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禽流感病毒_百度百科

毒_百度百科 网页新闻贴吧知道网盘图片视频地图文库资讯采购百科百度首页登录注册进入词条全站搜索帮助首页秒懂百科特色百科知识专题加入百科百科团队权威合作下载百科APP个人中心禽流感病毒播报讨论上传视频一种甲型流感病毒收藏查看我的收藏0有用+10本词条由“科普中国”科学百科词条编写与应用工作项目 审核 。禽流感病毒（AIV）属甲型流感病毒。流感病毒属于RNA病毒的正黏病毒科，分甲、乙、丙3个型。其中甲型流感病毒多发于禽类，一些甲型也可感染猪、马、海豹和鲸等各种哺乳动物及人类；乙型和丙型流感病毒则分别见于海豹和猪的感染。就是禽类的病毒性流行性感冒，是由A型流感病毒引起禽类的一种从呼吸系统到严重全身败血症等多种症状的传染病。禽流感容易在鸟类间流行，过去在民间称为“鸡瘟”，国际兽疫局将其定为甲类传染病。禽流感1994年、1997年、1999年和2003年分别在澳大利亚、意大利、中国香港、荷兰等地暴发，2005年则主要在东南亚和欧洲暴发 [1]。2022年4月5日，日本在北海道札幌市内一只狐狸的尸体上检测出高致病性禽流感病毒。 [4]外文名AIV多发群体儿童，老人常见发病部位呼吸道传染性有传染性传播途径呼吸中医学名禽流感病毒目录1预防禽流感病毒2病毒形态▪成分▪表现3流行病学▪传染源▪传播途径▪易感人群▪流行特征▪与人类关系4病理改变▪单纯型流感▪肺炎型流感▪严重并发症5特征▪致病能力▪适应能力▪分子特征6新型H5N17预防治疗▪疫苗▪抑制药物8各地疫情▪中国▪加拿大▪日本▪美国▪捷克▪荷兰▪秘鲁▪柬埔寨▪智利▪巴黎▪哥伦比亚▪阿根廷▪英国预防禽流感病毒播报编辑禽流感一般发生在春冬季，一般不会在人与人之间传染。预防禽流感应注意以下几点:a．勤洗手，远离家禽的分泌物，接触过禽、鸟或禽、鸟粪便要注意用消毒液和清水彻底清洁双手，避免到疫区旅行；b．养成良好的个人卫生习惯，咳嗽时用手或卫生纸捂住嘴，加强室内空气流通，每天1～2次开窗换气半小时，要有充足的睡眠和休息，均衡的饮食，注意多摄入一些富含维生素C等增强免疫力的食物；c．吃禽肉要煮熟、煮透，食用鸡蛋时蛋壳先用流水清洗，烹调加热充分，不吃生的或半生的鸡蛋 [1]。病毒形态播报编辑成分甲型流感病毒呈禽流感病毒多形性，其中球形直径80～120nm，有囊膜。基因组为分节段单股负链RNA。依据其外膜血凝素（H）/和神经氨酸酶（N）蛋白抗原性的不同，可分为16个H亚型（H1～H16）和9个N亚型（N1～N9）。感染人的禽流感病毒亚型主要为H5N1、H9N2、H7N7，其中感染H5N1的患者病情重，病死率高。表现研究表明，原本为低致病性禽流感病毒株（H5N2、H7N7、H9N2），可经6～9个月禽间流行的迅速变异而成为高致病性毒株（H5N1）。流行病学播报编辑传染源禽流感病毒攻击健康细胞禽流感病毒可在水禽的消化道中繁殖。主要为患禽流感或携带禽流感病毒的家禽，另外野禽或猪也可成为传染源。许多家禽都可感染病毒发病：火鸡、鸡、鸽子、珍珠鸡、鹌鹑、鹦鹉等陆禽都可感染发病，但以火鸡和鸡最为易感，发病率和死亡率都很高；鸭和鹅等水禽也易感染，并可带毒或隐性感染，有时也会大量死亡。各种日龄的鸡和火鸡都可感染发病死亡，而对于水禽如雏鸭、雏鹅其死亡率较高。除野禽，如天鹅、燕鸥、野鸭、海岸鸟和海鸟等外，还从以下多种鸟中分离到流感病毒；燕八哥、石鸡、麻雀、乌鸦、寒鸦、鸽、岩鹧鸪、燕子、苍鹭、加拿大鹅及番鸭等。据国外报道，已发现带禽流感病毒的鸟类达88种，而鼠类不能自然感染流感病毒。不同品种的家禽感染禽流感的几率不同，但目前尚未发现高致病性禽流感的发生与禽的性别有关，高致病性禽流感病毒也可通过鸡蛋传播。高致病性禽流流在禽群之间的传播主要依靠水平传播，如空气、粪便、饲料和饮水等；而垂直传播的证据很少。但通过实验表明，实验感染鸡的蛋中含有流感病毒，因此不能完全排除垂直传播的可能性。所以，不能用污染鸡群的种蛋做孵化用。病毒可以随病禽的呼吸道、眼鼻分泌物、粪便排出，禽类通过消化道和呼吸道途径感染发病。被病禽粪便、分泌物污染的任何物体，如饲料、禽舍、笼具、饲养管理用具、饮水、空气、运输车辆、人、昆虫等都可能传播病毒。传播途径主要经呼吸道传播，通过密切接触感染的禽类及其分泌物、排泄物，受病毒污染的水等，以及直接接触病毒毒株被感染。在感染水禽的粪便中含有高浓度的病毒，并通过污染的水源泉由粪便-口途径传播流感病毒。还没有发现人感染的隐性带毒者，尚无人与人之间传播的确切证据。易感人群一般认为任何年龄均具有易感性，但12岁以下儿童发病率较高，病情较重。与不明原因病死家禽或感染、疑似感染禽流感家禽密切接触人员为高危人群。流行特征禽流感是世界范围分布的，1994年、1997年、1999年和2003年分别在澳大利亚、意大利、中国香港、荷兰等地爆发，2005年则主要在东南亚和欧洲爆发。除鸡群中的禽流感主要发生在冬、春季节外，没有其他明显的规律性。高致病性禽流感疫情的蔓延引起世界关注。我国气象专家对疫情地气候特征的分析表明，禽流感“不喜”晴热天气。世界卫生组织（WHO）认为，病禽粪便是传播的主要渠道，也有专家认为，候鸟的迁徙也是传播途径之一。天气气候条件作为自然环境中的一个重要因子，其变化或异常通常会对一些疾病的发生、加重或缓解起一定作用。专家认为，禽流感病毒喜欢冷凉和潮湿，阳光中的紫外线对病毒有一定的杀灭作用。冬末春初，冷空气活动频繁，气温忽高忽低，对控制和预防禽流感的发生将是不利的。另外，随着气温的回暖，候鸟将会向北迁徙，候鸟传播病毒的范围将会扩大，对控制禽流感发生也将是不利的。WHO认为，病鸡粪便中的H5N1禽流感病毒株会散布在空气中，并被风带走而传播禽流感。从日照时数看，分析材料显示，日照较少的地区易发生禽流感。这与农业专家提出的禽流感病毒在阳光下只能存活24～28h，一般多在冬春两季流行，在5～10月份就基本平复的观点是一致的。高致病性禽流感病毒主要通过空气进行传染，借助病毒表面的血凝素（H），与呼吸道黏膜上皮细胞表面的相应受体结合，吸附可宿主的呼吸道上皮细胞上。又借助病毒表面的神经氨酸酶（N）作用于核蛋白的受体，使病毒和上皮细胞的核蛋白结合，在核内组成RNA型可溶性抗原，并渗出至胞质周围，复制子代病毒，通过神经氨酸本作用，以出芽方式排出上皮细胞。一个复制过程的周期为4～6h，排出的病毒扩散至附近细胞，产生炎症反应，临床上出现发热，肌肉痛和白细胞减低等全身毒血症样反应。病毒主要侵入呼吸道黏膜的上皮细胞，引起上皮细胞增生、坏死、黏膜局部充血、水肿和浅表溃疡等卡他性病变。4～5d后，基底细胞层病变可扩展到支气管、细支气管、肺泡和支气管周围组织，引起黏膜水肿、充血、淋巴细胞浸润，并伴有微血管栓塞、坏死、小动脉瘤形成和出血等，引发全身毒血症样反应。少数重症进行性肺炎除细支气管炎症变化外，可有肺泡壁充血水肿、纤维蛋白渗出，单核细胞浸润和透明膜形成，以及肺出血等，引起诸多并发症。高致病性禽流感病毒毒力较强，引发的传染性变态反应（IV型变态反应）是导致进行性肺炎、急性呼吸窘迫综合证（ARDS）和多器官功能障碍综合征（MODS）等严重并发症的根本原因。与人类关系人类对禽流感的研究和防治工作已有100多年的历史。基因片段，除非禽流感病毒与人流感病毒发生基因重组，否则它很难侵犯人类，导致人与人间传播。人禽流感的发生，只可能是因接触的病禽而感染。人感染病 毒的几率很小。禽流感病毒属甲型流感病毒。流感病毒属于RNA病毒的正黏病毒科，分甲、乙、丙3个型。病理改变播报编辑单纯型流感仅有上呼吸道卡他性炎症变化，黏膜可见充血、水肿及淋巴细胞浸润。纤维上皮细胞变性、坏死、脱落。肺炎型流感肺脏是暗红样水肿。气管、支气管内有血性分泌物、黏膜充血，其纤毛上皮细胞坏死脱落，黏膜下层灶性出血、水肿和白细胞浸润，肺泡中有纤维蛋白渗出液，含中性粒细胞及淋巴细胞。肺中叶肺泡有出血，肺泡内可有透明膜，肺组织易分离出流感病毒。严重并发症主要病理改变为肺实变。由于肺间质水肿、间质负压减小，增加小气道陷闭倾向，导致肺不张；肺泡膜表面活性物质减少，肺泡亦陷隐闭；加之肺充血，使肺容量减小和肺顺应性下降，导致急性呼吸急迫综合征等严重并发症。特征播报编辑致病能力原形毕露的h5n1型禽流感病毒一般来说，禽流感病毒与人流感病毒存在受体特异性差异，禽流感病毒是不容易感染给人的。个别造成人感染发病的禽流感病毒可能是发生了变异的病毒。变异的可能性一是两种以上的病毒进入同一细胞进行重组，如猪既可感染人流感病毒，又可能感染禽流感病毒，每种病毒都具有8个基因片段，从理论上讲，可以形成256个新的重组病毒；二是病毒基因位点由于某种因素的影响，1983年4月，美国宾夕法尼亚州曾暴发H5N2型病毒引起的鸡和火鸡低致病性禽流感，由于没有及时得到有效控制，到同年10月份，同样的H5N2型毒株突然由低致病性变成高致病性，造成禽类大量死亡。适应能力禽流感病毒对乙醚、氯仿、丙酮等有机溶剂均敏感。常用消毒剂容易将其灭活，如氧化剂、稀酸、十二烷基硫酸钠、卤素化合物（如漂白粉和碘剂）等都能迅速破坏其传染性。禽流感病毒对热比较敏感，65°C加热30min或煮沸（100°C）2min以上可灭活。病毒在粪便中可存活1周，在水中可存活1个月，在pH﹤4.1的条件下也具有存活能力。病毒对低抗温抵力较强，在有甘油保护的情况下可保持活力1年以上。病毒在直射阳光下40～48h即可灭活，如果用紫外线直接照射，可迅速破坏其传染性。分子特征分子结构禽流感病毒聚合酶的晶体结构由H5N1亚型禽流感病毒引起的疫情广泛传播对人类的健康造成全球性的重大威胁。由于病毒的不断变异，开发新型抗流感药物成为各国极为迫切的重大课题。其中，揭示与流感病毒密切相关的蛋白质的三维结构不仅对揭示流感病毒复制机制具有重要科学意义，而且对开发抗流感病毒药物具有重要价值。由中科院生物物理研究所刘迎芳研究员领导的研究组和饶子和院士领导的研究小组在这一领域取得突破性进展，他们在国际上率先揭示了流感病毒聚合酶关键部分PA亚基与PB1多肽复合体的精细三维结构。流感A病毒聚合酶由三种蛋白组成——PA、PB1和PB2，是转录和复制的关键。两个小组报告了禽流感病毒H5N1 PA 的C-端区域在与PB1的PA结合区域所形成的复合物中的晶体结构。这项结构研究对于新型抗病毒药物的设计可能会有用。流感病毒基因组含有8个RNA片段，已知可以编码11种病毒蛋白质。其中，由PA,PB1和PB23个亚基组成的聚合酶复合体是负责病毒基因组RNA复制以及病毒mRNA转录的关键组分，同时由于它的高度保守性、低突变率，成为抗流感病毒药物设计的重要靶点。多年来的研究认为，PB1是病毒RNA聚合酶的催化亚基，负责病毒RNA的复制以及转录；PB2是负责以一种称为“Snatch”的方式夺取宿主mRNA的CAP帽子结构用于病毒mRNA转录。而PA亚基不但参与病毒复制过程，而且还参与病毒RNA转录、内切核酸酶活性、具有蛋白酶活性以及参与病毒粒子组装等多种病毒活动过程，因而在整个聚合酶复合体的研究中显得格外重要。在经过晶体生长条件筛选、晶体质量优化、高分辨率数据收集、相位解析、电子密度图解释以及结构修正等难关，他们利用全新的思路，解析了PA与PB1氨基端多肽蛋白复合体的2.9埃分辨率晶体结构。该结构清晰显示了PA与PB1多肽相互作用模式，发现该作用位点的氨基酸残基在流感病毒中高度保守，这为广谱抗流感(包括人流感和禽流感)药物研究提供了一个理想的靶蛋白。同时，根据该复合体结构以及已知的一些蛋白突变体研究结果，推测了PA亚基在聚合酶中作用，为进一步功能研究提供了分子基础。这一复合体结构的揭示，对揭示流感病毒聚合酶作用机制以及开展针对流感病毒药物设计工作都具有十分重要意义。聚合酶系专司生物催化合成脱氧核糖核酸(DNA)和核糖核酸(RNA)的一类酶的统称。可分为以下几个类群:(1)依赖DNA的DNA聚合酶；(2)依赖RNA的DNA聚合酶；(3)依赖DNA的RNA聚合酶；(4)依赖RNA的RNA聚合酶。前两者是DNA聚合酶，它使DNA复制链按模板顺序延长。如在原核生物中仅就大肠杆菌中已被发现的就有三种(分别简称为P01Ⅰ，P01Ⅱ和P01Ⅲ等)；DNA聚合酶只能在有引物的基础上，即在DNA或RNA引物的3′-OH延伸，这DNA的合成方向记为5′→3′。换言之DNA聚合酶催化反应除底物(αNTP)外，还需要Mg2+、模板DNA和引物，迄今细胞内尚无发现可从单体起始DNA的合成。同样，上述(3)和(4)是催化RNA生物合成反应中最主要的RNA合成酶，它们以四种三磷酸核糖核苷(NTP)为底物，并需有DNA模板以及Mn2+及Mg2+的存在下，在前一个核苷酸3′-OH与下一个核苷酸的5′-P聚合形成3′，5′-磷酸二酯键，其新生链的方向也是5′→3′。RNA聚合酶也大量存在于原核和真核生物的细胞中。如大肠杆菌RNA聚合酶分子量4.8×105，由5条多肽链组成，分别命名为α，α，β，β′，和γ，全酶可用α2ββ′λ表示。真核生物RNA聚合酶分子大于5×105，由10～12个大小不等亚基组成。聚合酶除作为自然界生命活动中不可缺少的组分外，在实验室中大多用作生命科学研究的工具酶类之一。新型H5N1播报编辑联合国粮农组织29日指出，H5N1这种可以通过家禽传染给人类的高致病型禽流感病毒在最近几年有不断扩散的趋势。粮农组织首席兽医官员卢布罗夫指出，近几年H5N1禽流感病毒传播有扩散的趋势，而且在中国和越南还出现了H5N1变种病毒，能使现有疫苗失去作用。他呼吁各国做好准备，对病毒进行密切监控，防止疫情蔓延。卢布罗夫指出，鸟类移徙是造成H5N1禽流感病毒传播的罪魁祸首，家禽的生产和销售也促使了H5N1的传播。他还指出，在过去两年里，这种病毒通过鸟类长途移徙传播到了曾经根除此种病毒的国家。卢布罗夫同时还对在中国和越南出现的H5N1变种病毒表达了担忧。他指出，这种变种病毒能够抵御现有疫苗的作用，呼吁相关国家不要掉以轻心，应做好充分准备，对这种病毒加以监控。病毒学家周二警告称，尚无疫苗可防治在中国和越南传播的H5N1禽流感变异毒株，呼吁各界加强对该病毒的监控，以免传染人类。越南的兽医部门高度警惕，据说正在考虑秋季开展一项新的和具有针对性的疫苗接种运动。病毒在越南的传播直接威胁着柬埔寨、泰国和马来西亚,以及更远的朝鲜半岛和日本。野生鸟类的迁徙也会将病毒传播至其他大洲。联合国粮农组织（FAO）周一警告称，禽流感可能再度席卷而来，并称H5N1禽流感变异毒株正在亚洲及其它地区传播。科学家尚不确定新病株H5N1-2.3.2.1是否对人类更致命，但他们指出，该病株与原先病毒差异较大，人类针对原先病毒而研制的疫苗对其无效。香港大学病毒学家佩里斯（Malik Peiris）说道：“目前，世界卫生组织（WHO）推荐了一种人用的H5N1备选疫苗……但它无法全面防治（新毒株）。”“不过这很常见。H5病毒不断发生变化，因此我们也必须研发新疫苗来应对。” [2]预防治疗播报编辑疫苗流感病毒疫苗接种是当前人类预防流感的首选措施，然而，由于流感病毒血清型众多，一旦流感病毒疫苗株和流行株的抗原性不匹配，就会导致疫苗失效，无法提供相应的保护；同时由于流感病毒变异的速度很快，疫苗研发的速度落后于病毒变异的速度，新的流行株出现后，其对应疫苗的制备至少需要6个月的时间，造成疫苗制备一直处于被动状态，故无论传统灭活疫苗，还是基因工程疫苗、核酸疫苗等新型疫苗都无法对所有类型的流感病毒提供交叉保护。抑制药物用于治疗流感的化学药物有两大类：一是离子通道抑制剂，即以流感病毒的离子通道蛋白M2为靶标，通过干扰流感病毒M2蛋白的离子通道活性而阻碍流感病毒的复制，该药有较大的毒副作用，而且已经出现耐药株。二是神经氨酸酶抑制剂，即以流感病毒的神经氨酸酶NA为靶标的抑制剂，通过抑制该酶的活性而有效地抑制病毒粒子在宿主细胞膜表面的释放，从而抑制流感病毒感染新的宿主细胞的过程。在H5N1禽流感病毒感染的患者体内也出现了对该药的耐药株。此外还有些人工合成的唾液酸寡聚糖类似物和抗A型流感病毒的单味和复方中药制剂，但都因种种原因难以在大范围内推广。治疗家禽禽流感：国浩一针灵1ml/kg+干扰素+头孢先锋,病情严重者可再用急救扰干素饮水。各地疫情播报编辑中国2014年3月12日，澳门民政总署于批发市场的活禽样本中检测到H7禽流感病毒，当局立即采取行动，2014年3月13日凌晨开始扑杀批发市场内7500多只活禽。 [3]加拿大当地时间2022年4月7日，加拿大食品检验局表示近日在艾伯塔省和安大略省的部分家禽中发现了禽流感病例。 [5]2022年5月5日，加拿大食品检验局发布的一份报告显示，截至当天，加拿大全国至少有68个家禽养殖场受到h5n1禽流感病毒的影响，估计有至少170万只家禽死亡。 [9]当地时间2022年5月10日，加拿大媒体援引一些野生动物专家的说法报道称，正在加拿大传播的禽流感病毒不仅导致相当数量的鸟类死亡，甚至开始传染哺乳动物。5月5日，加拿大食品检验局发布的一份报告显示，截至当天，加拿大全国至少有68个家禽养殖场受到H5N1禽流感病毒的影响，估计有至少170万只家禽死亡。 [8]日本2022年4月16日，日本农林水产省宣布，北海道两家禽类养殖场出现高致病性禽流感疫情，当地决定扑杀超过50万只鸡和数百只鸸鹋。 [6]2022年11月27日，日本西南部鹿儿岛县出水市一家蛋鸡养殖场确认暴发禽流感，随即开始扑杀总计47万只鸡。日本农林水产省的数据显示，本次禽流感流行季（通常为当年秋冬至次年春）扑杀禽类数量已远超上一个流行季。 [11]当地时间2023年1月9日，据日本广播协会（NHK）报道，日本茨城县一家养鸡场确认发生高致病性禽流感疫情。从2022年10月下旬到2023年1月9日，本次禽流感流行季期间，日本23个一级行政区的养鸡场等设施已报告禽流感疫情56起，扑杀处理禽类总数约998万只，感染规模和扑杀处理数量均超过了此前在2020年11月至2021年3月间的最高纪录。 [13]当地时间2023年2月3日，日本最大的鸡蛋产地茨城县再次暴发养鸡场禽流感，大量蛋鸡被扑杀，给日本国内的鸡蛋供应带来冲击。截至2月3日，本次禽流感流行季日本国内已暴发74起禽流感疫情，涉及日本全国一半以上的一级行政区，扑杀禽类数量累计已超过1300万只。 [15]2023年3月2日，据日本广播协会（NHK）报道，日本福冈一养鸡场内扑杀了24万只以上感染禽流感病毒的鸡。报道称，本次病鸡所感染的病毒有可能是高致病性的H5型禽流感病毒。 [18]2023年3月8日，据日本共同社报道，由于禽流感疫情持续蔓延，日本已扑杀禽类约1600万只，扑杀数量创历史新高，导致鸡蛋价格飙升。 [22]2023年4月5日，据美国彭博社报道，日本暴发有史以来最严重的禽流感，全国扑杀超过1700万只鸡，全国大量扑杀鸡导致家禽数量大幅减少，鸡蛋价格飙升，甚至没有合适的土地用以填埋死禽。 [24]美国2022年5月，据美国疾控中心最新数据显示，美国目前已有29个州的养殖场发现禽流感病毒 。据路透社报道，今年以来，禽流感已经造成美国商业养殖场里超过1900万只蛋鸡死亡，占总数的6%，是过去7年来最严重的一次疫情 。 [7]2022年11月24日，美国农业部发布数据显示，禽流感导致美国今年5054万只禽鸟死亡。 [10]捷克2023年1月3日，捷克国家兽医管理局说，该国西部比尔森州一个大型养鸡场暴发禽流感疫情，约22万只蛋鸡将被扑杀，2022年12月30日，进行的样本检测确认死亡蛋鸡感染了高致病性H5N1型禽流感病毒。 [12]荷兰荷兰当局2023年1月25日通报，荷兰农业、自然及食品质量部当日发布的公告，弗里斯兰省西南弗里斯兰市一处养鸡场发现禽流感病例，为防疫情扩散，涉事农场约5.7万只肉鸡被扑杀。 [14]秘鲁2023年2月7日，秘鲁生态保护部门说，最近几周有585头海狮和5.5万只野生鸟因感染H5N1禽流感病毒死亡。 [16]柬埔寨2023年2月22日，柬埔寨东南部波萝勉省乡村地区一名11岁女孩感染高致病性禽流感病毒H5N1后死亡。这是该国2014年以来首例人感染H5N1病例。 [17]智利当地时间2023年3月7日，智利国家渔业和水产养殖局发布消息称，实验室人员在阿里卡地区发现的一具水獭尸体中检测出禽流感病毒。这是智利发现的第一例水獭感染禽流感病例。 [19]近来，智利多个地区暴发禽流感疫情，造成鸡蛋产量下降，价格大幅上涨，当地消费者不得不减少鸡蛋消费。去年年底以来，智利已出现了数千只家禽和野鸟感染高致病性禽流感病毒H5N1的情况，为此，智利政府已扑杀了超过100万只禽类，其中有约70万只为产蛋家禽 [25]。巴黎当地时间2023年3月7日，世界动物卫生组织发表报告称，近日在法国巴黎的赤狐身上发现禽流感病毒。 [20]哥伦比亚当地时间2023年3月13日，哥伦比亚官方宣布，2月下旬以来，在位于该国西部太平洋海域的戈尔戈纳国家海岛自然公园内持续发现死亡候鸟，已发现至少500只死亡候鸟。 [21]阿根廷当地时间2023年3月18日，阿根廷国家农牧食品质量检验检疫局发布消息称，自上月15日该国发现甲型H5高致病禽流感确诊病例以来，当地官方防疫部门已在全国11个省检测到59例确诊病例，300多例疑似感染病例。 [23]在确诊病例中，有49例为农户散养家禽，6例来自成规模的商业禽类养殖场，其余4例为野生鸟类。6个出现感染病例养殖场所饲养的70余万只禽类已被全部扑杀。 [23]2024年2月26日，路透社援引西班牙国家研究委员会的消息报道，阿根廷科研人员日前在阿根廷南极普里马韦拉站附近发现了死亡的掠食性海鸟贼鸥。与西班牙科研人员合作检测后，研究者24日确认其携带高致病性禽流感病毒。 [27]英国当地时间2023年7月14日，英国卫生安全局（UKHSA）透露，英国英格兰地区2家不同家禽饲养场的2名工人禽流感病毒检测呈阳性。 [26]新手上路成长任务编辑入门编辑规则本人编辑我有疑问内容质疑在线客服官方贴吧意见反馈投诉建议举报不良信息未通过词条申诉投诉侵权信息封禁查询与解封©2024 Baidu 使用百度前必读 | 百科协议 | 隐私政策 | 百度百科合作平台 | 京ICP证030173号 京公网安备110000020000

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Cell Reports | 高福院士团队深度解析H7N9亚型禽流感病毒血凝素蛋白的跨种传播机制 - 知乎

Cell Reports | 高福院士团队深度解析H7N9亚型禽流感病毒血凝素蛋白的跨种传播机制 - 知乎切换模式写文章登录/注册Cell Reports | 高福院士团队深度解析H7N9亚型禽流感病毒血凝素蛋白的跨种传播机制知乎用户C83gMD内聚人心，外树形象A型流感病毒（Influenza A virus，IAV）属于正黏病毒科，是一个有囊膜的、分节段的单股负链的RNA病毒[1]。它是一种重要的人畜共患病原，在历史上曾引起多次流感大流行事件以及散发性禽流感病毒（Avian influenza virus，AIV）感染人事件，严重威胁公共卫生安全和社会经济发展。流感病毒表面有两个重要的囊膜蛋白——血凝素蛋白（Hemagglutinin，HA）和神经氨酸酶（Neuraminidase，NA）。不同亚型流感病毒与受体的结合主要是靠HA蛋白实现的，HA与受体的结合具有种属特异性。 HA与受体的结合是流感病毒感染的第一步，因此HA受体结合偏好性的转变是流感病毒跨种传播的关键决定因素。根据前人在流感病毒跨种传播领域的成果[2]，目前已知不同亚型流感病毒HA分子跨种传播的分子机制有所差别【图1】。就H1亚型IAV而言，主要是由190和225位氨基酸起决定作用，在禽中分离的病毒主要是E190/G225，具有双受体结合特性，而在人中分离到的病毒主要是D190/D225，特异性结合人源受体。就H2和H3亚型IAV而言，主要由226和228位氨基酸决定，将Q226/G228突变成L226/S228即可使HA转变成人源受体结合偏好性。而在H5亚型IAV中，主要是226位氨基酸由谷氨酰胺（Glutamine，Q）到亮氨酸（Leucine，L）的转变以及158位糖基化的丢失等因素共同决定的。图1 不同亚型流感病毒HA的跨种传播分子基础[2]自2013年起，H7N9亚型禽流感病毒已引起1600多人感染，并于2017年出现一些高致病性禽流感毒株。然而到目前为止，H7亚型与受体结合的关键分子基础尚未被完全阐明，各个氨基酸在其中所起的作用以及病毒获得人源受体结合特性的演化过程也仍不清楚。2019年11月19日，中国科学院微生物研究所高福院士团队在Cell Reports杂志上发表了题为“Avian-to-Human Receptor-Binding Adaption of Avian H7N9 Influenza VirusHemagglutinin”的研究论文[4]，详细地阐述了H7N9亚型禽流感病毒血凝素蛋白由禽源受体偏好性向双受体结合特性演化的过程，该项成果对流感病毒防控工作具有重要指导意义。研究人员通过序列分析、PCR定点突变、表面等离子共振技术、免疫荧光染色技术、反向遗传学技术以及结构生物学等技术，分析带有不同氨基酸组合的HA突变体的受体结合特性、病毒复制能力及结构等性质的变化，从分子层面详尽地阐明了H7N9亚型HA的跨种传播机制。他们发现仅186位氨基酸由甘氨酸（Glycine，G）变成缬氨酸（Valine，V）,即可使禽受体结合特异性的SH1-H7N9 HA获得人源受体结合能力。而L226在其他三个位点存在亲水氨基酸时，是不利于人源受体和禽源受体的结合。基于结构分析，186位氨基酸的侧链可影响190-helix上E190侧链的走向，从而影响HA与受体的相互作用，而L226在没有其它三个疏水氨基酸（A138，V186和P221）搭配的情况下会降低220-loop的稳定性，从而降低HA对于人源和禽源两种受体的亲和力。生化实验和结构分析结构表明，186位氨基酸是决定H7N9 HA获得人源受体结合能力的关键；而226位并非关键位点。当L226与亲水氨基酸搭配时，对两种受体结合都是有不利影响的，因此推测在演化上，很可能需要186位氨基酸先发生变化，而后发生Q226L的突变。通过分析所有H7亚型流感病毒的HA序列的进化关系，研究人员发现天然毒株中也存在这样的演化趋势。总体而言，在H7N9亚型流感病毒HA在演化过程中，它首先由禽特异性结合的G186Q226变成双受体结合特性的V186Q226，最后演变成V186L226【图2】。其中186位氨基酸是H7N9 HA获得人源受体结合能力的关键氨基酸位点；而226位并非关键位点，在搭配亲水氨基酸时，反而不利于两种受体的结合。该项成果整合了生物化学、分子生物学、病毒学、生物信息学以及结构生物学等方法，阐明了H7N9亚型禽流感病毒的跨种传播机制及其独特的演化途径，从分子层面阐明H7N9 禽流感病毒的进化可能是由受体结合特性以及其它可能因素共同选择的结果。这些研究有利于深入理解H7亚型禽流感病毒跨种传播的分子机制，对于流感病毒疫情的预防与控制具有重要指导作用。图2 H7N9 HA受体结合特性演化模式图[3]据悉，中国科学技术大学徐颖博士为论文第一作者，中国科学院微生物研究所高福院士为论文通讯作者。另外，中国科学院微生物研究所的施一研究员、齐建勋研究员、张蔚副研究员、彭如超助理研究员等人在课题设计等方面给与了大量支持和帮助。1.Dowdle, W.R., et al., Orthomyxoviridae. Intervirology, 1975. 5(5): p. 245-51.2. Shi, Y., et al., Enabling the 'host jump': structuraldeterminants of receptor-binding specificity in influenza A viruses. NatRev Microbiol, 2014. 12(12): p.822-31.3. Xu Y., et al.,Avian-to-Human Receptor-Binding Adaption of Avian H7N9 Influenza VirusHemagglutinin. Cell Reports, 2019.https://doi.org/10.1016/j.celrep.2019.10.047.发布于 2019-11-21 03:01自然科学H7N9 病毒禽流感​赞同 7​​2 条评论​分享​喜欢​收藏​申请

史卫峰教授在《科学》杂志发表高致病性H5N8禽流感病毒观点文章_腾讯新闻

史卫峰教授在《科学》杂志发表高致病性H5N8禽流感病毒观点文章_腾讯新闻

史卫峰教授在《科学》杂志发表高致病性H5N8禽流感病毒观点文章

5月21日，SCIENCE perspective板块刊登了来自山东第一医科大学史卫峰教授和疾控中心高福院士共同发表的文章，指出候鸟在长途迁徙过程中对H5N8大流行的促进作用，呼吁全球重视H5N8的流行潜力。

1959年在苏格兰记录了禽类中首次确认的高致病性禽流感病毒（HPAIV）爆发以来，尽管该病毒自1878年以来在全球范围内记录了许多疑似HPAIV爆发。H5N1及其遗传重配体或变异体（包括H5N2、H5N5、H5N6和H5N8在全球引起数千起疾病爆发，并造成大量养殖禽和野禽死亡。

众所周知，H5Ny HPAIV对大多数养殖家禽都具有致死性，目前有效的补救方法是采用扑杀来防止其进一步传播。一些H5Ny AIV具有人畜共患和大流行的潜力，且已证明它们可以越过物种屏障传播给包括人类在内的哺乳动物。最新消息报道，欧亚大陆和非洲正经历一波高致病性H5Ny AIV爆发。但其人畜共患病潜力需要进行连续、警惕的监测，以防止可能造成的灾难性疾病大流行。

在四种（A到D）流感病毒中，A型倾向于人畜共患病，而天然宿主被认为是水禽。根据两种病毒糖蛋白的抗原性将甲型流感病毒进一步分为不同的亚型：血凝素（HA，其中H1至H18有18个亚型）和神经氨酸酶（NA，其中N1至N11有11个亚型）；目前已确定了AIV中的大多数HA-NA组合。AIV主要通过两种主要机制进化：从点突变引起的遗传漂移和通过分段基因组的重新排列进行的遗传交换。两种机制都可以赋予AIV具有新的遗传特征，进一步会影响传播性、致病性、甚至是抗原性。在一个亚型中，通常可以根据HA基因序列的相似性将流感病毒进一步分为各种进化枝和亚进化枝。科学家们提出了一个统一的命名系统，以根据其HA基因序列的系统发育特征和序列同源性来描述H5Ny AIV的不断进化。

1996年，中国首次鉴定并描述的H5Ny HPAIV菌株称为A/Goose/Guangdong/1/1996（H5N1）。2010年，在中国江苏一个潮湿的市场上，在一只家鸭中分离出H5N8 AIV进化枝2.3.4。

2014年初，这种进化枝的H5N8禽流感在韩国以及日本引起了家禽和野禽的暴发。随后的常规监测研究表明，早在2013年11月，中国浙江省的家禽中就已经存在类似韩国的H5N8禽流感病毒。

2014年下半年，在俄罗斯和其他几个欧洲国家以及美国，也鉴定出了进化枝2.3.4 H5N8禽流感病毒。另外，在加拿大发现了H5N2病毒，其中包含与H5N8相关的基因片段。贝叶斯系统进化分析显示，H5Ny AIV从欧亚大陆传入北美是可能通过长途迁徙而发生的。流行病学调查显示，鸟类在2014年8月通过白令海峡。

2016年，中国，蒙古，俄罗斯，欧洲和印度重新出现了2.3.4.4 H5N8 AIV进化枝。因此，进化枝2.3.4 H5 AIV，特别是H5N8亚型，显然表明候鸟在迁徙过程中对疾病快速全球传播的推进作用。

据报道，大多数的H5Ny进化枝和亚进化枝会引起人类感染，尤其是2.3.4进化枝，涉及H5N1和H5N6亚型。迄今为止，已向世界卫生组织报告了总共862例实验室确认的人类感染H5N1病例，其中455例死亡。这些案件来自17个国家，约76％来自埃及和印度尼西亚。尽管有报告说可能通过密切接触引起病例，但仍未记录到H5N1或H5N6禽流感病毒在人与人之间的持续传播。但是，研究表明，H5N1变异体在HA基因和H1N1人类流感病毒（2009年引起全球大流行）的其他七个基因片段中具有一些特定突变，能够通过实验室动物传播呼吸道飞沫，表明H5Ny AIV具有大流行的潜力。

H5Ny AIV的不断进化及其与其他亚型AIV的潜在重排显然值得密切关注。根据2014年以来在中国进行的全国AIV监测，H5N6已取代H5N1，成为2014-2016年期间华南地区主要的循环AIV亚型（尤其是鸭类）。相反，H9N2是从中国北方采集的鸟类中的主要亚型，这也引起了许多人类感染。在中国某些地区的健康家禽工作者中，H9N2特异性抗体的血清阳性率超过10％。但是，与2014年至2016年之间收集的数据相比，大多数地区活禽市场（LPM）的AIV阳性率在2016-2019年期间显着下降（分别为26.90％和12.73％）。自2013年初出现以来，H7N9禽流感病毒已导致1568例实验室确认的人类病例，包括616人死亡。然而，H7N9的阳性率在2016年至2019年期间也大幅下降，尤其是H9N2已取代H5N6和H7N9成为中国鸡鸭的主要AIV亚型。此外，新的重配子和病毒变体继续出现，包括H7N3，H9N9，H9N6和H5N6亚型。几乎所有的H9 AIV以及许多H7N9和H6N2病毒株都编码优先结合人的唾液酸细胞受体的HA，这提示人类感染的可能性增加。这些结果突出了动态和复杂的AIV循环模式，这对于最佳选择候选疫苗和最大程度地提高禽类疫苗效力非常重要。

由于发生了COVID-19大流行，因此采取了预防和控制措施，包括出行限制，增加使用口罩以及增加了与社会的距离和消毒力度，这些措施已大大降低了全球人类季节性甲型和乙型流感病毒的发生率。尽管如此，自2019年底以来，高致病性H5Ny AIV导致欧亚大陆和非洲大陆多个国家的鸟类频繁爆发，特别是在冬季。

高致病性H5Ny AIV（包括H5N1，H5N2，H5N5和H5N8亚型）导致整个中国台北的家禽和野禽在2020年持续暴发。高致病性H5N8 AIV还导致2020年南非禽类持续死亡。

此外，从2020年1月到2020年6月上旬，H5N8引起了中欧和东欧的多次暴发。在2020年秋冬季，欧亚大陆出现了H5N8 AIV的突然复发，高于其他亚型。受影响地区于9月中旬扩展到哈萨克斯坦；

2020年10月，在一些欧洲国家（包括丹麦，德国，爱尔兰，荷兰和英国）报道了在禽类和野禽中爆发H5N8的新潮。同时，在中东（以色列）和东亚（日本和韩国），禽和/或野禽中爆发了H5N8。

迄今为止，在韩国和日本已经宰杀了超过2000万只家禽，系统进化分析表明，病原体属于进化枝2.3.4.4b，这是先前鉴定出的H5Ny AIV的次要进化枝。

受影响的地理区域一直在不断扩大，至少有46个国家报告了高致病性的H5N8 AIV暴发。此外，这些H5N8 AIV的HA蛋白还具有几个令人关注的氨基酸取代，包括Thr160Ala，据报道该蛋白可增强与唾液酸受体的结合能力。2020年12月，俄罗斯报道了第一例人类感染H5N8流感病毒的病例：七名家禽农场工人检测结果呈阳性。系统发育分析表明，从人类病例中测序出的H5N8病毒也属于H5系统发育进化枝2.3.4.4b。因此，禽流感病毒，特别是H5N8亚型的全球传播已成为家禽养殖和野生动植物安全的重要问题，也是至关重要的全球公共卫生。

总结：

由于野生鸟类的长距离迁移，AIV的先天重组能力，人类受体结合能力的增强以及HPAIV的恒定抗原变异，H5N8 AIV的全球传播和潜在风险势在对家禽养殖、野生动物和全球公共卫生造成严重威胁。因此，对家禽场、活禽市场和野禽中的HPAIV的监视应恢复到COVID-19大流行之前或更高的水平。

此外，需要对2.3.4.4b H5N8的传播性、致病性和抗原性进行进一步评估。如果存在明显的抗原变异，应对HPAIV进行疫苗更新。此外，减少以家庭为基础的小规模家禽养殖，增加大规模的高标准现代化家禽养殖以及加强对活禽市场的管理，将有助于减少HPAIV的传播和潜在的人类感染。教育和宣传也很重要，包括在流感季节期间加强个人保护措施，远离野鸟以及避免狩猎和食用野鸟等。

参考文献：https://science.sciencemag.org/content/372/6544/784

来源：山东第一医科大学科研部、医学权威

编辑：Jo

AIV是什么？ - 知乎

AIV是什么？ - 知乎首页知乎知学堂发现等你来答​切换模式登录/注册电影AIV是什么？关注者2被浏览2,374关注问题​写回答​邀请回答​好问题​添加评论​分享​1 个回答默认排序珠海领航电气有限公司一家致力于智能电网解决方案服务提供商的公司。​ 关注您好！您这个问题如果是单纯问这三个字母组合起来有什么含义的话，其实是有多种含义的。但是主要还是指禽流感的意思。禽流感（Avian Influenza Virus）禽流感病毒（AIV）属于甲型流感病毒。流感病毒属于RNA病毒的正黏病毒科，分甲、乙、丙3个型。其中甲型流感病毒多发于禽类，一些甲型也可感染猪、马、海豹和鲸等各种哺乳动物及人类；乙型和丙型流感病毒则分别见于海豹和猪的感染。禽类的病毒性流行性感冒，是由A型流感病毒引起禽类的一种从呼吸系统到严重全身败血症等多种症状的传染病。禽流感容易在鸟类间流行，过去在民间称为“鸡瘟”，国际兽疫局将其定为甲类传染病。禽流感1994年、1997年、1999年和2003年分别在澳大利亚、意大利、中国香港、荷兰等地暴发，2005年则主要在东南亚和欧洲暴发。这种病毒呈多形性，其中球形直径80～120nm，有囊膜。基因组为分节段单股负链RNA。依据其外膜血凝素（H）/和神经氨酸酶（N）蛋白抗原性的不同，可分为16个H亚型（H1～H16）和9个N亚型（N1～N9）。感染人的禽流感病毒亚型主要为H5N1、H9N2、H7N7，其中感染H5N1的患者病情重，病死率高。研究表明，原本为低致病性禽流感病毒株（H5N2、H7N7、H9N2），可经6～9个月禽间流行的迅速变异而成为高致病性毒株（H5N1）。禽流感一般发生在春冬季，一般不会在人与人之间传染。预防禽流感应注意以下几点：a．勤洗手，远离家禽的分泌物，接触过禽、鸟或禽、鸟粪便要注意用消毒液和清水彻底清洁双手，避免到疫区旅行；b．养成良好的个人卫生习惯，咳嗽时用手或卫生纸捂住嘴，加强室内空气流通，每天1～2次开窗换气半小时，要有充足的睡眠和休息，均衡的饮食，注意多摄入一些富含维生素C等增强免疫力的食物；c．吃禽肉要煮熟、煮透，食用鸡蛋时蛋壳先用流水清洗，烹调加热充分，不吃生的或半生的鸡蛋。禽流感病毒，可在水禽的消化道中繁殖。主要为患禽流感或携带禽流感病毒的家禽，另外野禽或猪也可成为传染源。许多家禽都可感染病毒发病：火鸡、鸡、鸽子、珍珠鸡、鹌鹑、鹦鹉等陆禽都可感染发病，但以火鸡和鸡最为易感，发病率和死亡率都很高；鸭和鹅等水禽也易感染，并可带毒或隐性感染，有时也会大量死亡。各种日龄的鸡和火鸡都可感染发病死亡，而对于水禽如雏鸭、雏鹅其死亡率较高。除野禽，如天鹅、燕鸥、野鸭、海岸鸟和海鸟等外，还从以下多种鸟中分离到流感病毒；燕八哥、石鸡、麻雀、乌鸦、寒鸦、鸽、岩鹧鸪、燕子、苍鹭、加拿大鹅及番鸭等。据国外报道，已发现带禽流感病毒的鸟类达88种，而鼠类不能自然感染流感病毒。不同品种的家禽感染禽流感的几率不同，但目前尚未发现高致病性禽流感的发生与禽的性别有关，高致病性禽流感病毒也可通过鸡蛋传播。高致病性禽流流在禽群之间的传播主要依靠水平传播，如空气、粪便、饲料和饮水等；而垂直传播的证据很少。但通过实验表明，实验感染鸡的蛋中含有流感病毒，因此不能完全排除垂直传播的可能性。所以，不能用污染鸡群的种蛋做孵化用。它可以随病禽的呼吸道、眼鼻分泌物、粪便排出，禽类通过消化道和呼吸道途径感染发病。被病禽粪便、分泌物污染的任何物体，如饲料、禽舍、笼具、饲养管理用具、饮水、空气、运输车辆、人、昆虫等都可能传播此病毒。发布于 2021-04-01 14:11​赞同​​添加评论​分享​收藏​喜欢收起​​

Dominant subtype switch in avian influenza viruses during 2016–2019 in China | Nature Communications

Dominant subtype switch in avian influenza viruses during 2016–2019 in China | Nature Communications

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Dominant subtype switch in avian influenza viruses during 2016–2019 in China

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Published: 20 November 2020

Dominant subtype switch in avian influenza viruses during 2016–2019 in China

Yuhai Bi 

ORCID: orcid.org/0000-0002-5595-363X1,2,3 na1, Juan Li 

ORCID: orcid.org/0000-0001-9628-48504 na1, Shanqin Li2 na1, Guanghua Fu5 na1, Tao Jin 

ORCID: orcid.org/0000-0002-9620-16886 na1, Cheng Zhang1,7, Yongchun Yang8, Zhenghai Ma7, Wenxia Tian 

ORCID: orcid.org/0000-0001-6018-51809, Jida Li10, Shuqi Xiao11, Liqiang Li6, Renfu Yin 

ORCID: orcid.org/0000-0001-7431-252312, Yi Zhang10, Lixin Wang13, Yantao Qin14, Zhongzi Yao15, Fanyu Meng4, Dongfang Hu16, Delong Li17, Gary Wong18,19, Fei Liu1, Na Lv1, Liang Wang1, Lifeng Fu 

ORCID: orcid.org/0000-0003-0431-54241, Yang Yang2, Yun Peng2, Jinmin Ma 

ORCID: orcid.org/0000-0002-7993-70016, Kirill Sharshov20, Alexander Shestopalov20, Marina Gulyaeva 

ORCID: orcid.org/0000-0003-3945-533920, George F. Gao 

ORCID: orcid.org/0000-0002-3869-615X1,2,3,21, Jianjun Chen 

ORCID: orcid.org/0000-0002-2966-238815, Yi Shi 

ORCID: orcid.org/0000-0002-3053-26871,2, William J. Liu 

ORCID: orcid.org/0000-0003-3605-407021, Dong Chu22, Yu Huang5, Yingxia Liu3, Lei Liu3, Wenjun Liu1,2, Quanjiao Chen15 & …Weifeng Shi 

ORCID: orcid.org/0000-0002-8717-29424,23 Show authors

Nature Communications

volume 11, Article number: 5909 (2020)

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EpidemiologyGenomeInfluenza virusPhylogenetics

AbstractWe have surveyed avian influenza virus (AIV) genomes from live poultry markets within China since 2014. Here we present a total of 16,091 samples that were collected from May 2016 to February 2019 in 23 provinces and municipalities in China. We identify 2048 AIV-positive samples and perform next generation sequencing. AIV-positive rates (12.73%) from samples had decreased substantially since 2016, compared to that during 2014–2016 (26.90%). Additionally, H9N2 has replaced H5N6 and H7N9 as the dominant AIV subtype in both chickens and ducks. Notably, novel reassortants and variants continually emerged and disseminated in avian populations, including H7N3, H9N9, H9N6 and H5N6 variants. Importantly, almost all of the H9 AIVs and many H7N9 and H6N2 strains prefer human-type receptors, posing an increased risk for human infections. In summary, our nation-wide surveillance highlights substantial changes in the circulation of AIVs since 2016, which greatly impacts the prevention and control of AIVs in China and worldwide.

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IntroductionAvian influenza viruses (AIVs) of various subtypes, e.g. H9N2 low pathogenic AIV (LPAIV) and H5Ny highly pathogenic AIV (HPAIV), have been circulating throughout China and elsewhere in the world1,2, causing huge economic losses. In particular, these AIVs were shown to be able to infect humans3,4,5. As of 24 June 2019, at least 861 human cases with H5N1 infections have been reported globally6. Although there were only 50 reported human cases since the first human infection with H9N2 AIVs in 19984,5, a seroprevalence rate of 11.20% against H9N2 AIVs among healthy occupational workers was observed in several provinces of China during 2014–16, which is substantially higher than those against H7N9, H5N1, H5N6, H6N1, and H6N6 AIVs7, implying that H9 AIV has a higher infectivity to humans than other AIVs and can cause transient human infections.Worryingly, a number of novel reassortant subtypes including H7N9, H6N1, H10N8, H5N6, and H7N4 were reported to infect humans5,8,9,10,11,12. In particular, evidence has shown that H9N2 contributed to the emergence and evolution of these novel human-infecting AIVs (e.g. H7N9, H10N8, and H5N6) and that poultry carrying H9N2 in live poultry markets (LPMs) may act as the genetic incubator for creating novel reassortant AIVs13,14,15,16. This highlights the importance of continuous surveillance of AIVs in LPMs.In our previous report, we have established the Center for Influenza Research and Early-warning, Chinese Academy of Sciences (CASCIRE) surveillance network and performed monitoring studies for AIVs during 2014–16 in LPMs in China13,17. We found that while H9N2 was the dominant subtype in northern China, H5N6 has replaced H5N1 as a dominant AIV subtype in southern China. Importantly, H5N6 seems to be more virulent than H5N1 in humans based on the clinical data and case fatality rates (CFRs) (H5N6: ~69.60% and H5N1: ~52.50%)18, even though only 23 human H5N6 cases have been reported thus far5. In addition, H9N2 was primarily isolated from chickens, while H5N6 was mainly isolated from ducks13. Almost simultaneously, H5N8 HPAIV spread globally and caused outbreaks in migratory birds in Asia, Europe, and North America1,5,19. Furthermore, H7N9 HPAIV emerged in 201620,21 with a higher CFR compared to H7N9 LPAIV in humans22. Remarkably, the number of human H7N9 cases reported in the 2016–17 influenza season alone approximately equalled all of the previously recorded cases during 2013–165,23.In the present study, we continued our previous work from 2014–16 and report the results of nation-wide AIV surveillance in China during 2016–19. Our results show that the AIV positive rate at LPMs substantially decreased compared with that during 2014–16. H9N2 has become the dominant subtype both in chickens and ducks across China. In contrast, H7N9 has almost disappeared in 2018. Furthermore, H7N3 reassortants, H5N6 HPAIV variants, as well as H9N9 and H9N6 LPAIV reassortants have emerged, warranting constant monitoring.ResultsAIV positive rates significantly decreased during 2016–19A total of 16,091 samples were collected from May 2016 to February 2019 from 37 cities in 23 provinces, municipalities and minority autonomous regions in China (Fig. 1a), in which 2048 samples were identified to be AIV positive by next generation sequencing (NGS), with a positive rate of 12.73% (Supplementary Data 1–5).Fig. 1: The distribution of sampling sites and avian influenza viruses (AIVs) in LPMs across China.a Map of the AIV sampling sites and isolation rates in LPMs. AIV surveillance sites in 37 cities (indicated by black dots) of 23 provinces or municipalities or minority autonomous regions in China are divided into seven different regions: North (Inner Mongolia, NM and Jilin, JL; orange), East-Central (Shanxi, SX; Ningxia, NX; Shandong, SD; Shaanxi, SaX and Henan, HeN; light green), South-Central (Anhui, AH; Hunan, HuN; Jiangxi, JX and Fujian, FJ; yellow), Yangtze River Delta (Jiangsu, JS and Zhejiang, ZJ; pink), South-West (Sichuan, SC; Chongqing, CQ; Yunnan, YN; and Guizhou, GZ; orange red), South (Guangxi, GX; Guangdong, GD and Hainan, HaN; dark green), and West (Xinjiang, XJ; Qinghai, QH; and Xizang, XZ; light purple). The red portion in each pie chart indicates the isolation rate of AIV in this region. The standard map was downloaded from Ministry of Natural Resources of the People’s Republic of China (http://bzdt.ch.mnr.gov.cn/), and the collection sites of LPMs in our study were marked on the map using ArcGIS. b AIV positive rates of the present study (2016–19) and the previous study in 2014–1613. The regions included North, East-Central, South-Central, Yangtze River Delta, South-West, and South. The numbers on the column represent the AIV isolation rate. c Subtype proportions of AIVs in the pure isolates with a single HxNy subtype. d The proportion of HA and NA from the impure isolates containing over two HA or NA subtypes. Source data are provided as a Source Data file.Full size imageTo better analyze the geographical distribution of AIVs in LPMs in China, 23 provinces were divided into seven different regions on the basis of geographic proximity: North (Inner Mongolia, NM; Jilin, JL), East-Central (Shanxi, SX; Ningxia, NX; Shandong, SD; Shaanxi, SaX; Henan, HeN), South-Central (Anhui, AH; Hunan, HuN; Jiangxi, JX; Fujian, FJ), Yangtze River Delta (Jiangsu, JS; Zhejiang, ZJ), South-West (Sichuan, SC; Chongqing, CQ; Yunnan, YN; Guizhou, GZ), South (Guangxi, GX; Guangdong, GD; Hainan, HaN), and West (Xinjiang, XJ; Qinghai, QH; Xizang, XZ). The AIV positive rates in the seven regions were 5.01%, 9.50%, 20.48%, 20.83%, 8.11%, 8.80%, and 4.84%, respectively (Fig. 1a, b). Remarkably, aside from the East-Central region, the AIV positive rates in the other five regions (the North, South-Central, Yangtze River Delta, South-West, and South) substantially decreased during 2016–19 compared to those during 2014–16, especially in the South (from 32.40% to 8.80%) and South-West (from 31.78% to 8.11%) regions (Fig. 1b).Further analysis revealed that the AIV isolation rate in ducks was the highest (17.88% [525 positive/2,936 samples]), followed by geese (14.52% [63/434]), chickens (12.47% [1,290/10,344]), environmental samples (9.29% [144/1,550]), and then pigeons (3.14% [26/827]) (Supplementary Data 1–5). The results demonstrated that the AIV isolation rates were higher in waterfowl (ducks and geese) than those of land poultry (chickens and pigeons).H9N2 AIV is dominant in LPMs in ChinaThe 2048 AIV-positive isolates were then sequenced using NGS. The isolates with single HxNy subtype (pure isolates) were found in 70.41% (1442/2048) of the 2048 samples, and the isolates with over two HA or NA subtypes (impure isolates) were found in the remaining 29.59% (606/2,048) of the samples (Supplementary Data 1–5). Among the 1442 pure viruses with the AIV subtype clearly determined, H9N2 was the dominant subtype (n = 1049, 72.75%), with the proportions ranging from 57.69% (West) to 95.95% (East-Central) in the seven defined regions (Fig. 1c and Supplementary Data 1–5). However, the proportion of subtype composition and the prevalent subtype in the seven regions were slightly different. The isolation rates of H5 subtypes were higher in the North (33.33%) and in the West regions (42.31%: 30.77% for H5N8 and 11.54% for H5N6) compared to those in other regions (Fig. 1c). However, only 6 and 26 pure isolates were identified in the North and West regions, respectively (Supplementary Data 1–5).H7N9 AIVs mainly circulated in the Yangtze River Delta with an isolation rate of 14.29% and in the South-Central region with 9.54%. H6N6 was prevalent primarily in three adjacent regions (South-Central, South, and South-West), with isolation rates between 6.20% and 9.32%. Overall, the top four subtypes circulating in LPMs in China included H9N2 (72.75%), H5N6 (7.84%), H7N9 (5.89%), and H6N6 (5.20%), respectively (Fig. 1c), and H9N2 has become dominant in LPMs in both Northern and Southern China.The proportion of each specific HA and NA gene in the impure AIV isolates based on the NGS results were also analyzed. The top five HA and four NA subtypes for the impure isolates were H9 (41.15%), H5 (25.10%), H6 (14.49%), H3 (8.66%), H7 (7.39%), and N2 (45.14%), N6 (39.35%), N8 (6.31%), and N9 (4.91%), respectively (Fig. 1d and Supplementary Fig. 1a, b). The H9 and N2 were the dominant HA and NA subtypes, respectively. Meanwhile, the proportions of H9 and H5 subtypes in the 71 impure isolates were 42.25% and 7.04% in the North region, respectively, and 43.48% and 41.30% in the 92 impure samples in the West region (Supplementary Data 1–5). It should be noted that a few rare HA and NA subtypes such as H1, H3, H4, H10, H11, N1, N3, and N4 were observed in the impure samples, and a number of rare subtypes, such as H7N2/N3/N6/N7, H6N2/N8, and H9N6/N9, were also identified from the pure isolates (Fig. 1c and Supplementary Fig. 1c).Therefore, there was a similar trend in the proportion of each HA and NA subtype between the pure and impure isolates, and the dominant HA and NA subtypes were the same in both groups. The top five HA subtypes in the pure isolates were H9 (74.41%), H5 (8.67%), H7 (8.25%), H6 (5.76%), and other (2.91%), whereas those in the impure isolates included H9 (41.15%), H5 (25.10%), H6 (14.49%), H7 (7.39%), and other (11.87%). The top five NA subtypes in the pure isolates were N2 (73.86%), N6 (13.73%), N9 (7.28%), N8 (1.87%), and other (3.26%), while those in the impure isolates were N2 (45.14%), N6 (39.35%), N8 (6.31%), N9 (4.91%), and other (4.29%) (Fig. 1d and Supplementary Data 1–5).To explore the distribution of virus subtypes in LPMs over the last few years, the subtype composition based on the NGS results between 2016 and 2019 was analyzed (Fig. 2a and Supplementary Fig. 1a–c). From 2016 to 2018, the proportion of H9N2 AIVs in the pure isolates steadily increased (54.05% in 2016, 65.63% in 2017, and 84.88% in 2018; Supplementary Fig. 1c). All 35 pure isolates from four provinces (Anhui, Henan, Shandong, and Shanxi) belonged to H9N2 during January and February of 2019 (Fig. 2a and Supplementary Data 1–5), and the H9 subtype was also found in 51.11% of the impure isolates. However, the proportion of pure H5Ny, H6Ny, and H7Ny AIVs decreased from 2016 to 2018 (Fig. 2a). Notably, the proportion of H7N9 isolates reached the peak in 2017 (11.72%), but almost disappeared in 2018 (Supplementary Fig. 1c), with just one H7N9 impure isolate identified containing H7 (151,233 reads), N9 (62,015 reads), and H9 (485 reads) gene sequences. Alternatively, H7N3 AIVs were identified in 2018 with a proportion of 5.33% (Fig. 2a and Supplementary Fig. 1c).Fig. 2: Virus subtype proportions and host species distributions of the pure isolates with a single HxNy subtype.a The proportion of various HA subtypes of pure isolates with a single HxNy subtype isolated between 2016 and 2019. The major prevalent subtypes include H5, H6, H7, and H9. H5 viruses include H5N6 and H5N8; H6 viruses include H6N2, H6N6, and H6N8; H7 viruses include H7N2, H7N3, H7N6, H7N7, and H7N9; H9 viruses include H9N2, H9N6, and H9N9. b Host species distributions of H5N6, H6N6, H7N3, H7N9, H9N2, and other subtypes. Source data are provided as a Source Data file.Full size imageOur previous study has shown that different host species carried distinct major AIV subtypes13. As shown in Supplementary Fig. 2a, both H9N2 and H7N9 AIVs were mainly isolated from chickens (83.61% vs. 72.95%), and both H6N6 and H5N6 AIVs were mostly isolated from ducks (83.99% vs. 57.51%). Additionally, most of the rare subtypes were primarily isolated from ducks (65.84%). In contrast to our previous report that H9N2 and H5N6 were dominant in chickens and ducks, respectively, H9N2 was the prevalent subtype in both chickens (89.95%) and ducks (35.71%; Fig. 2b and Supplementary Fig. 2b). It should also be noted that for the three subtypes (H9N2, H7N9, and H5N6), more strains were isolated from the oropharyngeal swabs of chickens or ducks (50.05%, 17.65%, and 23.89%) than those from cloacal samples (16.97%, 4.71%, and 15.04%). Regarding the H6N6 subtype, strains isolated from cloacal samples (41.33%) were more than those from oropharyngeal swabs of ducks (25.33%; Supplementary Fig. 2a).Genetic evolution of H9N2 AIVsSince H9N2 AIVs have now become dominant in China, we performed a phylogenetic analysis of 7521 HA genes of H9N2 AIVs from China, including 1477 sequences described in the present study (Fig. 3a). The HA phylogenetic tree revealed that Chinese H9N2 AIVs diverged approximately during 2012–13, resulting in three Clades (C1–C3) with between-group distance of ≥1% (Supplementary Data 6). C1 continued to diverge into several highly similar small sub-clades C1.1–C1.5 (with between-group distance of ≥0.3%, Supplementary Data 6), and most have been co-circulating during our surveillance period. In contrast, C2 and C3 viruses circulated at very low levels, with few viruses isolated from 2012 to 2016. However, the prevalence of C2 and C3 remarkably increased during 2017 and 2018. In detail, 2498 H9 strains isolated since 2017 belonged to C1, 783 viruses belonged to C2, and 211 belonged to C3. Regarding our H9 isolates since 2017 (n = 1350), 937 strains fell within C1, 393 in C2, and 20 in C3.Fig. 3: Phylogenetic analysis of the HA gene of H9Ny AIVs and the NA gene of H9N2 AIVs.a Phylogenetic tree of the HA gene of H9Ny AIVs. b Phylogenetic tree of the NA gene of H9N2 viruses. Viruses are marked with different colors according to the collection dates (before 2017: blue violet, in 2017: orange, in 2018: light green, and in 2019: light blue). Both trees are rooted using CK/BJ/1/1994(H9N2). The light blue and red triangles represent H9N6 and H9N9 viruses, respectively. All blue dots in the phylogenetic trees (a) represent H9N2 and H9N9 strains used for the receptor-binding test in this study. The labels with gray lines indicate all of the H9 isolates sequenced in this study.Full size imageAlthough the majority of the H9 isolates belonged to the H9N2 subtype, several H9N9 and H9N6 viruses were also found to be co-circulating, scattering amongst the tree with H9N2 AIVs, without forming separate clusters (Fig. 3a). Similarly, in the NA phylogenetic tree of the H9N2 AIVs, there were two major Clades (C1 and C2, with between-group distance of ≥1.5%, Supplementary Data 6), and they also diverged during 2012–13 (Fig. 3b). The majority of our isolates since 2017 (n = 1151) belonged to C1 and 161 isolates belonged to C2. Therefore, multiple clusters of H9N2 AIVs have been co-circulating in China after 2012–13.Several amino acids (Q226L, I155T, and H183N) affecting the receptor-binding preference of H9Ny AIVs were analyzed. The majority of the H9 strains possessed 226L (99.93% [1,438/1,439]), 155T (99.58% [1,433/1,439]), and 183N (99.93%, [1,438/1,439]; Supplementary Data 7 and 8), suggesting that they may have acquired human receptor (α2-6-SA) binding capacity. In total, 99.43% (1395/1403) of the sequenced H9N2 strains had NA stalk deletions (positions 62–64), and no NA inhibitor (NAI)-resistant mutations were found in the NA proteins of H9Ny (Supplementary Data 7).Continued evolution and emergence of H5, H7, and H6 variantsThe H5 subtype was detected in 384 of the isolates sequenced from 2016 to 2019. H5N6 subtype AIVs (n = 344) accounted for the majority (89.58%), followed by H5N8 (n = 18, 4.69%) and H5N2 (n = 16, 4.17%). All of the H5N6, H5N8, and H5N2 AIVs fell within Clade 2.3.4.4 (Fig. 4a), which could be classified into four sub-clades, with between-group distance of ≥3% (Supplementary Data 6). Clades 2.3.4.4a and 2.3.4.4d corresponded to the minor and major lineages designated in our previous report13. Clades 2.3.4.4b and 2.3.4.4c were already found to exist in our previous research, but were not designated then. In total, 344 strains, including 332 H5N6 and 12 H5N2 AIVs, fell within Clade 2.3.4.4d (the previously designated major lineage), whereas 28 strains (H5N2, n = 4; H5N6, n = 10; H5N8, n = 14) clustered in 2.3.4.4b and 6 strains (H5N6, n = 2; H5N8, n = 4) clustered in 2.3.4.4c. Notably, none of our strains belonged to Clade 2.3.4.4a (the previously designated minor lineage). Although 344 strains were classified into 2.3.4.4d, most (n = 324) formed a separate sub-clade within 2.3.4.4d with a distance of 1.2%. In addition, >80% strains in this unique sub-clade possessed distinct amino acid substitutions in the HA antigenic regions according to the H3 structure24,25,26. It should be noted that only six strains from 2018 belonged to the H5N1 subtype, and all of them fell within Clade 2.3.2.1c (Fig. 4a).Fig. 4: Phylogenetic analysis of the HA gene sequences of H5 and H7 AIVs.a Phylogenetic tree of the HA gene of H5 AIVs. The orange, light blue, red, and light green lines in the tree represent viruses described in this study isolated from 2016, 2017, 2018, and 2019, respectively. The dark blue lines represent the reference strains previously reported by Bi et al.13. The subtrees marked with a pink and light blue background represent the major lineage (Clade 2.3.4.4d) and the minor lineage (Clade 2.3.4.4a), respectively. The purple lines represent other reference strains from the Influenza Virus Resource at NCBI and the GISAID databases. b Phylogenetic tree of the HA gene of H7 AIVs. The subtrees marked with a pink and light blue background represent H7 strains belonging to the Yangtze River Delta lineage and Pearl River Delta lineage, respectively. The subtree of the H7N9 HPAIVs previously analyzed by Quan et al.23 is marked with the blue background on the upper right. The orange, light blue, and red lines of the tree represent strains isolated from 2016, 2017, and 2018, respectively. The subtree displayed in the dashed frame on the upper right included the HA genes of 33 H7N3 isolates in this study. The dotted lines represent H7N2 (n = 3), H7N6 (n = 3), and H7N8 (n = 1) viruses identified in this study. c The topology of the HA tree of H7 AIVs was shown at the bottom-right, with dots represent 160 H7 AIV strains identified in our surveillance during 2016–19. All blue dots in the phylogenetic trees (a, b) represent the H5 and H7 strains used for receptor-binding test in this study. In addition, the red pentagrams represent the H5/H7 bivalent vaccine strains, A/chicken/Guizhou/4/2013(H5N1) and A/pigeon/Shanghai/S1069/2013(H7N9), respectively.Full size imageOur surveillance identified a total of 160 H7 AIV strains during 2016–19. To our surprise, they belonged to at least six different subtypes: H7N9 (n = 119), H7N3 (n = 33), H7N2 (n = 3), H7N6 (n = 3), H7N8 (n = 1), and H7N7 (n = 1; Fig. 4b, c). Phylogenetic analysis of the HA gene showed that apart from one H7N7 strain Dk/JX/1-07 NCDZT35N-C/2016, all of the remaining H7 strains (n = 159) clustered together with the human-infecting H7N9 AIVs (Fig. 4c) within the Yangtze River Delta lineage. Apart from H7N3, other H7 subtypes, e.g. H7N2, H7N6, and H7N8 AIVs scattered in the Yangtze River Delta lineage with LPAIV H7N9 contemporarily circulating in LPMs in different regions of China (Fig. 4b).Of note, 31 of 33 H7N3 strains isolated from ducks and two strains from chickens from Fujian in 2018 formed an independent cluster within the H7N9 HPAIV lineage (Fig. 4b). The NA gene sequences of the H7N3 AIVs showed that they were closely related to AIVs of the N3 subtype circulating in ducks in southern China during 2017–18 (Supplementary Data 9). We have performed a complete phylogenetic analysis of the eight gene segments of 615 H7N3 AIVs (584 strains from public databases). Our analyses revealed that the H7N3 AIVs had diverged into the North American lineage and the Eurasian lineage. These strains could be further classified into 26 genotypes (Supplementary Fig. 3 and Supplementary Data 10), with 14 belonging to the North American lineage and 12 belonging to the Eurasian lineage (Supplementary Fig. 3 and Supplementary Data 9 and 10). Our 31 H7N3 AIVs with whole genome (two isolates only had HA sequences) described here belonged to G11 (n = 30) and G12 (n = 1), respectively. They were different from a reassortant H7N3 strain identified from Japan, A/duck/Japan/AQ-HE30-1/2018(H7N3)27 (G10), in the PB2 gene. Dk/FJ/1.25 FZHX0009-C/2018(H7N3) (G12) differed from the remaining 30 H7N3 strains (G11) in the MP and NS genes. Therefore, all of these H7N3 strains were not closely related to H7 AIVs from other countries, such as Mexico and the USA, and were novel reassortants.All of the H5 viruses (n = 384) described in the present study possessed multiple basic amino acid residues at the cleavage site, whereas the H7N9 and H6Ny LPAIVs had less basic amino acids (PKGRGL or PQIETRGL). All of the H7N3 viruses (n = 33) also possessed multi-basic cleavage sites (PKRRRTARGL). Regarding the receptor-binding associated sites, 100% (401/401) of the H5 viruses had 226Q (H3 numbering). In all, 73.89% (116/157) of the H7 AIVs had 226L, and 99.36% (156/157) had 186V. All of the 33 H7N3 isolates possessed 186V and 226Q. Almost all 169 H6 strains possessed 190E, 226Q, and 228G (Supplementary Data 7).Receptor-binding properties of the major AIVsIn order to identify and provide early-warning of the potential public risks of the AIVs, a total of 43 representative strains including H9N9 (n = 7), H9N2 (n = 3), H5N6 (n = 8), H7N9 (n = 7), H7N3 (n = 9), H6N6 (n = 5), and H6N2 (n = 4) were selected for receptor-binding test using trisaccharide receptors.All tested H9 isolates possessed residue 226L (Supplementary Data 7). As expected, six H9N9 and two H9N2 testing strains (Ck/JX/08.24 NCDZT12X2-OC/2017(H9N9), Ck/JX/4.30 NCDZT44N2-OC/2017(H9N9), Ck/JX/4.30 NCDZT59N2-OC/2017(H9N9), Ck/JX/08.24 NCDZT49X2-OC/2017(H9N9), Ck/JX/6.26 NCDZT51R2-OC/2017(H9N9), Ck/JX/4.30 NCDZT36N2-OC/2017(H9N9), Ck/JX/8.26 NCDZTY76-O/2016(H9N2), and Ck/HuN/7.21 YYGKy9-O/2016(H9N2)) exclusively bound to human-type receptors (α2-6-SA). Only one H9N9 strain (Ck/JX/4.30 NCNP8N2-OC/2017(H9N9)) and one H9N2 (Ck/GD/4.18 SZBJ011-O/2018(H9N2)) presented a dual receptor-binding ability, with preference for human-type receptors (Fig. 5, Supplementary Fig. 4a, and Supplementary Data 8).Fig. 5: Receptor-binding properties of representative AIV isolates.a A/Anhui/1/2013(H7N9) was used as a reference for comparison with the tested H7 strains. Two human strains, A/California/04/2009(H1N1) and A/Vietnam/1194/2004(H5N1), were used as controls. b Receptor-binding properties of the representative AIV strains to human (α2-6-SA) and avian (α2-3-SA) receptors were tested using the solid-phase direct binding assay with trisaccharide receptors. Red and blue lines represent human- and avian-type receptors, respectively. Two replications presented similar results and the mean values were shown. Source data are provided as a Source Data file.Full size imageAll tested H5N6 strains possessed 226Q and a loss of glycosylation site at the positions 158–160 (Supplementary Data 7), which mainly bound to avian-type receptors. As expected, the four tested strains (Dk/HuN/12.27 YYGK89J2-O/2016(H5N6), Gs/XJ/11.29 WLMQXL001-O/2017(H5N6), Gs/FJ/10.26 FZHX0002-C/2017(H5N6) (mixed Q (57.82%) and R (41.76%) at position 227), and Ck/SD/2.28 TAWM016-C/2017(H5N6)) displayed weak affinities to human-type receptors (Fig. 5, Supplementary Fig. 4a, and Supplementary Data 8).All seven H7N9 strains were found to possess the ability to bind both avian and human-type receptors. It was notable that four strains (Ev/JX/2.05 SRXZBJT038-E/2017(H7N9) (186V and 226L; mixed R (49.59%) and K (49.27%) at position 173), Ev/JL/04.11 CCHSL037-E/2018(H7N9) (186V and 226I), Ev/JX/2.16 SRGFYK089-E/2017(H7N9) (186V and 226L), and Ev/JX/1.11 NCDZT98F2-E/2017(H7N9) (186V, 226L, 122T, and 236I)) preferred binding to human-type receptors compared to the precursor A/Anhui/2013(H7N9) and other tested strains with 186V and 226L (Fig. 5, Supplementary Fig. 4a, and Supplementary Data 8), suggesting that the transmissibility from avian to humans may have increased for these H7N9 isolates. For the H7N3 reassortants with HA gene from H7N9 HPAIV, six of the nine strains (Dk/FJ/1.25 FZHX0049-O/2018(H7N3), Dk/FJ/1.25 FZHX0017-O/2018(H7N3), Dk/FJ/1.25 FZHX0011-O/2018(H7N3), Dk/FJ/1.25 FZHX0045-C/2018(H7N3), Dk/FJ/1.25 FZHX0014-C/2018(H7N3), and Dk/FJ/1.25 FZHX0046-O/2018(H7N3)) bound to both avian and human-type receptors and the affinities to avian-type receptors were slightly stronger than those to human-type receptors, whereas three strains (Dk/FJ/1.25 FZHX0005-O/2018(H7N3), Dk/FJ/1.25 FZHX0013-O/2018(H7N3), and Dk/FJ/1.25 FZHX0013-C/2018(H7N3)) only bound to avian-type receptors (Fig. 5, Supplementary Fig. 4, and Supplementary Data 8).For the H6 subtype, the tested strains also displayed diverse receptor-binding abilities. Three H6N6 strains with 190E and 228G (Dk/HuN/2.06 YYGK86J3-OC/2018(H6N6), Dk/JX/5.28 NCNP34N3-OC/2018(H6N6), and Dk/HuN/5.29 YYGK100P3-OC/2018(H6N6)) only bound to avian-type receptors. However, another two H6N6 strains also with 190E and 228G (Ck/HuN/1.12 YYGK22H3-OC/2018(H6N6) and Dk/HuN/11.30 YYGK54E3-OC/2018(H6N6)) possessed both avian- and human-type receptor-binding abilities and preferred avian-type receptors (Fig. 5, Supplementary Fig. 4, and Supplementary Data 8). In contrast to H6N6, all four H6N2 representative strains possessed double receptor-binding abilities. Gs/GD/10.21 SZBJ001-O/2016(H6N2) (190V and 228G) and Gs/GD/10.21 SZBJ001-C/2016(H6N2) (190V and 228G) possessed higher affinities to avian-type receptors, while Gs/GD/10.21 SZBJ004-O/2016(H6N2) (190A, 222I, and 228G) and Gs/GD/10.21 SZBJ003-O/2016(H6N2) (190V and 228S) displayed a preference for human-type receptors (Fig. 5, Supplementary Fig. 4, and Supplementary Data 8).The predominance of human-type receptor-binding preference of the tested H7N9, H9N2, and H9N9 strains was further confirmed using pentasaccharide receptors (Supplementary Fig. 4b). The receptor-binding affinities to both trisaccharide and pentasaccharide receptors were also similar for the tested strains of other subtypes, although Dk/FJ/1.25 FZHX0005-O/2018(H7N3) and Dk/HuN/2.06 YYGK86J3-OC/2018(H6N6) displayed slight binding avidities to human-type pentasaccharide receptors, compared with single affinities to avian-type trisaccharide receptors (Fig. 5, Supplementary Fig. 4, and Supplementary Data 8). These data indicated that many H5, H6, H7, and H9 AIVs have acquired a capability for binding to human-type receptors.DiscussionCompared to our previous study13, the AIV positive rates substantially decreased from 2016 to 2019. Several factors may have accounted for this decline. Due to LPMs as a transmission source and even potential incubator for human infections with AIV28,29, more and more provinces have started to close LPMs30,31,32 or take special measures at the human-animal interface to lower the risks of human infection. For example, the “1110” strategy for markets (cleaning every day, disinfecting every week, shutting down once per month, and butchering all unsold live birds before closing every day) was first proposed and implemented in Guangdong Province, China in 2014 (http://www.chinanews.com/fz/2014/12-06/6851778.shtml). Similar strategies have since been implemented in other Chinese provinces. In 2018, the Ministry of Agriculture of China required all Chinese provinces to implement the “1110” strategy (http://www.moa.gov.cn/nybgb/2018/201803/201805/t20180528_6143196.htm). In addition, the H5/H7 bivalent vaccine may have also contributed to the decreased AIV positive rates33. However, after using the H9 and H5 vaccines for ~2134 and 1535 years, respectively, these viruses are still circulating and evolving in China. Although the factors contributing to the decreased AIV positive rates in China need to be further investigated, the “1110” strategy may be effective, and lower AIV positive rates in LPMs would be expected as a result.Since 2016, the dominant AIV subtypes have substantially changed. During 2014–16, H9N2 and H5N6 were the dominant subtypes in Northern and Southern China, respectively13. However, the proportion of H9N2 AIVs gradually increased and has now become the most prevalent subtype in both Northern and Southern China. Coupled with the nation-wide and disordered transportation of poultry carrying H9N2, the emergence of H9N9 and H9N6 reassortants, and the dynamic reassortments among H9 and different AIV subtypes14,16, the circulation of H9 LPAIVs has become highly complicated in China. Remarkably, despite the widespread circulation of H7N9 AIVs during 2016–1723, it almost disappeared in 2018. The shift of the AIV subtypes in the poultry was not likely associated with intraspecies transmission between chicken and ducks, but may be caused by changes in the management of LPMs, the vaccination strategy, and different sensitivities of various viruses to the disinfectants used in the “1110” strategy. However, these results highlight the distinct change of the dominant AIV subtypes in China and will have a profound influence on prevention strategies against AIVs, including vaccine development and usage.Moreover, the emergence of a number of variants was notable, especially the H7N3 variant with an HA gene of the H7N9 HPAIV origin and the H5N6 variant. The antigenicity of these mutants, the effectiveness of the current H5/H7 bivalent vaccine against these variants, as well as the reason for H7N9 being replaced by H7N3, warrant further investigation. In addition, AIV isolation rates in the Yangtze River Delta and the South-Central regions only slightly decreased and were still higher than 20.00%. The co-infection or “impure” AIVs may also lead to antigenic or subtype shift. Including the present study, the existence of impure isolates with different subtypes has also been reported in many studies36,37. All the results highlight the necessity of constant surveillance of AIVs in LPMs.It is known that five out of the 12 AIV subtypes that have been detected in cases of human infections are H7 subtypes, including H7N2, H7N3, H7N4, H7N7, and H7N93,10,38,39,40. In this study, we revealed that five H7 (H7N2, H7N3, H7N6, H7N7, and H7N9) subtypes were co-detected in LPMs, in which most were isolated from ducks (except for H7N9), suggesting that ducks may also act as a “mixing vessel” for the H7 AIV reassortants. In fact, most of the other rare subtypes with diverse genetic constellations were also found in ducks. This may be partly due to the more contacts between domestic duck and wild waterfowl, which was considered as the natural reservoir of AIVs. H9N2 has also become the major subtype in ducks. Therefore, the probability of emergence of novel AIVs by reassortment among the diverse genetic constellations may likely be higher in ducks, not only because of the high diversity of AIV genetic constellation in ducks but also the excellent genetic compatibilities among H9N2 and other influenza subtypes including H7N9, pandemic H1N1, H5N1, H5N6, and so on13,16,41,42,43. Therefore, several AIV subtypes potentially infecting humans were circulating in LPMs and intensive surveillance of AIVs particularly among ducks should be performed continuously.Receptor binding was considered as the first step of influenza infection to host cells44,45,46,47. Almost all H9Ny isolates possessed 226L on HA, and all the tested H9N2 and H9N9 strains mainly bound to human-type receptors. 96.58% (113 out of 117) of the H7N9 isolates possessed both 186V and 226L, which were considered as the critical sites for human-type receptor binding of H7N9 AIVs46,48,49, and all the tested H7N9 strains presented affinities to both avian- and human-type receptors. Notably, several representative H7N9 strains during 2017–18 preferred human-type receptors, and the binding avidities were much stronger than a previous H7N9 strain (A/Shenzhen/Th001/2016), which also preferred to bind human-type receptors50. Six of the nine tested H7N3 HPAIVs displayed dual receptor-binding abilities though preference to avian-type receptors. This phenomenon was also seen in the H7N9 HPAIVs48,50,51, indicating potentially similar infectivity of H7N3 and H7N9 HPAIVs to the hosts.All the sequenced H5N6 strains had 226Q, while some tested strains presented slight preference for human-type receptor, which could be partly explained by the loss of a glycosylation site at the positions 158–16052,53,54. E190V and G228S mutations on HA contributed to the human-type receptor-binding abilities for H6 viruses55,56. Although almost H6 strains possessed 190E and 228G, several H6N2 strains were found to have E190V and/or G228S mutations, which could explain the dual receptor-binding ability. However, H6N6 strains with 190E and 228G were also found to bind to both receptors. Taken together, our receptor-binding tests highlight that only few AIV strains showed pure binding abilities to avian-type receptors, whereas the majority presented human-type receptor-binding capacity, particularly the dominant H9 AIVs. Therefore, despite lower positive rate in LPMs, AIVs showed increased abilities and risk to infect humans, which deserves closer attention.In summary, our latest nation-wide AIV surveillance data revealed a decrease of AIV positive rate and H9N2 has become the prevalent subtype throughout China. Most AIVs have obtained human-type receptor-binding abilities, including H5, H6, H7, and H9 subtypes, in which the H7N9 and H6N2 variants and almost all H9Ny strains preferred binding to human-type receptors. Furthermore, mutations associated with antigenic variation have been found in the H7N9, H7N3, and H5N6 variants. In fact, sporadic human cases caused by H7N9, H5N6, and H9N2 continue to be reported5,57, and the seroprevalence rate of H9N2 AIVs in the poultry workers posed an increasing trend after 2009 in China7,58. Therefore, constant monitoring on AIVs should be more closely conducted for agricultural and public health.MethodsEggsEmbryonated chicken eggs obtained from Beijing Vital River Laboratory Animal Technology Company were incubated at 37 °C and 80% humidity for 10 days before being used for virus isolation.Sample collection and virus isolationOropharyngeal and cloacal swabs from apparently healthy poultry, as well as environmental samples, were collected in LPMs in 37 cities and counties across 23 provinces or municipalities or minority municipalities in China. Poultry included chickens, ducks, geese, and pigeons. Environmental samples included swabs from cages, poultry drinking water, defeathering machines, chopping boards, and feces in the LPMs. Sampling was collected from May 2016 to February 2019 (samples collected once a month, unless the LPM was closed, and there were no samples collected in the corresponding month), a period of 26 months spanning three flu seasons. Compared to our previous study, the same or nearby LPMs in Inner Mongolia, Jilin, Henan, Shandong, Jiangsu, Zhejiang, Hunan, Jiangxi, Anhui, Fujian, Guangdong, Guangxi, Sichuan, and Yunnan were chosen for sampling13. Furthermore, sampling was also performed in several additional provincial level administrative regions, including Xinjiang, Xizang, Qinghai, Guizhou, Hainan, Shaanxi, Shanxi, Ningxia, and Chongqing. The swabs were placed into viral transport media and transported to the laboratory within 24 h in a handheld portable 4 °C refrigerator, and frozen at −80 °C immediately for future use. Avian influenza viruses were isolated in 10-day-old specific pathogen-free (SPF) chicken embryos according to the WHO manual59. After culture, all the hemagglutinin-positive and -negative allantoic fluids were further tested by RT-PCR using universal primers13 targeting the PB1 and/or M gene as listed in Supplementary Data 11.Whole-genome sequencing of AIV isolatesViral RNA was extracted directly from AIV-positive allantoic fluid with MagaBio plus Virus RNA Purification Kit (BIOER, China). The whole-genome of AIV isolates were sequenced using Next generation sequencing (NGS)13. Briefly, RT-PCR and DNA synthesis were performed using the PrimeScript One Step RT-PCR kit (Takara). Next, the sequencing libraries were prepared. The libraries were sequenced on the BGI500 and Illumina HiSeq 4000. Sequencers by 200 bp or 250 bp paired-end sequencing, and sequencing depth for AIV isolates was about 0.2G per sample. The accuracy of the NGS method was confirmed by the published qRT-PCR method60 and qRT-PCR kits (Mabsky Biotech Co., Ltd.) with reference samples.Sequencing data assemblyRaw NGS reads were processed by filtering out low-quality reads (eight bases with quality <66), adapter-contaminated reads (with >15 bp matched to the adapter sequence), poly-Ns (with 8Ns), duplication and host contaminated reads (SOAP2 version 2.21; less than five mismatches)13,61. The filtered reads were mapped to the INFLUENZA database (downloaded on 1 June 2018)62 to choose best-matching reference sequences. Burrows-Wheeler Aligner (BWA version 0.7.12)63 and SAMtools (version 1.4)64 were then used to perform reference-based assembly.Based on the NGS data, each cultured sample with ≥2 HA or NA subtypes was defined as “impure isolate”, while those with single HA and NA subtype were defined as “pure isolate”. The AIV positive samples are the cultured samples including both pure and impure isolates. The AIV positive rate was then calculated by “the numbers of AIV positive (cultured) samples” divided by “the total numbers of cultured samples”. The percentage of the impure or pure isolate was calculated as “the numbers of impure or pure isolates” divided by “the total number of AIV positive samples”.Phylogenetic analysesComplete genomes of the AIVs isolated in China were downloaded from the Influenza Virus Resource at the National Center for Biotechnology Information (https://www.ncbi.nlm.nih.gov/genomes/FLU/Database/nph-select.cgi)62 and the GISAID (https://www.gisaid.org/)65 database on 2019. Repetitive sequences in the two databases were removed by matching strain names using Bioedit (version 7.1.3.0)66. Only full-length genomes were kept and sequence with obvious errors (e.g. frameshifts or total number of ambiguous bases >100) were excluded manually. The remaining sequences were combined with those generated in the present study, and the sequences of H9Ny, H5Ny, H7Ny, and H6Ny isolates were phylogenetically analyzed.Multiple sequence alignment was performed using Muscle (version 3.8.31)67 and then adjusted manually in Bioedit (version 7.1.3.0)66. Phylogenetic analysis of the aligned HA and NA datasets were performed using RAxML (version 8.1.6)68, with GTRGAMMA applied as the nucleotide substitution model with 100 bootstrap replicates. Trees were visualized using FigTree (version 1.4.3).The H5 clades in the phylogenetic trees were defined according to the nomenclature system proposed by FAO/WHO/OIE (https://www.who.int/influenza/gisrs_laboratory/h5_nomenclature_clade2344/en/) and previous publications13,69. The classification of Yangtze River Delta and Pearl River Delta lineages in HA genes of the human-infecting H7N9 AIVs are defined based on previous publications23,70,71. The HA and NA clades of H9N2 were defined based on pairwise distance between taxa calculated with default parameters in MEGA (version 5.2)72. A HA or NA clade was defined when the between-group distance was ≥1%.Receptor-binding assayThe pure isolates in different HA clades, within three passages and presenting ≥64 HA titers, were selected as the representative strains for receptor-binding testing using the solid-phase direct binding assay73. Briefly, 96-well microtiter plates were coated with biotinylated glycans α2-3-SA receptors (trisaccharide: Neu5Acα2-3Galβ1-4GlcNAcβ-SpNH-LC-LC-Biotin and pentasaccharide: NeuAcα2-3Galβ1-4GlcNAcβ1-3Galβ1-4GlcNAcβ1-SpNH-LC-LC-Biotin) and α2-6-SA receptors (trisaccharide: Neu5Acα2-6Galβ1-4GlcNAcβ-SpNH-LC-LC-Biotin and pentasaccharide: NeuAcα2-6Galβ1-4GlcNAcβ1-3Galβ1-4GlcNAcβ1-SpNH-LC-LC-Biotin). Virus dilutions containing 64 HA units with the NAIs (10 μM each of Oseltamivir and Zanamivir) were incubated. Virus-receptor-binding was detected with rabbit antisera against the influenza viruses (H1, H5, H6, H7, or H9, CASCIRE)74 and HRP-linked goat-anti-rabbit antibody (Bioeasytech). HRP-linked goat-anti-rabbit antibody was diluted 2000 times in phosphate buffer saline (PBS) with 1% bovine serum albumin (BSA). The results were measured by tetramethylbenzidine (TMB) at 450 nm. A/Anhui/1/2013(H7N9) was used as a reference for comparison with the tested H7 strains. Two human strains, A/California/04/2009(H1N1) and A/Vietnam/1194/2004(H5N1) were used as control.Biosafety statement and facilityRoutine surveillance samples were processed in the biosafety level 2 (BSL-2) labs of CASCIRE. Coveralls, gloves, and N95 masks were used during the working in BSL-2 labs, and all wastes were autoclaved. The experiments with live H7N9, H7N3, and H5N6 viruses were conducted in biosafety level 3 (BSL-3) labs of CASCIRE or CASCIRE Network Surveillance Unit (NSU). This study was approved by the Ethics Committee of Institute of Microbiology, Chinese Academy of Sciences (SQIMCAS2016016).Measures against cross-contaminationFirst, during the sample collection process, all the tubes with samples were placed into different cells in sample box. Second, our longitude study included >16,000 samples, however, samples were not detected at the same time. In fact, samples from the same site were detected as soon as possible after collection by month, and usually no more than 200 samples were identified in each experiment. Third, before the inoculation or identification of the original and cultured samples, the surfaces of tubes were disinfected with disinfectant (Benzalkonium bromide or 75% alcohol). Fourth, RNAs were extracted by an automatic nucleic acid purification machine (Nucleic Acid Purification System NPA-32) rather than manually. Fifth, all the experiments associated with original and cultured samples, as well as RNAs (sample handling, virus isolation, PCR system preparation, and NGS library preparation), were performed in biosafety cabinets with tweezers and tips with filters. Tubes with samples were centrifuged at 5000 × g for ~10 s, and then were opened using tweezers, which will be disinfected by flameless infrared heater after each usage. In addition, disposable coveralls, N95 marks (Zhuozhou Fumeishendun Biotechnology Co., Ltd., China), and double-deck gloves (the inner shorter gloves cover the cuff by adhesive tape, and the outer longer gloves also cover the cuff but without adhesive tape for easy changing if they were contaminated) were strictly dressed in each experiment.

Data availability

Data supporting the findings of this study are available within the article and its Supplementary Information files. The H9Ny, H5Ny, H7Ny, and H6Ny sequences reported in this paper have been deposited into Global Initiative on Sharing All Influenza Data databases (GISAID; https://www.gisaid.org), and the accession numbers are listed in the Supplementary Data 7. These sequences have also been deposited into GenBank (accession numbers MW094306 - MW110364) and the China National Microbiological Data Center (accession number NMDC10017696 and genome accession numbers NMDCN0000230 - NMDCN0000HOQ). Source data are provided with this paper.

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Download referencesAcknowledgementsThis work was supported by the Strategic Priority Research Program of the Chinese Academy of Sciences (CAS; Grant No. XDB29010102), National Science and Technology Major Project (Grant No. 2018ZX10101004, 2018ZX10201001, 2018ZX10733403, and 2020ZX10001-016), Second Tibetan Plateau Scientific Expedition and Research Program (STEP; Grant No. 2019QZKK0304), National Key Research and Development Project of China (Grant No. 2016YFE0205800), National Natural Science Foundation of China (NSFC; Grant No. 31870163 and 32061123001), Shenzhen Science and Technology Research and Development Project (Grant No. JCYJ20180504165549581), RFBR Research Project (Grant No. 19-54-55004), Earmarked Fund for Modern Agro-industry Technology Research System (CARS-42) from the Ministry of Agriculture of P. R. China, Cooperative Innovation Project (The Shanghai Cooperation Organization Science and Technology Partnership Program; Grant No. 2017E01022), China-U.S. Collaborative Program on Emerging and Re-emerging Infectious Diseases (Grant No. 5U01IP001106-01), and Academic Promotion Programme of Shandong First Medical University (Grant No. 2019QL006 and 2019PT008). W.S. is supported by the Taishan Scholars program of Shandong Province (ts201511056). Y.B. is supported by the NSFC Outstanding Young Scholars (Grant No. 31822055), and Youth Innovation Promotion Association of CAS (Grant No. 2017122).Author informationAuthor notesThese authors contributed equally: Yuhai Bi, Juan Li, Shanqin Li, Guanghua Fu, Tao Jin.Authors and AffiliationsCAS Key Laboratory of Pathogenic Microbiology and Immunology, Institute of Microbiology, Center for Influenza Research and Early-warning (CASCIRE), CAS-TWAS Center of Excellence for Emerging Infectious Diseases (CEEID, Chinese Academy of Sciences, 100101, Beijing, ChinaYuhai Bi, Cheng Zhang, Fei Liu, Na Lv, Liang Wang, Lifeng Fu, George F. Gao, Yi Shi & Wenjun LiuUniversity of Chinese Academy of Sciences, 101408, Beijing, ChinaYuhai Bi, Shanqin Li, Yang Yang, Yun Peng, George F. Gao, Yi Shi & Wenjun LiuShenzhen Key Laboratory of Pathogen and Immunity, Guangdong Key Laboratory for Diagnosis and Treatment of Emerging Infectious Diseases, State Key Discipline of Infectious Disease, Second Hospital Affiliated to Southern University of Science and Technology, Shenzhen Third People’s Hospital, 518112, Shenzhen, ChinaYuhai Bi, George F. Gao, Yingxia Liu & Lei LiuKey Laboratory of Etiology and Epidemiology of Emerging Infectious Diseases in Universities of Shandong, Shandong First Medical University & Shandong Academy of Medical Sciences, 271016, Taian, ChinaJuan Li, Fanyu Meng & Weifeng ShiInstitute of Animal Husbandry and Veterinary Medicine, Fujian Academy of Agricultural Sciences, 350013, Fuzhou, ChinaGuanghua Fu & Yu HuangChina National Genebank-Shenzhen, BGI-Shenzhen, 518083, Shenzhen, ChinaTao Jin, Liqiang Li & Jinmin MaCollege of Life Science and Technology, Xinjiang University, 830046, Urumchi, ChinaCheng Zhang & Zhenghai MaZhejiang Provincial Engineering Laboratory for Animal Health Inspection & Internet Technology, College of Animal Science and Technology & College of Veterinary Medicine of Zhejiang A&F University, 311300, Hangzhou, ChinaYongchun YangCollege of Animal Science and Veterinary Medicine, Shanxi Agricultural University, 030801, Taigu, ChinaWenxia TianInstitute of Zoonosis, College of Public Hygiene, Zunyi Medical University, 563003, Zunyi, ChinaJida Li & Yi ZhangCollege of Veterinary Medicine, Northwest A&F University, 712100, Yangling, Shaanxi, ChinaShuqi XiaoDepartment of Veterinary Preventive Medicine, College of Veterinary Medicine, Jilin University, 130062, Jilin, ChinaRenfu YinSchool of Basic Medicine and Life Science, Hainan Medical University, 571101, Haikou, ChinaLixin WangDiqing Tibetan Autonomous Prefecture Centers for Disease Control and Prevention, 674400, Shangri-la, ChinaYantao QinCAS Key Laboratory of Special Pathogens and Biosafety, Wuhan Institute of Virology, Center for Biosafety Mega-Science, CASCIRE, Chinese Academy of Sciences, 430071, Wuhan, ChinaZhongzi Yao, Jianjun Chen & Quanjiao ChenCollege of Animal Science and Technology, Henan Institute of Science and Technology, 453003, Xinxiang, ChinaDongfang HuCollege of Animal Science, Southwest University, 402460, Chongqing, ChinaDelong LiInstitut Pasteur of Shanghai, Chinese Academy of Sciences, 200031, Shanghai, ChinaGary WongDépartement de microbiologie-infectiologie et d’immunologie, Université Laval, Québec City, G1V 0A6, CanadaGary WongFederal Research Center of Fundamental and Translational Medicine, Federal State Budget Scientific Institution, Siberian Branch of Russian Academy of Sciences, Novosibirsk State University, Novosibirsk, Russia, 630090Kirill Sharshov, Alexander Shestopalov & Marina GulyaevaNational Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), 102206, Beijing, ChinaGeorge F. Gao & William J. LiuGeneral Station for Surveillance of Wildlife-borne Infectious Diseases, State Forestry and Grassland Administration, 110034, Shenyang, Liaoning Province, PR ChinaDong ChuSchool of Public Health, Shandong First Medical University & Shandong Academy of Medical Sciences, 271000, Taian, ChinaWeifeng ShiAuthorsYuhai BiView author publicationsYou can also search for this author in

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PubMed Google ScholarContributionsConceptualization by Y.B., W.S., and G.F.G.; Methodology by Y.B, W.S., J.L., S.L., and G.F.; Formal analysis by Y.B., J.L., S.L., Q.C., and W.S.; Investigation by Y.B., J.L., S.L., Q.C., G.F., T.J., C.Z., Yo.Y., Z.M., W.T., Ji.L., S.X., L.L., R.Y., Y.Z., Lx.W., Y.Q., Z.Y., F.M., D.H., D.L., G.W., F.L., N.L., L.W., L.F., Y.Y., Y.P., J.M., K.S., A.S., M.G., J.C., Y.S., W.J.L., D.C., Y.H., Y.L., L.L., W.L., and W.S.; Resources by Y.B., W.S., and G.F.G; Writing – original draft by Y.B., W.S., and Q.C.; Writing – review and editing by Y.B., W.S., G.W., J.L., S.L., Q.C., and G.F.G; Supervision by Y.B., W.S., and G.F.G.; Project administration by Y.B., S.L., J.L., and W.S.; Funding acquisition by Y.B., W.S., and G.F.G.Corresponding authorsCorrespondence to

Yuhai Bi, Quanjiao Chen or Weifeng Shi.Ethics declarations

Competing interests

The authors declare no competing interests.

Additional informationPeer review information Nature Communications thanks Guadalupe Ayora-Talavera, Marie Culhane, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. Peer review reports are available.Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.Supplementary informationSupplementary InfomationDescription of Additional Supplementary FilesSupplementary Data 1Supplementary Data 2Supplementary Data 3Supplementary Data 4Supplementary Data 5Supplementary Data 6Supplementary Data 7Supplementary Data 8Supplementary Data 9Supplementary Data 10Supplementary Data 11Reporting SummarySource dataSource DataRights and permissions

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Reprints and permissionsAbout this articleCite this articleBi, Y., Li, J., Li, S. et al. Dominant subtype switch in avian influenza viruses during 2016–2019 in China.

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禽流感病毒研究进展及抗H7N9型病毒疫苗与抗体研究-Progress in research of avian influenza virus and human monoclonal antibody and vaccines against H7N9 virus

禽流感病毒研究进展及抗H7N9型病毒疫苗与抗体研究-Progress in research of avian influenza virus and human monoclonal antibody and vaccines against H7N9 virus

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文章摘要

王雨潇,李靖欣,刘沛,朱凤才.禽流感病毒研究进展及抗H7N9型病毒疫苗与抗体研究[J].中华流行病学杂志,2021,42(9):1700-1708

禽流感病毒研究进展及抗H7N9型病毒疫苗与抗体研究

Progress in research of avian influenza virus and human monoclonal antibody and vaccines against H7N9 virus

收稿日期:2021-03-23  出版日期:2021-09-27

DOI：10.3760/cma.j.cn112338-20210323-00242

中文关键词: 流感病毒  禽流感病毒  H7N9型  单克隆抗体  疫苗  临床试验

英文关键词: Influenza virus  Avian influenza virus  H7N9  Monoclonal antibody  Vaccine  Clinical trial

基金项目:

作者单位E-mail王雨潇 东南大学公共卫生学院流行病与卫生统计学系, 南京 210000  李靖欣 江苏省疾病预防控制中心疫苗临床评价所, 南京 210000  刘沛 东南大学公共卫生学院流行病与卫生统计学系, 南京 210000 liupeiseu@126.com 朱凤才 江苏省疾病预防控制中心疫苗临床评价所, 南京 210000 jszfc@vip.sina.com 

摘要点击次数: 2267

全文下载次数: 773

中文摘要:

      禽流感病毒（avian influenza virus，AIV）是一种可引起急性呼吸道传染病的人畜共患病毒。自2013年我国出现了全球首例人感染H7N9型AIV病例以来，人们对该病毒产生了担忧与恐慌。AIV在全球广泛传播，人感染不同型别AIV事件也持续发生，造成了巨大的经济损失。目前尚无针对该病的特异性治疗措施与药物，疫苗成为最有可能预防控制病毒传播的手段。现有针对H7N9型AIV的兽用与人用疫苗种类繁多，其中，4类人用H7N9型AIV疫苗已经率先进入了临床试验阶段，主要包括了病毒样颗粒疫苗、减毒活疫苗、灭活疫苗及DNA疫苗，并显示出了良好的安全性和免疫原性。因为暂无上市的人用AIV疫苗，所以其真实效力不得而知。此外，现有的流感疫苗在人群中虽然具有良好的安全性和免疫原性，但对H7N9型AIV并无交叉抗体反应。本文回顾AIV的病原学、流行病学、职业暴露人群调查与防控策略、H7N9型AIV疫苗及H7N9型AIV全人源单克隆抗体研究进展，讨论尚存的问题和挑战以及未来的发展方向，为加深对疾病的了解以及控制AIV在全球的蔓延提供防控策略与方针。

英文摘要:

      Avian influenza virus (AIV) is a kind of zoonotic virus which can cause acute respiratory infectious diseases. Since the report of the world's first human infection case of avian influenza A (H7N9) virus in China in 2013, close attention has been paid to the virus. AIV spreads widely around the world, and human infection with different types of AIV continues to occur, causing huge economic losses. At present, there are no specific treatment and drugs against the disease, and vaccination is considered as the most promising and effective method to control the human infection with AIV. So far, there are many kinds of veterinary and human vaccines for H7N9 AIV, among which four types of human H7N9 AIV vaccines have entered the clinical trial stage, including virus-like particles vaccine, attenuated live vaccine, inactivated vaccine and DNA vaccine, which have shown good safety and immunogenicity. However, the true efficacies of the AIV vaccines remain unknown because no human vaccines are currently available in the market. In addition, although the existing influenza vaccine has good safety and immunogenicity in the human population, there is no cross-antibody response to H7N9 AIV. This paper summarizes the research progress of AIV etiology and epidemiology, the occupational exposure population investigation, the infection prevention and control strategies, and H7N9 AIV vaccine and H7N9 AIV anthropogenic monoclonal antibody, and discuss the remained problems, challenges and future trends in the research of AVI to improve the understanding of the disease and the prevention and control of global spread of AIV.

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H5N8亚型高致病性禽流感病毒的全球流行概况

H5N8亚型高致病性禽流感病毒的全球流行概况

  微生物学报  2022, Vol. 62 Issue (1): 10-23

  DOI: 10.13343/j.cnki.wsxb.20210239.

http://dx.doi.org/10.13343/j.cnki.wsxb.20210239

中国科学院微生物研究所，中国微生物学会，中国菌物学会

0

文章信息

李仪, 刘化金, 李祥, 吕欣孺, 柴洪亮. 2022

Yi LI, Huajin LIU, Xiang LI, Xinru LV, Hongliang CHAI. 2022

H5N8亚型高致病性禽流感病毒的全球流行概况

Global epidemiology of H5N8 subtype highly pathogenic avian influenza virus

微生物学报, 62(1): 10-23

Acta Microbiologica Sinica, 62(1): 10-23

文章历史

收稿日期：2021-04-23

修回日期：2021-07-22

网络出版日期：2021-11-04

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引用本文

李仪, 刘化金, 李祥, 吕欣孺, 柴洪亮. H5N8亚型高致病性禽流感病毒的全球流行概况[J]. 微生物学报, 2022, 62(1): 10-23.

Yi LI, Huajin LIU, Xiang LI, Xinru LV, Hongliang CHAI. Global epidemiology of H5N8 subtype highly pathogenic avian influenza virus[J]. Acta Microbiologica Sinica, 2022, 62(1): 10-23.

H5N8亚型高致病性禽流感病毒的全球流行概况

李仪1

#,

刘化金2

#,

李祥1

,

吕欣孺1

,

柴洪亮1

    

1. 东北林业大学野生动物与自然保护地学院, 黑龙江 哈尔滨 150040;

2. 黑龙江兴凯湖国家级自然保护区管理局, 黑龙江 密山 158300

收稿日期：2021-04-23；修回日期：2021-07-22；网络出版日期：2021-11-04

基金项目：国家自然科学基金（31970501）

摘要：H5N8亚型高致病性禽流感病毒（highly pathogenic avian influenza virus，HPAIV）随候鸟的迁徙活动及商业贸易活动现已蔓延至亚洲、欧洲、非洲、美洲等国家和地区。2014-2015和2016-2019年H5N8亚型HPAIV已引发两波全球疫情，现正经历第三波疫情，导致家禽及野生鸟类大量死亡，造成严重的经济损失。已有研究发现，病毒基因位点突变能使其对犬、鼠、水貂等哺乳动物毒力增强，值得关注的是2021年2月俄罗斯首次报道人感染H5N8病毒事件，具有重要的公共卫生意义。本文针对在全球出现的家禽及野鸟H5N8亚型HPAIV疫情及流行情况进行综述，探讨其来源以及危害，建议加强野生鸟类特别是迁徙候鸟禽流感病毒的主动监测，早发现、早预警，最大程度减少禽流感疫情带来的经济损失及对人类健康带来的威胁。

关键词：高致病性禽流感    H5N8亚型禽流感病毒    流行病学    

Global epidemiology of H5N8 subtype highly pathogenic avian influenza virus

Yi LI1

#,

Huajin LIU2

#,

Xiang LI1

,

Xinru LV1

,

Hongliang CHAI1

    

1. College of Wildlife and Protected Area, Northeast Forestry University, Harbin 150040, Heilongjiang, China;

2. Khanka Lake National Nature Reserve of Heilongjiang, Mishan 158300, Heilongjiang, China

Received: 23 April 2021; Revised: 22 July 2021; Published online: 4 November 2021

*Corresponding author:

CHAI Hongliang, E-mail: hongliang_chai@hotmail.com.

Foundation item: Supported by the National Natural Science Foundation of China (31970501)

#These authors contributed equally to this work.

Abstract: H5N8 subtype highly pathogenic avian influenza virus (HPAIV) has spread to Asia, Europe, Africa, the Americas, and other countries and regions with the migration of wild birds and commercial trade activities. H5N8 HPAIV caused two waves of pandemic in 2014-2015 and 2016-2019, and the third wave has broken out, leading to the death of a large number of poultry and wild birds and serious economic loss. Previous studies have shown that mutation can enhance the virulence of the virus to mammals such as canines, mice, and minks. The first human infection event was reported in February 2021, which is of important public health significance. This article reviewed the global epidemic situation of the H5N8 HPAIV in recent years, and discussed its origin and hazards. We suggest strengthening the active surveillance of AIV in wild birds, especially migratory birds, and performing early warning to reduce economic loss and threats to human health.

Keywords:

highly pathogenic avian influenza    H5N8 subtype avian influenza virus    epidemiology    

禽流感(avian influenza，AI)是一种高度传染性疾病，鸟类活动是其在全球范围传播的重要因素。禽流感病毒(avian influenza virus，AIV)能感染家禽、野鸟和哺乳动物甚至人类。根据其致病力大小可分为高致病性禽流感(highly pathogenic avian influenza，HPAI)和低致病性禽流感(low pathogenic avian influenza，LPAI)，其中HPAI在家禽中造成高死亡率，被世界动物卫生组织列为A类疫病，被我国列为一类传染病。截至目前，HPAI均由H5或H7血凝素(hemagglutinin，HA)亚型病毒引起。 自1996年在中国广东首次分离到H5N1亚型HPAIV (A/goose/Guangdong/1/1996)以来，根据H5基因的进化分析发现，病毒已进化出10个分支(0–9)和许多亚分支以及次亚分支[1]，并已传播至亚洲、欧洲、北美洲及非洲，感染了家禽、野鸟以及哺乳动物(包括人类)。家禽、野鸟的H5N1亚型AIV不断发生重组与突变，产生不同亚型的H5Nx病毒，包括N2、N3、N5、N6、N8和N9[2-3]。 2008年WHO、OIE、FAO对H5N1的H5基因制定分类标准，将核苷酸差异 < 1.5%的定义为一个分支(clade)[1]，2015年对H5命名系统进行更新，新增2.3.4.4分支以替换临时使用的2.3.4.6分支[4]，并将该分支细分为group A–D。H5N8亚型HPAIV主要集中在2.3.4.4分支的group A和B。2019年末，为了确切描述2.3.4.4分支H5基因的遗传进化规律，H5的命名系统再次修订，将2.3.4.4分支的H5基因分为8个分支2.3.4.4 a–h[5]，而H5N8亚型HPAIV主要集中在2.3.4.4 b分支。这种编号系统客观地反映了H5之间的谱系关系，消除地理名称，例如：2005年“福建系”现归为2.3.4的三级谱系，2005年“青海系”划归为2.2的二级谱系。 2010年2.3.4分支的H5N8亚型HPAIV首次在中国家禽中发现，但没有引发大规模疫情。2014年，韩国的家禽以及野鸟暴发了多起H5N8亚型HPAI疫情，随后，中国、日本以及欧洲、北美各国亦有发生，进而引发第一波洲际流行。到2016年，H5N8亚型HPAI传播至欧洲、中东以及非洲等国家和地区，导致第二波全球H5N8亚型HPAI疫情的出现。现阶段，第三波全球H5N8亚型HPAI正在世界范围内流行，大量野生鸟类及家禽死亡，造成极大的经济损失。2020年12月，首次出现H5N8亚型HPAIV感染人的事件，H5N8亚型HPAIV现已成为威胁全球的重要生物安全问题之一。 1 全球H5N8亚型HPAI流行趋势

1.1 首次发现H5N8亚型HPAIV

2010年，在中国江苏活禽市场的家禽中首次分离到2.3.4分支的H5N8亚型HPAIV (A/duck/Jiangsu/k1203/2010[H5N8])[6-8]，此次发现的病毒虽未引发家禽疫情以及人感染病例，但动物感染实验证明，病毒在小鼠中表现出的毒力呈中到高等，并可能对流感药物有耐药性。2013年，在中国浙江省家禽中分离到2株由A/duck/Jiangsu/k1203/2010 (H5N8)、A/environment/ Jiangxi/28/2009 (H11N9)、A/duck/Hunan/8-19/2009 (H4N2)等毒株重组而来的H5N8亚型HPAIV (W24、6D18)，动物感染实验表明，这2株病毒对家鸡具有高致病性，对小鼠不易感[8]，表明其对于哺乳动物(包括人类)的感染能力有限。同年，中国上海首次监测到野鸟源H5N8亚型HPAIV[9]，与浙江W24、6D18同属于2.3.4.4分支的group B。2014年，从上海的大杓鹬(Numenius madagascariensis)分离到7株H5N8亚型HPAIV，与2014年韩国、欧洲、北美流行的H5N8毒株同属于group A。 1.2 H5N8亚型HPAI第一波洲际流行(2014–2015年)

1.2.1 亚洲疫情:

2014年1月16日，韩国全罗北道一水库附近的养鸭场的家鸭出现了产蛋量下降、死亡率上升等典型HPAIV感染症状，并在次日向OIE报告此波疫情。1月17日，距离水库5 km的一个养殖场也报告了家鸭出现流感典型症状[10]。对此次疫情代表毒株分析发现，其与2010年中国江苏家禽源H5N8亚型HPAIV以及中国上海野鸟源毒株高度同源。通过对H5基因进行遗传进化分析发现，其属于2.3.4.6分支(此分支在2015年被重新修订为2.3.4.4)，并将毒株Buan2以及Gochang1分别作为H5N8亚型AIV在2.3.4.4分支group A和B的代表株。尽管韩国采取了严格的疫情防控管理措施，然而直到一年后的2015年1月，疫情仍未得到有效控制，影响了韩国369家养殖场，其中73%是家鸭养殖场，与此同时，也从野鸟中监测到H5N8亚型HPAIV[11]。据统计，自疫情开始，截至2015年7月6日，韩国已有782个农场的近1 900万只家禽被扑杀。随后此波疫情逐渐蔓延至中国、日本等周边国家以及欧洲、北美各国。 2014年2月到4月，中国开始出现疫情：浙江、江苏、山东的家禽及上海野鸟中均分离到毒株，其中江苏、山东鹅源H5N8亚型HPAIV的相关实验表明，其能结合α-2, 3唾液酸受体和α-2, 6唾液酸受体[12]，表明病毒对养殖业以及公共卫生安全具有潜在威胁。 同年4月，日本九州岛养鸡场出现H5N8亚型HPAI疫情，其中熊本县扑杀超11.2万只鸡，严格的防控措施起到了一定效果，在2014年11月候鸟到达日本越冬之前，此波疫情没有进一步暴发。然而当12月野鸟迁徙进入日本境内，日本开始大面积暴发家禽H5N8亚型HPAI疫情，2014年12月发生3起家禽疫情，紧接着2015年1月又发生2起，这几起疫情均发生在养鸡场[13]。同时从鸳鸯(Aix galericulata)、小天鹅(Cygnus columbianus)、白枕鹤(Grus vipio)等野生禽类的粪便和环境中也监测到了H5N8亚型HPAIV[14]。通过对在日本疫情中分离到的毒株A/chicken/Kumamoto/1-7/2014 (Kum14)基因分析表明，所有基因片段与2014年韩国疫情家禽源分离株Buan14高度同源(> 99.59%)[15]。 2014年9月，疫情不断向西蔓延，在中国浙江的家禽和环境样本以及俄罗斯东北部赤颈鸭(Anas penelope)中发现了H5N8亚型HPAIV。 2015年1月到2月，中国台湾的86个鸡场、44个鸭场和636个鹅场出现了H5亚型HPAI疫情，扑杀大约150万只鸡、20万只鸭和220万只鹅，后经检测发现此次疫情由H5N2、H5N3、H5N8亚型HPAIV共同导致，其中H5N8亚型与日本、北美H5N8亚型HPAIV有直接的共同祖先，都属于2.3.4.4分支的group A[16-18]。

1.2.2 欧洲疫情:

2014年11月3日，德国东北部一家火鸡养殖场16周龄的育肥火鸡突然大量死亡，后经研究发现，这是由H5N8亚型HPAIV引起的疫情，由此H5N8亚型HPAIV开始进入欧洲并引发流行。发生疫情的养殖场位于一湿地附近，周围有大量野鸟出没，但该地区家禽密度低，四周被森林、农田包围，出入受限，相对隔离。养殖场的6个鸡舍中，靠近养殖场入口的鸡舍首先出现火鸡死亡，相邻鸡舍相继出现大量死亡的情况。流行病学调查排除了以下导致疫情发生的原因：(1) 火鸡蛋或雏禽带毒；(2) 受污染的水、饲料或垃圾传播病毒；(3) 在韩国等东亚地区被病毒污染的物品或人员导致病毒传播等[18]。而17日德国吕根岛的绿翅鸭(Anas crecca)拭子样本呈H5N8亚型HPAIV阳性更加证实了这一点：病毒来源可能为常出没在附近湿地携带有AIV的野鸟，它们导致垃圾、饲料、水等污染，促使病毒传播至养殖场，最终导致火鸡感染。根据获得基因的遗传进化及系统发育分析发现：这些毒株与同年来自日本的H5N8亚型HPAIV相似。 2014年11月9日，荷兰一个拥有6个鸡舍、12.4万只家禽的养鸡场，其中1个鸡舍的鸡死亡数量呈指数型增长[19]。自此次荷兰养鸡场暴发H5N8亚型HPAI疫情之后[20]，H5N8疫情便在欧洲盛行：英国、意大利等国相继出现多起疫情。荷兰于2015年4月29日宣布这波疫情的结束，2016年全年未出现H5N8疫情报道，直到2017年再次出现。通过对荷兰疫情毒株的分析发现，此次疫情可能由与在西伯利亚的亚洲候鸟有重叠的迁徙路线或共同的繁殖区的迁徙候鸟带来。英国在11月18日报告：约克郡一个养鸭场暴发H5N8亚型HPAI。意大利于12月15报告了H5N8亚型HPAI疫情，导致火鸡养殖场3万余只火鸡死亡或被扑杀。这几起疫情毒株均与荷兰疫情毒株高度同源。 2015年，匈牙利、瑞典等欧洲国家首次出现H5N8亚型HPAI疫情，该波疫情在欧洲地区持续至2015年年中，造成严重经济损失。

1.2.3 北美疫情:

2014年12月，在美国华盛顿的猎鹰等野鸟以及家禽中发现了与2.3.4.4分支Buan2-like相近的H5N8亚型HPAIV，这是北美地区首次发现H5N8亚型HPAIV，经分析发现：病毒可能在2014年春天由迁移候鸟携带至西伯利亚和白令海峡地区，并在繁殖季节不断重组、进化，随后在秋季随着鸟类迁徙路线传入北美[21]。这些病毒作为基因供体，重组出之后在北美流行的H5N2。北美地区的加拿大也于2015年首次出现H5N8亚型HPAI疫情。 1.3 H5N8亚型HPAI第二波洲际流行(2016–2019年)

1.3.1 亚洲疫情:

2016年5月和6月，在中国青海湖和俄罗斯乌布苏湖的斑头雁(Anser indicus)、苍鹭(Ardea cinerea)、普通鸬鹚(Phalacrocorax carbo)等死亡野鸟中分离到2.3.4.4分支group B的H5N8亚型HPAIV，从此开启了第二波H5N8亚型HPAI全球疫情[22-24]：2016年秋冬至2017年，H5N8亚型HPAIV在欧洲、非洲、亚洲的多个国家被分离到，并作为基因供体不断重组，产生随后在欧洲流行的H5N5亚型AIV。对青海湖及乌布苏湖疫情流行病学调查发现：青海湖在4月就存在这些病毒，其中HA、NA和NS基因与2014年中国东部的H5N8同源性较高，PB1、PB2、PA、NP和M基因与蒙古、中国和越南发现的LPAIV同源性较高，推测其可能由起源于孟加拉湾越冬地的迁徙候鸟，在2016年春季沿中亚迁徙路线向北扩散并不断重组，导致H5N8亚型HPAIV引入中国青海湖地区，当候鸟继续北迁，导致病毒传播到乌布苏湖和西伯利亚等候鸟繁殖地。在疫区环境水样中发现的与死亡野鸟相同的毒株，进一步证明了栖息地的水环境可能对野鸟之间的病毒传播起到了重要作用，推断野鸟可能通过环境感染病毒并传播。这波疫情跨越亚洲、欧洲和非洲。 2016年10月，印度两家动物园的水禽暴发H5N8亚型HPAI，此次动物园水禽疫情暴发的时间正好是中亚迁徙路线的候鸟秋季迁徙到达印度的时间[24]。印度是2016年继中国青海湖和俄罗斯乌布苏湖暴发疫情后最早发生H5N8亚型HPAI疫情的国家。对HA基因的系统发育分析表明，这些分离株与欧亚地区的H5N8亚型HPAIV聚集在2.3.4.4分支group B，并与中国青海湖及俄罗斯乌布苏湖H5N8密切有关。NS基因的42S突变和PB1基因的13P突变表明病毒对小鼠的毒力有所增加。 2016年11月，伊朗德黑兰省一蛋鸡养殖场发生H5N8亚型HPAI疫情，造成4 455只蛋鸡死亡，这是伊朗首次发现H5N8亚型HPAIV。HA基因的遗传和系统发育分析表明，伊朗H5N8亚型HPAIV属于2.3.4.4分支的group B，与2016年年中在俄罗斯发现的H5N8基因序列相似性极高。溯源研究发现，病毒可能通过从俄罗斯和东南亚返回的候鸟传入伊朗，再由候鸟向养殖场传播[25]。通过对2017年在伊朗冠鸦(Platylophus galericulatus)体内分离到的H5N8亚型HPAIV遗传进化分析发现：其PA、NS、PB1、PB2和M与韩国2016年和2017年H5N8毒株的遗传关系非常密切，NP基因与欧洲谱系H5N8毒株具有较高的相似性，与伊朗家禽源H5N8高度同源，这一追溯性研究更加支持了伊朗养殖场暴发的疫情是由候鸟迁徙带来并传播给家禽的这一观点。这株H5N8存在PB1基因的P598L、PB2基因的E627K等突变情况[26]，会导致病毒与α-2, 6唾液酸受体的亲和力增加，对哺乳动物具有潜在威胁。 2017年12月19日，沙特阿拉伯一家活禽市场发现各种禽类大量死亡，截至2018年5月，在沙特多省监测的7 273只禽类中805例呈H5N8阳性，其中利雅得报告了693例，是最严重的省份，受到影响的养殖场包括22个蛋鸡养殖场、2个肉鸡养殖场和1个鹌鹑养殖场[27]。HA基因的系统发育分析显示，它们均属于2.3.4.4分支group B。PA、HA、NP、NA、M和NS片段与来自不同地区的野生候鸟的H5N8病毒相似，PB1和PB2片段与在俄罗斯远东地区和欧洲分离到的由H5N8重组而来的H5N5亚型HPAIV关系密切。2018至2019年间，中东地区(以色列、伊朗、伊拉克和科威特)以及巴基斯坦不断有H5N8疫情暴发的报道。

1.3.2 欧洲疫情:

2016年10月，这波疫情在欧洲开始出现。10月19日，匈牙利报道了第一起野鸟源H5N8亚型HPAI疫情，11月1日在家禽中暴发，随后疫情蔓延至欧洲多个国家。欧洲的这波疫情可分为2个阶段：第一阶段始于2016年11月，一直持续到年底。克罗地亚、瑞士、德国、奥地利、荷兰、丹麦、法国等国从11月开始相继暴发疫情，其中，较为严重的德国、荷兰、丹麦、法国均是先在野鸟中发现病毒，随后在家禽中暴发。而疫情同样严重的瑞士只是在野鸟中暴发疫情，并在一周内迅速传播，从东北(康斯坦斯湖)和西南(日内瓦湖)迅速蔓延至瑞士中部高原，但大规模养殖场以及家庭散养家禽未发生疫情[28]，这可能与当地严格的防控措施有关。在这一阶段中，法国不仅发生80余起H5N8亚型HPAI疫情，还发生了136起与H5N8亚型HPAIV密切相关的H5Nx亚型HPAI疫情，80%的H5N8疫情发生在水禽养殖场(主要是养鸭场)[29]。第二阶段从2017年2月开始，野鸟及家禽感染数量显著增加，特别是法国、德国、波兰、罗马尼亚的疫情暴发次数均超过百起，整个欧洲暴发次数超1 300起；影响范围更广，几乎遍布整个欧洲，并不断向非洲蔓延。

1.3.3 非洲疫情:

2016年冬季，非洲地区开始出现H5N8亚型HPAI疫情。首先在离欧洲较近的埃及地区的迁徙野鸟中分离到2.3.4.4分支group B的H5N8。随后，埃及多省又报告数起家禽H5N8亚型HPAI疫情。多株埃及H5N8亚型HPAIV的NS1基因含S42，可增加AIV在哺乳动物中的毒力；HA基因存在T156A的突变，该突变能使病毒经呼吸道感染雪貂；PB2基因中存在的V667I突变，能够增强病毒致病性以及向人类传播的能力。小鼠实验表明，埃及这些毒株对小鼠具有感染性。而这些毒株对于埃及目前使用的H5疫苗并不敏感，这将增加大面积发生疫情的风险[30]。 在2016年12月，在乌干达中南部维多利亚湖沿岸出现大规模的鸥类死亡，随后出现家禽死亡现象[31]。2017年4月底，刚果伊图里省位于鲁文佐里山脉和乌干达之间的阿尔伯特湖亦发生家禽和野鸟大量死亡的情况[32]。后经研究发现，这两起疫情均为2.3.4.4分支group B的H5N8亚型HPAIV引起，并与2016年中国青海湖、俄罗斯乌布苏湖的毒株有密切关系。 2017年6月初，非洲南部的津巴布韦报告一起养殖场疫情。6月19日，南非出现H5N8亚型HPAI疫情：第一起疫情发生在南非一肉鸡养殖场，随后在家庭散养禽类、鸵鸟、企鹅等众多家禽及野鸟中发现该病毒。南非是此次疫情发生最严重的非洲国家，到2017年11月，南非9个省中只有2省未受疫情影响[33]。进一步调查显示，导致该国发生疫情的H5N8亚型HPAIV属于2.3.4.4分支group B，与同年来自西非的尼日尔、尼日利亚、喀麦隆等国H5N8亚型HPAIV有共同的祖先。在这波疫情中，非洲暴发的H5N8亚型HPAI疫情均与同年欧洲疫情及2016年中国青海湖和俄罗斯乌布苏湖疫情有密切关系。 2018年南非全年暴发H5N8亚型HPAI疫情60余次，仅次于发生81次疫情的俄罗斯。自2019年开始，H5N8亚型HPAI疫情在非洲的流行范围更加广泛。2019年1月，非洲纳米比亚哈利法克斯岛的非洲企鹅突然大量死亡，对样本进行分析发现为H5N8亚型HPAIV导致，这也是纳米比亚境内首次发现H5N8亚型HPAIV[34]，对HA和NA基因的序列分析证实该病毒与2017年在南非发现的H5N8亚型HPAIV高度同源，随后尼日利亚、南非、埃及等非洲国家不断出现疫情。 1.4 H5N8亚型HPAI第三波洲际流行(2020年)

2019年12月31日，波兰暴发由2.3.4.4 b的H5N8亚型HPAIV引起的禽流感疫情[35]，随后，罗马尼亚、斯洛伐克、捷克、保加利亚、德国、匈牙利、以色列等欧洲国家及伊拉克、伊朗、沙特等中东国家的野鸟和家禽在2020年上半年相继暴发H5N8亚型HPAI疫情，引起这些疫情的毒株与2016–2019年流行毒株核苷酸一致性较低，但具有相同的进化来源：主要由非洲地区2.3.4.4分支group B的H5N8亚型HPAIV和欧亚谱系的LPAIV发生重组而来。 2020年，非洲地区仅有南非出现疫情，其疫情原因为本国上次疫情的延续，与2020年新一波疫情关联不大。 俄罗斯于2020年7月底开始出现疫情。2020年下半年，亚洲的韩国、日本也出现疫情。韩国自2018年4月以来，长期对野鸟和家禽进行大规模的主动监测，均未监测到H5N8亚型HPAIV毒株，但2020年10月，在野鸟禽流感主动监测中，从一只鸳鸯的粪便中分离出一株属于2.3.4.4分支group B的H5N8亚型HPAIV (A/Mandarin duck/Korea/K20-551-4/2020 [H5N8])[36]。在遗传进化分析中，K20-551-4的所有8个基因片段与2016–2018年在韩国流行的同属于2.3.4.4分支group B的H5N8毒株遗传距离较远，但与2020年初在欧洲家禽和野鸟中检测到的2.3.4.4分支group B的H5N8毒株关系密切。同期，日本在迁徙候鸟的粪便样中分离到2.3.4.4 b分支的H5N8亚型HPAIV (A/northern pintail/Hokkaido/M13/2020 [H5N8])[37]，序列分析结果表明，M13与2017–2018年冬季东亚地区毒株遗传关系较远，与2019冬季到2020年欧洲毒株的序列高度同源，推测M13是通过鸟类迁徙从欧洲传入，而不是本土2.3.4.4 b分支的H5亚型HPAIV毒株重组的产物。综合这两起疫情来看，此波疫情中的亚洲毒株主要还是由于野鸟活动从欧洲引入。 时隔两年，我国再次出现H5N8亚型HPAI疫情：2020年10月，内蒙古自治区巴彦淖尔的乌梁素海湖发生野生天鹅H5N8亚型HPAI疫情[38]；2020年11月，山西运城市平陆县三湾大天鹅景区发生野生天鹅H5N8亚型HPAI疫情，该区域栖息野生天鹅4 000余只，发病2只、死亡2只[39]；2021年1月山东省东营市黄河三角洲自然保护区大汶流管理站发生野生天鹅H5N8亚型HPAI疫情，疫点栖息野生禽类249只，发病35只、死亡35只[40]；2021年2月北京市海淀区圆明园遗址公园发生野生天鹅H5N8亚型HPAI疫情，疫点栖息野生禽类15只，发病3只、死亡3只[41]；2021年2月5日，江苏省连云港市云台山景区发生野禽H5N8亚型HPAI疫情，疫点栖息野生禽类约647只，发病17只、死亡17只[42]。病毒溯源工作还在进行中。 1.5 全球H5N8亚型HPAI流行趋势小结

从2010年发现第一例H5N8亚型HPAIV开始，至今已引发三波洲际疫情，受影响大洲包括欧洲、亚洲、非洲以及北美洲(图 1)。

图 1 H5N8亚型HPAIV流行情况 Figure 1 The epidemic situation of the H5N8 subtype HPAIV.

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第一波疫情始于2014年韩国，受疫情影响的国家包括中国、日本和北美、欧洲各国等：2014年1月在韩国家禽和野生禽类中发现H5N8亚型HPAIV，并确定了2.3.4.4分支group A和B的H5N8亚型AIV代表株。对2014年这波疫情中所获基因片段的遗传分析表明：欧洲家禽和野生禽类H5N8亚型HPAIV的基因组与亚洲韩国和日本的家禽和野生禽类H5N8亚型HPAIV的基因组非常相似。欧洲(德国、意大利、荷兰和英国)、俄罗斯远东地区、北美(美国、加拿大)、日本、中国台湾、中国上海以及部分韩国的毒株之间有密切的遗传关系，同属于group A。 第二波疫情始于2016年4–6月中国青海湖和俄罗斯乌布苏湖，相较2014年的疫情，2016年这波疫情受影响范围更广，持续时间更长：受影响地区包括亚洲、欧洲、非洲等地区国家，多数国家均为首次出现H5N8亚型HPAI疫情。这波疫情的前期主要集中在欧洲，后期向非洲蔓延，造成严重的经济损失。在此期间，奥地利、比利时、波黑、保加利亚、克罗地亚、捷克、丹麦、芬兰、法国、德国、希腊、匈牙利、爱尔兰、意大利、立陶宛、卢森堡、马其顿、荷兰、波兰、葡萄牙、罗马尼亚、俄罗斯、塞尔维亚、斯洛伐克、斯洛文尼亚、西班牙、瑞典、瑞士、英国和乌克兰共计30个欧洲国家报告了家禽、野鸟的H5N8亚型HPAI疫情。在这30个国家中，有19个国家首先在野鸟中检测到H5N8亚型HPAIV，6个国家首先在家禽中检测到，5个国家几乎同一时期在野鸟和家禽中检测到H5N8亚型HPAIV，法国、德国和匈牙利是受疫情影响最严重的几个欧洲国家。非洲疫情主要由野鸟的持续迁徙从欧洲带至非洲，而欧洲疫情由2016年中国青海湖和俄罗斯乌布苏湖疫情扩散导致。 这波疫情后期(2018–2019年)主要集中在中东、非洲以及俄罗斯等地区，欧洲地区仅有瑞典、意大利以及位于东南欧的保加利亚，除中东地区以外的亚洲地区仅巴基斯坦出现疫情。2018年发生疫情的国家和地区数量较2017年下降了近60%。2018至2019年中国、日本、韩国、东南亚以及北美洲、南美洲均未报告家禽或野鸟发生H5N8亚型HPAI疫情，2016–2019年疫情毒株同属2.3.4.4分支group B，推测2018至2019年疫情为2016年疫情的延续。 第三波疫情始于2019年年底至2020年年初的欧洲，至今还未结束，截至目前已导致欧洲、亚洲多国野鸟及家禽的死亡事件，并在我国引发多起野生鸟类H5N8亚型HPAI疫情，这波疫情均由2.3.4.4 b分支的H5N8引起。 2020年前，全球对2.3.4.4分支的H5主要采用group A–D的分支方式，其中H5N8主要集中在group A和B。Group A分支以A/broiler duck/Korea/Buan2/2014为代表，主要包括2014年早期中国毒株以及2014–2015年源于韩国并传播至中国台湾、日本、欧洲、北美等地区流行的H5N8毒株；group B分支以A/breeder duck/Korea/Gochang1/2014为代表，主要包括2013年中国南方、2016年疫情至今在全球流行的大部分毒株。Group B流行范围更广，影响程度更大。通过对H5N8亚型HPAIV的遗传进化分析发现：group A已由2.3.4.4 c替代，group B已由2.3.4.4 b替代(图 2)。由于主动监测力度不足以及各国之间防控政策的差异，导致禽流感数据空白较多，对于H5N8的溯源工作相对较难，至今仍不清楚2010年H5N8亚型HPAIV的来源。

图 2 H5N8亚型HPAIV遗传进化树 Figure 2 Maximum-likelihood phylogenetic tree of HA gene of the H5N8 subtype HPAIV. Sequences were downloaded from NCBI and GISAID. The representative strains of 2.3.4.4a–h were selected as WHO recommended (https://apps.who.int/iris/bitstream/handle/10665/336259/WER9544-525-539-eng-fre.pdf?sequence=1&isAllowed=y). Different periods of the H5N8 subtype HPAIV are colored in different colors. Other H5 subtype strains are colored in black. EU: Europe; NA: North America; AF: Africa.

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2 野鸟对H5N8亚型HPAIV传播的影响

到目前为止，H5N8亚型HPAIV已从亚洲、欧洲、非洲、北美洲等的多个国家和地区的多种野鸟中分离出来，宿主包括雁鸭类、鸻鹬类、鹤类、鹰隼类。据统计，25%的家禽疫情暴发点在12.1 km范围内有野鸟暴发疫情，50%在21.3 km范围内有野鸟疫情发生，80%在33 km范围内有野鸟疫情发生[43]，这一现象表明，野鸟与家禽发生疫情存在关联。回顾2014年开始的三波全球H5N8亚型HPAI疫情，大多数国家首先在野鸟中发现病毒，之后在家禽中暴发，且三波疫情均由迁徙候鸟携带并传播，导致野鸟及家禽的感染。每年全球大量的迁徙候鸟从分布在欧洲、亚洲、非洲、美洲等地区的越冬地沿着各自的迁徙通道迁徙到西伯利亚地区进行繁殖，之后又会沿着各自的路线迁徙到达越冬地。相互重叠的迁徙通道、直接或间接与病鸟或污染环境接触，导致候鸟间携带的AIV相互传播、重组，这促进了病毒的全球传播。 我国位于东亚-澳大利亚、中亚-印度、西亚-中非的重要迁徙通道上，特别是2020年以来，韩国、日本等邻国不断有H5N8亚型HPAI暴发的报道，2020年10月内蒙古自治区巴彦淖尔、2020年11月山西运城、2021年1月山东东营、2021年2月北京海淀区及江苏连云港等多地发生野生禽类H5N8亚型HPAI疫情。我们应警惕暴发大规模疫情，加强对野生鸟类特别是迁徙候鸟的禽流感主动监测，早发现、早预警。 3 H5N8亚型HPAIV具有重要的公共卫生意义

2014年韩国疫情期间，一只饲养在发生疫情养殖场的犬被检测到抗体，利用H5N8亚型HPAIV进行犬感染实验时，部分犬只出现体温升高的情况，但并未在其体内分离到病毒或者检测到抗体[44]。有实验证明，H5N8部分位点的突变会使其适应雪貂，从而导致雪貂感染[45]，并且不断有发现例如：PB1基因的P598L、PB2基因的K627E、HA基因的T156A等能导致病毒对哺乳动物毒力增强的突变。波兰分别在2016年11月和2017年4月，从两只灰海豹肺部样本中检测到2.3.4.4分支group B的H5N8亚型HPAIV[46]，与当时欧洲禽流感疫情暴发期间在野鸟中流行的H5N8亚型HPAIV同源性为99.7%–100%。两只海豹相隔5个月被感染，推测可能由野鸟的种间传播导致，但也不能排除灰海豹种内传播的可能。有研究发现，同属2.3.4.4分支group B的H5N6亚型HPAIV是由H5N8亚型AIV发生重组产生[47-48]，例如：2017年我国福建发生的人感染2.3.4.4分支group B的H5N6亚型HPAIV，是由2016年湖北黑天鹅H5N8亚型AIV与野鸟源H6N6亚型LPAIV重组产生，并在家禽中不断传播进化，最终由家禽传播给人类。 随着病毒的不断重组突变，跨物种传播能力逐渐显现。2020年12月，在俄罗斯南部一个暴发H5N8亚型HPAI疫情的养殖场中，首次发现人感染H5N8亚型HPAIV。7名被感染者为29至60岁的养殖场工人，被感染者尽管均为无症状感染，未发现人传人现象，但能确定的是H5N8亚型HPAIV已经具备了感染人的能力，不排除将来对人的毒力增强的可能。此次H5N8主要由家禽传染给人，并不具备人传人的能力。我们需对H5N8保持高度警惕，重视H5N8亚型HPAIV的公共卫生意义。 4 关于禽流感防控的建议

作为禽流感病毒的天然储存库，野生鸟类在禽流感病毒防控中的地位不容小觑：从来自多个国家的野生鸟类中检测到同源性极高的AIV，并通过进化分析论证，支持了AIV的全球传播是由迁徙候鸟驱动的这一理论，“野鸟→家禽→野鸟→家禽”的传播链促进病毒不断重组进化。对于野生鸟类，应加强主动监测，禁止非法贸易；发现野外死鸟应及时向相关部门报告。 作为重要的经济和食物来源，家禽的禽流感防控也应格外注意：(1) 严格限制和控制与家禽的接触：限制访客的数量和车辆，并让其尽可能远离禽舍，在进入养殖场时，应穿上清洁的工作服和鞋子，以避免将病毒带到养殖场；(2) 建立有效的野鸟及虫鼠防治制度：通过诱饵诱捕来监测野鸟、害虫及老鼠的活动，饲料仓库和饲喂槽必须定期清洁、维护和适当密封，以防止野鸟、鼠类等进入并污染饲料；(3) 避免将疾病状态不明的野鸟引入禽群：在养殖场周围设立围栏，不要在养殖场内存放可能吸引野鸟的物品，包括放置的家禽饲料产品等；(4) 在适当的情况下为家禽接种疫苗；(5) 若出现异常死亡情况，应向兽医部门报告，并在指导下采取正确措施，妥善处置粪便、垃圾及死禽，同时进行积极监测。 人类感染禽流感的主要风险因素是接触被感染的活禽、死禽或受污染的环境，如活禽市场；在家庭环境中，处理家禽生肉制品也是危险因素之一。个人应遵守良好的食品卫生安全以及手部卫生规范。应尽量避免前往已知暴发禽流感疫情的地区或国家，如需前往，应避免前往农场、活禽市场、动物屠宰场等与禽类密切接触的地方，避免接触任何疑似被动物粪便污染的表面。目前，还没有预防人类禽流感感染的疫苗，若住在或曾去过禽流感暴发的地区，并出现类似流感的症状，如发烧、咳嗽和呼吸困难，应立即就医，并说明相关情况。

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PLOS pathogens|廖明教授团队最新揭示H5N1禽流感病毒感染诱导鸡免疫损伤的关键宿主因子_腾讯新闻

PLOS pathogens|廖明教授团队最新揭示H5N1禽流感病毒感染诱导鸡免疫损伤的关键宿主因子_腾讯新闻

PLOS pathogens|廖明教授团队最新揭示H5N1禽流感病毒感染诱导鸡免疫损伤的关键宿主因子

近日，廖明教授/代曼曼副教授课题组在在国际知名期刊PLOS pathogens在线发表了题为“Dissection of key factors correlating with H5N1 avian influenza virus driven inflammatory lung injury of chicken identified by single-cell analysis”的研究论文，揭示了H5N1禽流感病毒感染诱导鸡免疫损伤的关键宿主因子。 

目前，关于鸡肺脏中免疫细胞对AIV感染的应答反应仍有许多关键问题尚未得到解答。特别是与宿主保护和免疫应答损伤相关的关键免疫细胞类型、抗病毒和炎症相关因子尚未得到系统研究和鉴定。课题组结合流式分选，SMART-Seq2单细胞测序等技术，系统解析了H5N1 AIV和H9N2 AIV感染后16种类型细胞中的病毒载量及其应答反应。

研究发现H9N2 AIV只能在部分细胞类型（如巨噬细胞和DC细胞等）中进行感染和复制，而H5N1 AIV能够广泛感染所有鉴定的细胞类型。与H9N2 AIV感染相比， H5N1 AIV能够同时在大部分细胞中诱导广泛病毒复制和免疫应答反应。炎性巨噬细胞、促炎细胞因子（IFN-β、IL1β、IL6和IL8），以及通过CCL4、CCL19和CXCL13发生的不同细胞之间的通讯互作，导致了H5N1 AIV感染诱导的炎性肺损伤。

图1. H9N2 AIV和H5N1 AIV感染后鸡肺脏单细胞图谱分析

（PLOS pathogens; Dai et al., 2023）

本研究丰富了家禽重要免疫细胞标记基因信息及其应答反应数据库，为禽流感病毒的有效控制提供新的靶点和方向，为深入研究家禽病毒与不同免疫细胞之间的互作奠定了重要基础。 

附文献信息：

Abstract：

Chicken lung is an important target organ of avian influenza virus (AIV) infection, and different pathogenic virus strains lead to opposite prognosis. Using a single-cell RNA sequencing (scRNA-seq) assay, we systematically and sequentially analyzed the transcriptome of 16 cell types (19 clusters) in the lung tissue of chickens infected with H5N1 highly pathogenic avian influenza virus (HPAIV) and H9N2 low pathogenic avian influenza virus (LPAIV), respectively. Notably, we developed a valuable catalog of marker genes for these cell types. Compared to H9N2 AIV infection, H5N1 AIV infection induced extensive virus replication and the immune reaction across most cell types simultaneously. More importantly, we propose that infiltrating inflammatory macrophages (clusters 0, 1, and 14) with massive viral replication, pro-inflammatory cytokines (IFN-β, IL1β, IL6 and IL8), and emerging interaction of various cell populations through CCL4, CCL19 and CXCL13, potentially contributed to the H5N1 AIV driven inflammatory lung injury. Our data revealed complex but distinct immune response landscapes in the lung tissue of chickens after H5N1 and H9N2 AIV infection, and deciphered the potential mechanisms underlying AIV-driven inflammatory reactions in chicken. Furthermore, this article provides a rich database for the molecular basis of different cell-type responses to AIV infection.

Author summary

The low-pathogenicity avian influenza virus (LPAIV), H9N2, and highly pathogenic avian influenza virus (HPAIV), H5N1 are the main epidemic subtypes, resulting in great economic losses on poultry and potentially threat to human. Thus, in-depth exploration of AIV pathogenesis in chickens is necessary for developing efficient control methods. In our study, using a single-cell RNA sequencing analysis of 16 cell types in the chicken lung, we revealed complicated and distinct immune response landscapes after H5N1 and H9N2 AIV infection, and identified key factors contributing to H5N1 AIV driven inflammatory lung injury. Therefore, our study potentially provides new targets and direction for AIV control.

科研进展 | 高福/刘金华团队合作揭开H3N8禽流感病毒感染人的潜在机理_腾讯新闻

科研进展 | 高福/刘金华团队合作揭开H3N8禽流感病毒感染人的潜在机理_腾讯新闻

科研进展 | 高福/刘金华团队合作揭开H3N8禽流感病毒感染人的潜在机理

H3N8禽流感病毒(AIVs)在中国于2022年导致两例确诊的人类感染，随后在2023年报告了一例致命病例。H3N8病毒在鸡群中广泛存在；然而，H3N8病毒的人畜共患特征尚不清楚。

2023年9月4日，中国农业大学刘金华及中国科学院微生物研究所高福共同通讯在Cell 在线发表题为”Airborne transmission of human-isolated avian H3N8 influenza virus between ferrets“的研究论文，该研究证明了H3N8病毒能够在器官型正常人支气管上皮细胞(NHBE)和肺上皮细胞(Calu-3)中有效地感染和复制。与鸡分离株相比，H3N8人分离株毒性更强，在小鼠和雪貂中引起严重病理。重要的是，从一名重症肺炎患者身上分离到的H3N8病毒可以通过呼吸道飞沫在雪貂之间传播；它获得了人类受体结合偏好和空气传播所需的氨基酸取代PB2-E627K。即使接种了人类H3N2病毒疫苗，人类群体对新出现的哺乳动物适应的H3N8 AIV似乎在免疫上”幼稚“，并且可能容易受到流行病或大流行比例的感染。

总之，来自中国鸡群的突发禽流感H3N8病毒似乎表现出越来越多的哺乳动物适应特征的积累，这些特征促进了水平传播和致病性。因此，需要及时检测病毒表型特征、诊断并通知疑似感染H3N8禽流感病毒的个体，以确保能够追踪、隔离接触者，并在必要时进行治疗，以控制传播并防止流行病/大流行的发展。

禽流感病毒(AIVs)是对全球公共卫生的持续威胁。H5N1、H7N9和H9N2亚型已引起散发的人感染AIV。历史上，只有H1、H2和H3亚型的甲型流感病毒会导致大流行，H1N1和H3N2病毒仍在世界各地的人类中广泛传播。因此，在人类中出现新的H1或H3亚型病毒是一个潜在的公共卫生问题。

2022年4月，在中国河南省1名4岁男童中发现一种新型禽流感H3N8病毒(A/Henan/4-10/2022 [HN/4-10])。这是第一例报告的人感染H3N8 AIV病病毒病例；患者出现严重的急性呼吸窘迫综合征，但痊愈。2022年5月，中国湖南省另一例禽流感H3N8病毒(A/Changsha/1000/2022 [CS/1000])病例在一名5岁男童中被诊断出来。该患者出现发热、发冷、喉咙痛和流鼻涕等轻度症状，7天后消退。

2023年3月27日，中国广东省报告了第三例确诊病例。该患者为一名56岁女性，因严重肺炎住院，随后死亡。所有3例人间病例均有活禽接触史，这表明禽类接触是H3N8 AIV传播的一个来源。流行的H3N8病毒是通过与欧亚鸟类H3基因、北美鸟类N8基因和H9N2内部基因的三重重组事件进化而来的。2022年，在中国的养鸡场和活禽市场频繁检测到H3N8病毒，动物研究表明，H3N8病毒在鸡体内具有良好的适应性。

文章模式图（图源自Cell ）

为研究新型H3N8病毒的人畜共患特征，采用人、鸡分离的病毒在体外培养的人呼吸道上皮细胞和哺乳动物模型中研究其感染性能。确定了宿主-受体结合偏好、病毒pH稳定性和聚合酶活性。还评估了人群中宿主对H3N8 AIV的免疫。

总之，来自中国鸡群的突发禽流感H3N8病毒似乎表现出越来越多的哺乳动物适应特征的积累，这些特征促进了水平传播和致病性。因此，需要及时检测病毒表型特征、诊断并通知疑似感染H3N8禽流感病毒的个体，以确保能够追踪、隔离接触者，并在必要时进行治疗，以控制传播并防止流行病/大流行的发展。

参考资料：

https://www.cell.com/cell/fulltext/S0092-8674(23)00891-7