control of avian influenza in China.[Method]From 2019 to 2022,cloacal and throat swabs were collected from live poultry markets and breeding farms across 25 provinces or autonomous regions in China.7 H6N1 viruses were isolated by inoculating into chicken embryos.The complete genome sequences were determined,followed by analyzing their phylogenetic relationships,receptor binding properties,as well as replication in SPF chickens and BALB/c mice.[Result]The phylogenetic analysis revealed that the genes of the 7 H6N1 AIVs were highly homologous to those of wild bird-origin viruses from North America and Southeast Asia,indicating a complex genetic origin with significant genetic diversity.According to the Bayesian evolution analysis,the HA gene of H6 subtype AIVs had many times of intercontinental transmission in the history,and the Eurasian lineage strains also had a long time of circulation in North America.The HA gene of one strain of the virus was highly homologous to that of the North American strain.Based on the results of Bayesian evolutionary analysis,it was hypothesized that the virus was introduced to China via wild birds after undergoing complex genetic reassortment in wild birds.Analysis of specific amino acid sites revealed that the cleavage site of HA protein was PQIETR↓GLF,which was the signature of low pathogenic AIVs.In addition,one other virus had a Y52H mutation in the NP protein,which was critical in BTN3A3 evasion.Receptor binding analysis demonstrated that some of the H6N1 AIVs bound to both avian-type receptor and human-type receptor,however,their affinity towards human receptors was weaker compared with avian receptors.Infectivity experiments on SPF chickens indicated that flocks was still able to shed virus up through oropharyngeal and cloacal routes after infection with A/chicken/Jiangxi/S40445/2019(H6N1)and that the virus could be transmitted via contact within flocks.Only a few chickens infected with A/duck/Jiangxi/S10941/2019(H6N1)shed virus through their oropharyngeal tract,and the virus could not be transmitted via contact among chickens.The infectivity experiments conducted on mice showed that H6N1 subtype AIVs could replicate in the respiratory organs of infected mice without prior adaptation,but display low pathogenicity levels in mice.[Conclusion]Most of the genes of H6N1 subtype AIV isolated in China from 2019 to 2022 were derived from wild bird-origin viruses,and those migratory birds could introduce the viruses into China via the East Asia-Australasian migratory flyway.Some of the H6 AIVs bound to human-type receptors and replicate in the respiratory organs of mice suggested that H6N1 viruses posed a potential threat to human health.

陈源;王燕;邓国华;陈化兰;崔鹏飞;施建忠;张元成;于晴晴;颜成;张亚萍;王丛丛;张洁

中国农业科学院哈尔滨兽医研究所/动物疫病防控全国重点实验室/国家禽类实验动物资源库,哈尔滨 150069

H6N1禽流感病毒跨洲际传播重配感染性

H6N1avian influenza virusintercontinental transmissionreassortmentinfectivity

《中国农业科学》 2024 (009)

1820-1832 / 13

国家重点研发计划(2021YFD1800201)

10.3864/j.issn.0578-1752.2024.09.015

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