【摘要】：研究背景人感染禽流感是禽流感病毒跨種傳播引起的人類疾病。繼H5N1、H9N2、 H7N7、H7N2、H7N3和H10N8禽流感病毒感染人類之后,2013年2月我國(guó)華東地區(qū)首次出現(xiàn)人感染新型H7N9亞型禽流感病例,因其引起的臨床重癥及高病死率,迅速引起全球關(guān)注。雖然病例呈散發(fā)態(tài)勢(shì),但國(guó)內(nèi)已有部分省份數(shù)起家庭聚集性病例的報(bào)告,其流行的潛力,依然是嚴(yán)重的公共衛(wèi)生問(wèn)題。已確診的H7N9禽流感病例中80%以上有禽或禽類相關(guān)環(huán)境(活禽市場(chǎng))暴露史,傳播途徑主要是由禽到人的傳播。若能在人感染H7N9禽流感疫情流行的早期及時(shí)發(fā)現(xiàn)被H7N9禽流感病毒污染的場(chǎng)所,并采取對(duì)應(yīng)的防控措施如關(guān)閉活禽市場(chǎng)等,將最大可能減少病例的發(fā)生,達(dá)到有效的防控效果。禽流感病毒要突破種間屏障感染人必須發(fā)生受體結(jié)合偏好性改變,這種偏好性取決于病毒HA受體結(jié)合位點(diǎn)的關(guān)鍵氨基酸,病毒重要蛋白NA、聚合酶PB1/PB2/PA等關(guān)鍵功能位點(diǎn)上氨基酸的差異是決定病毒毒力和跨種傳播的分子基礎(chǔ)。目前抗流感病毒的藥物主要為針對(duì)NA的神經(jīng)氨酸酶抑制劑和M2離子通道抑制劑,這兩種蛋白耐藥位點(diǎn)關(guān)鍵氨基酸突變會(huì)導(dǎo)致耐藥毒株的出現(xiàn)。本研究通過(guò)山東省2013年至2015年7例人感染H7N9禽流感病例流行病學(xué)調(diào)查資料和疫情發(fā)生地外環(huán)境污染狀況調(diào)查資料,分析病例發(fā)病特點(diǎn)以及感染來(lái)源,尋找防控重點(diǎn)；通過(guò)毒株遺傳進(jìn)化及關(guān)鍵氨基酸位點(diǎn)分析,掌握毒株進(jìn)化特征及其致病性,指導(dǎo)早期臨床用藥,也為進(jìn)一步闡明H7N9禽流感病的致病機(jī)制提供科學(xué)依據(jù)。研究目的1、通過(guò)H7N9禽流感確診病例個(gè)案調(diào)查資料,分析病例流行病學(xué)特點(diǎn)；對(duì)家庭聚集性病例的感染來(lái)源、傳播方式和防控措施進(jìn)行分析,為有效防控人感染H7N9禽流感疫情提供科學(xué)依據(jù)；2、通過(guò)對(duì)疫情發(fā)生地周圍活禽市場(chǎng)及家禽養(yǎng)殖場(chǎng)的環(huán)境標(biāo)本的調(diào)查資料分析,初步探討外環(huán)境H7N9禽流感病毒污染情況,尋找防控重點(diǎn),對(duì)早期發(fā)現(xiàn)、預(yù)防疫情的發(fā)生提供參考；3、通過(guò)病毒遺傳進(jìn)化及關(guān)鍵氨基酸位點(diǎn)分析,研究病毒來(lái)源、基因組特征以及相互間的分子差異,掌握山東省H7N9禽流感病毒進(jìn)化特征及其致病性,并對(duì)早期臨床用藥進(jìn)行指導(dǎo),為進(jìn)一步闡明H7N9禽流感病的致病機(jī)制提供科學(xué)依據(jù)。研究方法1、描述性流行病學(xué)：對(duì)病例流行病學(xué)資料整理分析,描述病例流行病學(xué)特征和發(fā)病特點(diǎn)；對(duì)疫情發(fā)生地周圍活禽市場(chǎng)及家禽養(yǎng)殖場(chǎng)H7N9禽流感病毒污染狀況調(diào)查資料整理分析,描述外環(huán)境H7N9禽流感病毒污染情況。2、禽流感病毒核酸提取與檢測(cè)：應(yīng)用實(shí)時(shí)熒光定量PCR對(duì)標(biāo)本中H7N9禽流感病毒核酸進(jìn)行檢測(cè),Ct值≤40.0的樣本為陽(yáng)性。3、禽流感病毒分離：對(duì)7例病人深部呼吸道標(biāo)本及58份環(huán)境H7N9陽(yáng)性標(biāo)本用SPF雞胚進(jìn)行病毒分離,并鑒定。4、遺傳進(jìn)化及關(guān)鍵氨基酸位點(diǎn)分析：基因測(cè)序由國(guó)家流感中心幫助完成。利用NCBI提供的BLAST程序進(jìn)行序列比對(duì)；分離株間8基因片段同源性使用DNAStar軟件中MegAlign程序進(jìn)行多序列同源性計(jì)算；使用Mega6.0軟件進(jìn)行基因進(jìn)化樹的建立；在ExPASy網(wǎng)站PROSITE數(shù)據(jù)庫(kù)對(duì)HA和NA蛋白N-糖基化位點(diǎn)進(jìn)行預(yù)測(cè)。結(jié)果1、人感染H7N9禽流感病例流行病學(xué)特征：(1)山東省7例人感染H7N9禽流感病例發(fā)病季節(jié)在冬春季(每年12月至次年5月)；病例以50歲以上中老年男性人群為主；(2)病例從暴露到發(fā)病最長(zhǎng)時(shí)間間隔為9天,最短的每天都暴露,潛伏期為5天；從發(fā)病到確診時(shí)間間隔1-16天,時(shí)間間隔中位數(shù)為7天；(3)山東省確診的H7N9禽流感病例感染來(lái)源主要是禽暴露或者訪問(wèn)活禽市場(chǎng)；(4)2起家庭聚集性疫情,其中1起有足夠的證據(jù)證明H7N9禽流感病毒的人間傳播,但傳播能力有限。2、H7N9環(huán)境污染狀況：(1)山東省檢出的H7N9禽流感病毒均來(lái)源于活禽市場(chǎng),雞養(yǎng)殖場(chǎng)禽類外環(huán)境標(biāo)本中均未檢出；(2)棗莊、煙臺(tái)和泰安三地活禽市場(chǎng)中H7N9禽流感病毒檢出率為12.8%,同時(shí)檢測(cè)到H7N9、H5和H9亞型禽流感病毒。3、山東省H7N9分離株遺傳進(jìn)化與關(guān)鍵氨基酸位點(diǎn)分析：(1)2013-2015年分離的H7N9禽流感病毒與同期國(guó)內(nèi)江西、浙江、江蘇和湖南流行的H7N9禽流感病毒高度同源,同源性為99%-100%；本土病例分離到的病毒與活禽市場(chǎng)環(huán)境中的病毒基因高度同源；活禽市場(chǎng)環(huán)境中或病例的病毒基因與鄰近省份病毒基因有較高的相似性；(2)山東省首起疫情分離的3株H7N9禽流感病毒H7血凝素基因來(lái)源于浙江鴨H7N3禽流感病毒的HA基因,NA基因來(lái)源于韓國(guó)野鳥的H7N9禽流感病毒,其余6個(gè)基因片段均來(lái)源于中國(guó)H9N2禽流感病毒；(3)2013-2015年H7N9禽流感病毒基因不斷發(fā)生進(jìn)化,并分化成不同的分支,部分H7N9禽流感病毒的6個(gè)內(nèi)部基因片段與H9N2病毒發(fā)生了重組；(4)本研究涉及的15個(gè)毒力相關(guān)位點(diǎn)中,有7個(gè)毒力增強(qiáng)位點(diǎn)；山東省5株人感染H7N9禽流感毒株均對(duì)神經(jīng)氨酸酶抑制劑仍然敏感,但耐離子通道抑制劑類藥物。結(jié)論1、山東省病例季節(jié)分布以冬春季為主,中老年男性人群可能是該病的危險(xiǎn)人群,傳播途徑為禽到人或環(huán)境(活禽市場(chǎng)/宰殺點(diǎn))到人,存在有限的人與人的傳播；2、活禽市場(chǎng)是人感染禽流感病毒的主要來(lái)源地,活禽市場(chǎng)外環(huán)境中存在多種亞型的禽流感病毒,不排除發(fā)生重組的可能性；3、山東省存在多個(gè)起源的H7N9禽流感病毒,H7N9禽流感病毒在傳播中不斷發(fā)生變異和進(jìn)化,并分化成不同的小分支。山東省分離到的H7N9禽流感病毒來(lái)源于當(dāng)?shù)鼗钋菔袌?chǎng),當(dāng)?shù)鼗钋菔袌?chǎng)的H7N9禽流感病毒來(lái)源于長(zhǎng)三角地區(qū)。目前尚未獲得經(jīng)飛沫傳播的充分條件,但同時(shí)病毒正在向適合感染哺乳類動(dòng)物的方向發(fā)展。H7N9病毒尚未對(duì)神經(jīng)氨酸酶抑制劑類藥物(如達(dá)菲)產(chǎn)生耐藥性,在病例發(fā)生早期使用達(dá)菲進(jìn)行治療可能減少重癥發(fā)生、縮短病程、提高治愈率。
[Abstract]:Background human infection of avian influenza is a human disease caused by the spread of avian influenza virus. Following H5N1, H9N2, H7N7, H7N2, H7N3 and H10N8 avian influenza virus infection, the first human infection of the new avian influenza avian influenza cases in eastern China in February 2013 has been caused by the severe clinical severity and high mortality. Note. Although the cases are sporadic, there are reports of family aggregation cases in some provinces in China, the potential of which is still a serious public health problem. More than 80% of the confirmed H7N9 avian influenza cases have the exposure history of poultry or poultry related environment (live poultry market), and the transmission routes are mainly from poultry to human transmission. The early detection of the epidemic of H7N9 avian influenza epidemic and the timely detection of the sites contaminated by the H7N9 avian influenza virus and the corresponding prevention and control measures, such as closing the live poultry market, will most likely reduce the occurrence of cases and achieve effective prevention and control effects. This preference depends on the key amino acids of the binding site of the virus HA receptor, the difference in amino acids on the key functional sites, such as the viral important protein NA and the polymerase PB1/PB2/PA, is the molecular basis for determining the virulence and trans species transmission of the virus. The current anti influenza virus drugs are mainly anti NA inhibitors of neuraminidase and the M2 ion channel. The key amino acid mutation of these two protein resistance loci could lead to the emergence of drug resistant strains. This study analyzed the epidemiological investigation data of 7 cases of H7N9 avian influenza infection from 2013 to 2015 in Shandong province and the investigation data of the situation of the outbreak of the epidemic situation, analyzed the characteristics of the disease and the source of the infection, and looked for the key point of prevention and control. Through the genetic evolution and analysis of key amino acid sites, the evolutionary characteristics and pathogenicity of the strains were mastered, the early clinical medication was guided, and the scientific basis for further clarifying the pathogenesis of H7N9 avian influenza was provided. Objective 1, the epidemiological characteristics of cases were analyzed through the cases of H7N9 avian influenza, and the epidemiological characteristics of cases were analyzed. The source of infection, the mode of transmission and the prevention and control measures were analyzed to provide a scientific basis for the prevention and control of human infection of H7N9 avian influenza. 2, through the analysis of the environmental specimens in the live poultry market and poultry farms around the outbreak area, the preliminary study of the environment of the H7N9 avian influenza virus in the external environment was conducted to find the prevention and control of the virus. The key point is to provide reference for early detection and prevention of the occurrence of the epidemic. 3, through the genetic evolution of the virus and analysis of the key amino acid sites, the origin of the virus, the characteristics of the genome and the molecular differences between each other are studied, and the evolution characteristics and pathogenicity of the H7N9 avian influenza virus in Shandong province are mastered, and the early clinical medication is guided to further clarify the H A scientific basis for the pathogenesis of 7N9 avian influenza disease was provided. 1, descriptive epidemiology: an analysis of the epidemiological data of cases, the description of the epidemiological characteristics and the characteristics of the cases, the analysis of the contamination status of the H7N9 avian influenza virus in the live poultry market and poultry farm, and the description of the outer ring. H7N9 avian influenza virus contamination situation.2, avian influenza virus nucleic acid extraction and detection: using real-time fluorescent quantitative PCR to detect H7N9 avian influenza virus nucleic acid, Ct value less than 40 samples were positive.3, avian influenza virus isolation: 7 cases of deep respiratory tract specimens and 58 environmental H7N9 positive specimens were used to carry out the virus of SPF chicken. Separation, and identification of.4, genetic evolution and analysis of key amino acid sites: gene sequencing was completed by the National Influenza Center. The BLAST program provided by the NCBI was used for sequence alignment; the homology of the 8 gene fragment between isolated strains was calculated by the MegAlign program in the DNAStar software, and the Mega6.0 software was used to carry out the gene entry. The establishment of the tree and the prediction of the HA and NA protein N- glycosylation sites on the ExPASy PROSITE database. Results 1, the epidemiological characteristics of human infected H7N9 avian influenza cases were: (1) 7 cases of human infection with H7N9 avian influenza in Shandong province were in winter and spring (from December to May); the cases were dominated by middle-aged and elderly men over 50 years old; (2) the longest time interval from exposure to onset was 9 days, the shortest day was exposed and the incubation period was 5 days; the interval from onset to diagnosis was 1-16 days, the median of time interval was 7 days; (3) the main source of H7N9 avian influenza case infection in Shandong province was avian exposure or visitors to live poultry market; (4) 2 family aggregated epidemic situation, of which 1 There is sufficient evidence to prove the spread of H7N9 avian influenza virus, but the transmission capacity is limited.2, H7N9 environmental pollution status: (1) the H7N9 avian influenza virus detected in Shandong province all originate from the live poultry market, and the chicken breeding farm outside the poultry environment specimens are not detected; (2) the detection of H7N9 avian influenza virus in the live poultry market in three places in Zaozhuang, Yantai and Tai'an. The rate was 12.8%, and H7N9, H5 and H9 subtype avian influenza virus.3 were detected. The genetic evolution and key amino acid site analysis of H7N9 isolates in Shandong province were analyzed. (1) the 2013-2015 year isolated H7N9 avian influenza virus was highly homologous to the prevalent H7N9 avian influenza virus in Jiangxi, Zhejiang, Jiangsu and Hunan, and the homology was 99%-100%; local cases were separated. The virus is highly homologous to the virus gene in the live bird market environment; the virus gene in the live bird market environment or the case has a high similarity with the adjacent province virus gene; (2) the first H7N9 avian influenza H7 hemagglutinin gene from Shandong province is derived from the HA gene of the H7N3 avian influenza virus of Zhejiang duck and the NA gene source. In South Korea, the H7N9 avian influenza virus of wild birds, the remaining 6 genes are derived from China's H9N2 avian influenza virus; (3) 2013-2015 years of H7N9 avian influenza virus gene constantly evolved, and differentiated into different branches, some of the 6 internal gene fragments of the H7N9 avian influenza virus were reorganized with the H9N2 virus; (4) 15 poison involved in this study. Among the force related loci, there are 7 virulence enhancement sites, and 5 strains of human infected H7N9 avian influenza in Shandong province are still sensitive to neuraminidase inhibitors, but they are resistant to ion channel inhibitors. Conclusion 1, the seasonal distribution of the cases in Shandong province is mainly in winter and spring, and the middle aged and old men can be the dangerous population of the disease and the transmission route is bird to human. Or the environment (live poultry market / slaughtering point) to people, there is limited human and human transmission; 2, live poultry market is the main source of human infection of avian influenza virus, there are many subtypes of avian influenza virus in the outside environment of live poultry, and the possibility of reorganization does not exclude; and 3, there are several H7N9 avian influenza viruses, H7N9 avian influenza, in Shandong province. The H7N9 avian influenza virus isolated from Shandong province is derived from the local live poultry market, and the H7N9 avian influenza virus in the local live poultry market is derived from the Yangtze River Delta region. The development of.H7N9 virus in dairy animals has not yet produced resistance to neuraminidase inhibitors, such as Tamiflu. Early use of Tamiflu for treatment may reduce the incidence of severe disease, shorten the course of the disease, and improve the cure rate.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2016
【分類號(hào)】：R511.7

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