关于H7N9发表在国际顶级刊物的文献（中英对照）
人感染一种新的禽源甲型流感病毒(H7N9)作者 ： Rongbao Gao et al
期刊名称：新英格兰医学杂志(NEJM)
发表时间：2013-04-11
索引：NEJM April 11, 2013
背景
禽类感染甲型H7流感病毒在世界范围有发生，但以前未观察到这个亚型流感病毒感染到亚洲人。2013年3月，中国上海或安徽3名城市居民，表现为进展迅速的下呼吸道感染，被发现是被一种新的重配禽源性甲型流感 (H7N9)病毒感染。
方法
我们获得和分析了来自这3名患者的临床、流行病学和病毒学资料。通过对呼吸道标本进行实时逆转录聚合酶链反应（RT-PCR）检测、病毒培养和序列分析检测流感病毒和其他呼吸道病毒。
结果
从所有3例患者的呼吸道标本中均分离到一种新的重配禽源甲型流感病毒，被鉴定为H7N9。测序分析揭示3株病毒所有基因都是禽源性，有6个内部的基因来自甲型禽流感(H9N2)病毒。在A/安徽/1/2013和A/上海/2/2013病毒株中发现在血凝素(HA)基因210环发生Q226L(H3编号)替代，但在A/上海/1/2013病毒中未发现此替代。所有3株病毒在HA基因150环中都鉴定出一个T160A突变，所有株3病毒在神经氨酸酶(NA)茎区发现5个氨基酸缺失。3例患者均表现为发热、咳嗽和呼吸困难。2例患者有近期禽类暴露史。胸部放射影像揭示弥漫性斑片影及实变。并发症包括急性呼吸窘迫综合征和多器官衰竭。3例患者均死亡。
结论
3例新的重配H7N9病毒感染患者均伴有严重和致死性呼吸病。(由中国国家基础研究项目和其他基金资助。)
作者名单
通讯作者
舒跃龙(Shu Yuelong）中国疾病预防控制中心病毒病预防控制所，国家卫生与计划生育委员会病毒重点实验室
袁正宏(Yuan Zhenghong）复旦大学上海医学院，基础医学院，医学分子病毒学重点实验室
并列第一作者（按论文中作者排序）
高荣保(Gao Rongbao）中国疾病预防控制中心病毒病预防控制所
曹 彬(Cao Bin）首都医科大学，北京呼吸病研究所，北京朝阳医院
胡芸文(Hu Yunwen）复旦大学上海医学院，上海市公共卫生临床中心
冯子建(Feng Zijian）中国疾病预防控制中心
王大燕(Dayan Wang）中国疾病预防控制中心病毒病预防控制所
胡万富(Hu Wanfu）安徽省疾病预防控制中心
陈 健(Chen Jian）上海市疾病预防控制中心
揭志军(Jie Zhijun）复旦大学，上海市第五人民医院
邱海波(Qiu Haibo）东南大学，中大医院
其他作者（按论文中作者排序）
许 可(Xu Ke）江苏省疾病预防控制中心
许学伟(Xu Xuewei）滁州疾病预防控制中心
卢洪洲(Lu Hongzhou）复旦大学上海医学院，上海公共卫生临床中心
朱闻斐(Zhu Wenfei）中国疾病预防控制中心病毒病预防控制所
高占成(Gao Zhancheng）北京大学人民医院
向妮娟(Xiang Nijuan）中国疾病预防控制中心
沈银忠(Shen Yinzhong）复旦大学上海医学院，上海公共卫生临床中心
何泽宝(He Zebao）复旦大学，上海市第五人民医院
顾 勇(Gu Yong）复旦大学,上海市第五人民医院
张志勇(Zhang Zhiyong）复旦大学上海医学院，上海公共卫生临床中心
杨 毅(Yang Yi）东南大学，中大医院
赵 翔(Zhao Xiang）中国疾病预防控制中心病毒病预防控制所
周 蕾(Zhou Lei）中国疾病预防控制中心
李晓丹(Li Xiaodan）中国疾病预防控制中心病毒病预防控制所
邹淑梅(Zou Shumei)中国疾病预防控制中心病毒病预防控制所
张 烨（Zhang Ye)中国疾病预防控制中心病毒病预防控制所
李希研（Li Xiyan)中国疾病预防控制中心病毒病预防控制所
杨 磊（Yang Lei)中国疾病预防控制中心病毒病预防控制所
郭俊峰（Guo Junfeng)中国疾病预防控制中心病毒病预防控制所
董 婕（Dong Jie)中国疾病预防控制中心病毒病预防控制所
李 群（Li Qun)中国疾病预防控制中心
董立波 (Dong Libo）中国疾病预防控制中心病毒病预防控制所
朱 云(Zhu Yun）中国疾病预防控制中心病毒病预防控制所
白 天(Bai Tian）中国疾病预防控制中心病毒病预防控制所
王世文(Wang Shiwen）中国疾病预防控制中心病毒病预防控制所
郝沛(Hao Pei）中国科学院上海巴斯德研究所
杨维中(Yang Weizhong）中国疾病预防控制中心
张彦平(Zhang Yanping）中国疾病预防控制中心
韩 俊(Han Jun）中国疾病预防控制中心病毒病预防控制所
余宏杰(Yu Hongjie）中国疾病预防控制中心
李德新(Li Dexin）中国疾病预防控制中心病毒病预防控制所
高 福 (Gao George F）中国疾病预防控制中心
武桂珍(Wu Guizhen）中国疾病预防控制中心病毒病预防控制所
王 宇(Wang Yu）中国疾病预防控制中心
BACKGROUND
Infection of poultry with influenza A subtype H7 viruses occurs worldwide, but the introduction of this subtype to humans in Asia has not been observed previously. In March 2013, three urban residents of Shanghai or Anhui, China, presented with rapidly progressing lower respiratory tract infections and were found to be infected with a novel reassortant avian-origin influenza A (H7N9) virus.
METHODS
We obtained and analyzed clinical, epidemiologic, and virologic data from these patients. Respiratory specimens were tested for influenza and other respiratory viruses by means of real-time reverse-transcriptase–polymerase-chain-reaction assays, viral culturing, and sequence analyses.
RESULTS
A novel reassortant avian-origin influenza A (H7N9) virus was isolated from respiratory specimens obtained from all three patients and was identified as H7N9. Sequencing analyses revealed that all the genes from these three viruses were of avian origin, with six internal genes from avian influenza A (H9N2) viruses. Substitution Q226L (H3 numbering) at the 210-loop in the hemagglutinin (HA) gene was found in the A/Anhui/1/2013 and A/Shanghai/2/2013 virus but not in the A/Shanghai/1/2013 virus. A T160A mutation was identified at the 150-loop in the HA gene of all three viruses. A deletion of five amino acids in the neuraminidase (NA) stalk region was found in all three viruses. All three patients presented with fever, cough, and dyspnea. Two of the patients had a history of recent exposure to poultry. Chest radiography revealed diffuse opacities and consolidation. Complications included acute respiratory distress syndrome and multiorgan failure. All three patients died.
CONCLUSIONS
Novel reassortant H7N9 viruses were associated with severe and fatal respiratory disease in three patients. (Funded by the National Basic Research Program of China and others.)
SARS发生十年后，H7N9禽流感再次引起中国社会的高度警惕作者 ： Mara Hvistendahl
期刊名称：Science
发表时间：2013-04-12
索引：Science 12 April 2013: Vol. 340 no. 6129 p. 130
Coming at the 10-year anniversary of the SARS outbreak, the Chinese government's announcement that a new influenza virus is killing people elicited suspicion from many Chinese. Why, some asked, did it take nearly 6 weeks after the first patient fell ill for the government to identify the H7N9 virus? But many scientists say that, while there are plenty of questions surrounding the new virus, China has actually come a long way when it comes to monitoring health and has been forthcoming with the international health community—a sharp contrast with the SARS episode, when it was unable to identify the new pathogen and tried to sweep a deadly epidemic under the rug.
新型禽流感病毒H7N9给中国带来的忧虑和困惑作者 ： Jon Cohen
期刊名称：Science
发表时间：2013-04-12
索引：Science 12 April 2013: Vol. 340 no. 6129 pp. 129-130
A novel bird flu virus, designated H7N9, has infected three humans in China, killing two of them. While the Chinese government has won praise for aggressively pursuing this outbreak and openly discussing its findings, how the confirmed cases became infected is a mystery. Still, many researchers are guardedly optimistic: There is no persuasive evidence that the virus spreads between people, an ability it would need to set off the next flu pandemic.
H7N9病毒通过变异更适宜于感染哺乳动物
作者 ： T Kageyama, S Fujisaki, E Takashita, H Xu, S Yamada, Y Uchida, G Neumann, T Saito, Y Kawaoka, M Tashiro
期刊名称：Eurosurveillance
发表时间：2013-04-11
索引：Eurosurveillance, Volume 18, Issue 15, 11 April 2013
近日一项在中国引发至少9人死亡的禽流感病毒引起了科学家的关注，对禽流感病毒的遗传分析显示，该病毒正在慢慢变异地更易于感染人类细胞，这就使得研究者更加关注全球禽流感病毒的大流行，并且确定其流行的潜在可能性。
刊登在国际杂志Eurosurveillance上的一篇研究报告中，来自日本国立传染病研究所等多个机构的研究者对来自病毒感染的受害者以及上海环境、禽类中的H7N9病毒进行了遗传测序分析研究。专家Kawaoka表示，患者机体中分离得到的毒株，和禽类以及环境中的并不同，其蛋白质发生了突变，这就使得其非常有可能在人类细胞中增殖，而且毒株更适于在人类上呼吸道的温度环境中生长增殖，而上呼吸道的温度低于鸟类的温度。
这项研究为新型禽流感病毒的流行提供了一定的分子线索，第一例H7N9患者是3月31日由中国疾控中心的研究者确证的，截至今日，这种新型病毒感染了至少33人，已经导致9人死亡。尽管研究者很早就预测其具有流行的潜力，但是证据显示，这种病毒正在变得易于感染人类，尤其是最终以人类为宿主进行感染传播。
解析病毒的遗传信息杜宇理解病毒如何变异，以及开发出新型疫苗预防感染非常重要。流感病毒依赖于吸附到宿主细胞上进行复制和扩散，而且禽流感病毒很少感染人类，但是有时候其却会变得易于感染人类，这就为人类健康带来了潜在的隐患。
禽流感病毒具有很多人流感病毒所具有的特点，这就使其易于感染人类，并且使得疾病流行。另外研究者发现，从病人中分离出的毒株包含另外一种突变，这就使得病毒可以在人类细胞中更加有效的复制。研究者指出，相同的突变可以使得禽流感病毒在人类上呼吸道的低温环境下正常生长增殖。
同样，研究者也预测了用于治疗人类流行性感染的药物，在治疗H7N9感染上的药物作用，发现一种常见的离子通道抑制剂抗病毒药物并不能有效控制病毒的感染和传播，而另外一种抗病毒药物奥司他韦可以却可以有效抑制病毒的发展。
Novel influenza viruses of the H7N9 subtype have infected 33 and killed nine people in China as of 10 April 2013. Their haemagglutinin (HA) and neuraminidase genes probably originated from Eurasian avian influenza viruses; the remaining genes are closely related to avian H9N2 influenza viruses. Several characteristic amino acid changes in HA and the PB2 RNA polymerase subunit probably facilitate binding to human-type receptors and efficient replication in mammals, respectively, highlighting the pandemic potential of the novel viruses.
Humans are rarely infected with avian influenza viruses, with the exception of highly pathogenic avian influenza A(H5N1) viruses, which have caused 634 infections and 371 deaths as of 12 March 2013 . A few isolated cases of human infection with viruses of the H7N2, H7N3, and H7N5 subtypes have been reported, but none were fatal . In 2003, in the Netherlands, 89 people were infected with an influenza virus of the H7N7 subtype that caused conjunctivitis and one fatality .
On 19 February 2013, an 87 year-old man in Shanghai developed a respiratory infection and died on 4 March, and on 27 February 2013, a 27 year-old pork seller in a Shanghai market became ill and died on 10 March. A 35 year-old woman in Chuzhou City in Anhui province (west of Shanghai), who had contact with poultry, became ill on 15 March 2013, and remains hospitalised in critical condition. There is no known epidemiological relationship among these three cases. A 38 year-old man in Hangzhou (Zhejiang province, south of Shanghai) became ill on 7 March 2013 and died on 27 March. All four cases presented with respiratory infections that progressed to severe pneumonia and breathing difficulties.
On 31 March 2013, the Chinese Centre for Disease Control and Prevention announced the isolation in embryonated eggs of avian influenza viruses of the H7N9 subtype (designated A/Shanghai/1/2013, A/Shanghai/2/2013, and A/Anhui/1/2013) from the first three cases. The sequences of the coding regions of all eight viral genes were deposited in the influenza sequence database of the Global Initiative on Sharing All Influenza Data (GISAID) on 31 March (Table 1). On 5 April 2013, the Hangzhou Center for Disease Control and Prevention deposited the haemagglutinin (HA), neuraminidase (NA), and matrix (M) gene sequences of A/Hongzhou/1/2013 virus (Table 1), which was isolated in cell culture from samples obtained from the 38 year-old man.
Figure 1. Phylogenetic analysis of the haemagglutinin (A) and neuraminidase (B) genes of the novel influenza A(H7N9) viruses, China, February - April 2013 (n=7)
Table 2. Nucleotide identity of novel influenza A(H7N9) virus genes and their closest relative, China, February - April 2013
The sequences of the remaining viral genes are closely related (>97% identity) to avian influenza A(H9N2) viruses, which recently circulated in poultry in Shanghai, Zhejiang, Jiangsu, and neighbouring provinces of Shanghai (Table 2, Figure 2). These findings strongly suggest that the novel influenza A(H7N9) viruses are reassortants that acquired their H7 HA and N9 NA genes from avian influenza viruses, and their remaining genes from recent influenza A(H9N2) poultry viruses (Figure 1, Figure 3, Table 2).
Figure 2. Phylogenetic analysis of the six remaining genes of the novel influenza A(H7N9) viruses, China, February – April, 2013 (n=7)
Figure3. Schematic diagram of novel influenza A(H7N9) virus generation
At the nucleotide level, A/Shanghai/2/2013, A/Anhui/1/2013, and A/Hangzhou/1/2013 share more than 99% identity and differ by no more than three nucleotides per gene, even though they were isolated in different cities several hundred kilometres apart. On 7 April 2013, the Harbin Veterinary Research Institute deposited the full genome sequences of isolates from a pigeon (A/pigeon/Shanghai/S1069/2013), a chicken (A/chicken/Shanghai/S1053/2013), and an environmental sample (A/environment/Shanghai/S1088/2013) that were collected on 2 and 3 April from a Shanghai market (Table 1). All eight genes of these three isolates are similar to those of A/Shanghai/2/2013 and A/Anhui/1/2013 at the nucleotide level, except for the PB1 gene of A/pigeon/Shanghai/S1069/2013, which belongs to a different lineage than the PB1 of the other H7N9 isolates (Figures 1 and 2).
Interestingly, A/Shanghai/1/2013 and A/Shanghai/2/2013 differ by 52 nucleotides (for example, there are 13 nucleotide and nine amino acid differences in their HA sequences) even though these two cases were identified in the same city and at around the same time. These findings suggest that A/Shanghai/2/2013, A/Anhui/1/2013, A/Hangzhou/1/2013, as well as the viruses from the chicken and the environment, share a closely related source of infection, whereas A/Shanghai/1/2013 and A/pigeon/Shanghai/S1069/2013 are likely to have originated from other sources.
Highly pathogenic avian influenza viruses are characterised by a series of basic amino acids at the HA cleavage site that enable systemic virus spread. The HA cleavage sequence of the novel influenza A(H7N9) viruses possesses a single basic amino acid (EIPKGR*GL; *indicates the cleavage site), suggesting that these viruses are of low pathogenicity in avian species.
The amino acid sequence of the receptor-binding site (RBS) of HA determines preference for human- or avian-type receptors. At this site, A/Shanghai1/2013 encodes an A138S* mutation (H3 numbering; Figure 4, Table 3), whereas A/Shanghai/2/2013, A/Anhui/1/2013, the two avian isolates, and the virus from the environmental sample encode G186V and Q226L mutations; any of these three mutations could increase the binding of avian H5 and H7 viruses to human-type receptors . The finding of mammalian-adapting mutations in the RBS of these novel viruses is cause for concern. The A/Hangzhou/1/2013 isolate encodes isoleucine at position 226, which is found in seasonal influenza A(H3N2) viruses.
Figure 4. Amino acid changes in the novel influenza A(H7N9) viruses that may affect their receptor-binding properties, China, February - April 2013 (n=7)
Table 3. Selected characteristic amino acids of the novel influenza A(H7N9) viruses, China, February - April 2013 (n=7)
In addition, all seven influenza A(H7N9) viruses possess a T160A substitution (H3 numbering; Table 3) in HA, which is found in recently circulating H7 viruses; this mutation leads to the loss of an N-glycosylation site at position 158 (H3 numbering; position 149 in H7 numbering), which results in increased virus binding to human-type receptors .
Lysine at position 627 of the polymerase PB2 protein is essential for the efficient replication of avian influenza viruses in mammals and has been detected in highly pathogenic avian influenza A(H5N1) viruses and in the influenza A(H7N7) virus isolated from the fatal case in the Netherlands in 2003 . PB2-627K is rare among avian H9N2 PB2 proteins (i.e. it has been found in only five of 827 isolates). In keeping with this finding, the avian and environmental influenza A(H7N9) viruses analysed here encode PB2-627E. By contrast, all four human H7N9 viruses analysed here encode PB2-627K (Table 3).
Antiviral compounds are the first line of defense against novel influenza viruses until vaccines become available. All seven novel influenza A(H7N9) viruses sequenced to date encode the S31N substitution in the viral ion channel M2 (encoded by the M segment) (Table 3), which confers resistance to ion channel inhibitors . Based on the sequences of their NA proteins, all H7N9 viruses analysed here, with the exception of A/Shanghai/1/2013, should be sensitive to neuraminidase inhibitors (Table 3). However, the R294K mutation in the NA protein of A/Shanghai/1/2013 is known to confer resistance to NA inhibitors in N2 and N9 subtype viruses , and is therefore of great concern.
All H7N9 viruses encode a deletion at positions 69–73 of the NA stalk region (Table 3), which is reported to occur upon virus adaptation to terrestrial birds. This finding suggests that the novel H7N9 viruses (or their ancestor) may have circulated in terrestrial birds before infecting humans. Moreover, this deletion is associated with increased virulence in mammals .
The influenza A virus PB1-F2 protein (encoded by the PB1 segment) is also associated with virulence. The available sequences indicate that the H7N9 PB1 genes of all of the human viruses encode a full-length PB1-F2 of 90 amino acids, but lack the N66S mutation that is associated with the increased pathogenicity of the 1918 pandemic virus and the highly pathogenic avian influenza A(H5N1) viruses . Interestingly, the pigeon isolate encodes a truncated PB1-F2 of only 25 amino acids; the significance of this truncation is unknown.
The NS1 protein (encoded by the NS segment) is an interferon antagonist with several functions in the viral life cycle. All available H7N9 NS1 sequences lack the C-terminal PDZ domain-binding motif; the lack of the PDZ domain-binding motif may attenuate these viruses in mammals .
Other amino acids in the NS1 and matrix (M1; encoded by the M segment) proteins of the novel viruses are also associated with increased virulence (Table 3) . However, these amino acids are found in many avian influenza viruses, and therefore, their significance for the biological properties of the novel influenza A(H7N9) viruses is currently unclear.
In conclusion, we here present a biological evaluation of the sequences of the avian influenza A(H7N9) viruses that caused fatal human infections in China. These viruses possess several characteristic features of mammalian influenza viruses, which are likely to contribute to their ability to infect humans and raise concerns regarding their pandemic potential.
对中国H7N9禽流感病毒感染者致死案例的分析研究作者 ： Feifei Yang, Jiali Wang, Lin Jiang, Jialin Jin, Lingyun Shao, Ying Zhang, Jiming Zhang, Xinhua Weng, Shu Chen and Wenhong Zhang
期刊名称：Emerging Microbes & Infections
发表时间：2013-04-10
索引：Emerging Microbes & Infections (2013) 2, e19
Since the highly pathogenic H5N1 avian influenza virus (AIV) was first transmitted from birds to humans in Hong Kong in 1997， other pathogenic AIVs， including H7N2， H7N3， H7N7， and H9N2 have been reported in China and other parts of the world.1，2，3，4 However， no human infections with the novel H7N9 virus have been reported until now from China. Here we report a fatal case caused by H7N9 AIV in the very early stage of this endemic.
A 52-year-old retired female resident in Shanghai was admitted to Fudan University affiliated Huashan Hospital due to 7-day history of pyrexia， accompanied by cough， chest stuffiness and dyspnea for the past two days. The patient had a sudden onset on March 27th， 2013 with rigors， and the highest temperature reached 40.6 °C but with no obvious symptoms of cough， pharyngalgia， stuffiness， dyspnea， nausea， vomiting， abdominal pain or diarrhea， and did not receive medication. The next day the patient visited emergency room and chest auscultation demonstrated rough breath sounds， absence of rales. Laboratory tests showed a leukocyte count of 5300/mm3， with 72% of neutrophils， and C reactive protein (CRP) of 26.8 mg/L. The patient was given antibiotics. On the third day， the patient took chest radiography and showed small patchy shadows in lower lobe of the right lung. The patient was given antibiotics intravenously for three consecutive days， still without cough， expectoration or shortness of breath， although her temperature was not resolved. On day 7 after onset of fever， due to quick progression of the symptoms， including cough， chest stuffiness and shortness of breath， the patient visited the emergency department of Fudan University affiliated Huashan Hospital again. Unfortunately， the arterial blood gas analysis showed severe hypoxemia， pH 7.54， PaCO2 4.33 kPa， PaO2 3.66 kPa， and saturation of oxygen 61.3% on room air. In the meantime， chest computed tomography (CT) demonstrated diffuse bilateral consolidation with right pleural effusion (Figure 1). Laboratory findings indicated a leukocyte count of 3290/mm3， with 92% of neutrophils and 5.5% of lymphocytes； platelets of 155 000/mm3； increased myocardial enzymes， prolonged prothrombin time and abnormal serum electrolytes. The patient was suspected severe flu with acute respiratory distress syndrome and thereafter was given endotracheal intubation and placed on a mechanical ventilator. Intravenous injection of methylprednisolone 40 mg was administered to inhibit inflammation and alleviate edema in the lung. On April 3rd (day 8)， antimicrobial regimen as well as immune globulin therapy and the methylprednisolone were maintained. However， the patient's condition worsened and died of acute respiratory distress syndrome.
谢谢蓝鱼老师的分享，下载与同仁分享{:1_1:} 蓝鱼o_0 发表于 2013-4-23 15:16 static/image/common/back.gif
SARS发生十年后，H7N9禽流感再次引起中国社会的高度警惕作者 ： Mara Hvistendahl
期刊名称：Science
发表 ...
很好的工作，正派上用场，谢谢了。{:1_17:}
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