本文選題：高通量測序 + 宏基因組�。� 參考：《北京協(xié)和醫(yī)學(xué)院》2013年博士論文

【摘要】：病毒是引起兒童急性呼吸道感染和中樞神經(jīng)系統(tǒng)感染的最主要的病原體。盡管目前應(yīng)用了多種檢測技術(shù),臨床上多數(shù)上述感染病例依然病原體不明。與以往傳統(tǒng)方法不同,高通量測序技術(shù)可以無需預(yù)知病原體的基因組信息而無偏倚地檢測臨床標(biāo)本中近乎所有的核酸背景,因而既可以用于病毒病原體的檢測也有助于一些新的以往未知的病毒病原體的發(fā)現(xiàn)。本研究即旨在應(yīng)用高通量測序技術(shù)對(duì)健康兒童和病原不明疑似急性病毒性呼吸道感染患兒的呼吸道標(biāo)本,以及常見腦炎相關(guān)病毒篩查陰性的疑似急性病毒性中樞神經(jīng)系統(tǒng)感染患兒的腦脊液標(biāo)本進(jìn)行分析,借助生物信息學(xué)方法了解上述各標(biāo)本中病毒群體的組成以及差異,為后續(xù)進(jìn)一步的探索疾病相關(guān)病毒病原體和新的未知病毒病原體提供前期研究基礎(chǔ)；同時(shí)探索建立一種有效的病毒檢測方法。 共選擇229份多種呼吸道病毒(包括部分常見的與近年新發(fā)現(xiàn)的呼吸道病毒)篩查均為陰性的疑似急性病毒性呼吸道感染患兒的鼻咽吸出物標(biāo)本、97份健康兒童的鼻咽拭子標(biāo)本、以及109份常見腦炎相關(guān)病毒篩查均為陰性的疑似病毒性中樞神經(jīng)系統(tǒng)感染患兒的腦脊液標(biāo)本。上述標(biāo)本首先按照每2-3份原始標(biāo)本混合成1份混合標(biāo)本的方式進(jìn)行預(yù)混,然后經(jīng)0.45/0.22μm濾膜過濾和DNase/RNase處理,提取純化核酸,進(jìn)而借助于序列非依賴性的隨機(jī)擴(kuò)增技術(shù)對(duì)純化的核酸進(jìn)行隨機(jī)擴(kuò)增,并對(duì)擴(kuò)增產(chǎn)物進(jìn)行Barcode標(biāo)記,等量混合擴(kuò)增產(chǎn)物構(gòu)建測序文庫。進(jìn)而完成454高通量測序,測序結(jié)果經(jīng)生物信息學(xué)分析,確定標(biāo)本中所有病毒同源序列。 急性呼吸道感染患兒與健康兒童呼吸道標(biāo)本的測序分別獲得2,642,142個(gè)和668,403個(gè)序列。在去除冗余序列、低質(zhì)量序列和屏蔽重復(fù)序列后,經(jīng)BLASTn和BLASTx比對(duì),兩組兒童的標(biāo)本分別獲得9,178個(gè)和1,205個(gè)含完整Barcode序列的非冗余病毒同源序列。急性呼吸道感染患兒標(biāo)本的檢出序列與來自于23個(gè)病毒科的58種不同的病毒顯示出不同程度的同源性,其中涵蓋了脊椎動(dòng)物和非脊椎動(dòng)物病毒、植物病毒和真核微生物病毒樣序列。最常檢出的病毒科包括Anelloviridae、Parvoviridae、Coronaviridae、Paramyxoviridae、Polyomaviridae和Orthomyxoviridae等。健康兒童標(biāo)本的檢出序列則與分屬于22個(gè)病毒科的39種病毒序列同源,涵蓋了脊椎動(dòng)物和非脊椎動(dòng)物病毒、植物病毒、真核微生物病毒和古細(xì)菌病毒。與急性呼吸道感染患兒不同,健康兒童標(biāo)本的檢出序列主要與來自于Anelloviridae、Polyomaviridae、Caliciviridae、Herpesviridae、Virgaviridae和Circoviridae等病毒科的病毒成員同源。在兩組人群的檢出序列中,部分檢出序列與數(shù)據(jù)庫中的病毒序列之間呈現(xiàn)出較低的Identity值,表明在所檢出的序列中可能含有一些來自于以往未知的病毒病原體的序列。 腦脊液標(biāo)本測序共獲得962,920個(gè)序列,平均讀長312bp。在經(jīng)過同上述相同的生物信息學(xué)分析后,共獲得1,061條含完整Barcode序列的非冗余病毒同源序列。這些非冗余序列的BLAST比對(duì)分析顯示他們與來自于25個(gè)病毒科的54種不同的病毒的序列具有相似性。Anelloviridae和Parvoviridae病毒科是序列比對(duì)分析中最常檢出的病毒科。這些檢出的病毒樣序列涵蓋了脊椎動(dòng)物和非脊椎動(dòng)物病毒、植物病毒、真核微生物病毒和古細(xì)菌病毒同源序列。除檢出了部分人和脊椎動(dòng)物病毒樣的序列,還同時(shí)檢出多種蟲媒病毒同源序列,如Brevidensovirus、Chloriridovirus和Densovirus等病毒的同源序列。與呼吸道標(biāo)本的測序結(jié)果相同,部分序列與數(shù)據(jù)庫中已知的病毒序列之間僅顯示出較低的同源性。 通過應(yīng)用病毒宏基因組學(xué)研究方法,我們獲得了兒童呼吸道標(biāo)本和腦脊液標(biāo)本中病毒群體的結(jié)構(gòu)和組成情況,研究結(jié)果顯示不同的臨床標(biāo)本以及不同的健康狀態(tài)下病毒群體的組成存在一定的差異,本研究中所獲得的序列信息同時(shí)也將為后續(xù)進(jìn)一步研究和探索疾病相關(guān)病毒提供了前期研究基礎(chǔ)。 人副腸孤病毒(human parechovirus, HPeV)是一種目前尚未被臨床工作者所熟知和了解,但在嬰幼兒腹瀉群體中并非鮮見的病原微生物,近些年有關(guān)其流行特征及與臨床疾病的相關(guān)性頗受關(guān)注。作為常規(guī)監(jiān)測的一部分,本研究的目的旨在了解近期HPeV在5歲以下急性腹瀉住院患兒人群中的流行情況,結(jié)合我們以往的監(jiān)測結(jié)果了解該病原體在本研究地區(qū)不同時(shí)期的流行特征的變化規(guī)律,以更全面的了解該病原體在本研究地區(qū)腹瀉兒童群體中的流行情況。 應(yīng)用基于HPeV5'UTR保守區(qū)的實(shí)時(shí)RT-PCR篩檢一整年期間內(nèi)收集的289份急性腹瀉住院患兒的糞便標(biāo)本。陽性標(biāo)本再經(jīng)巢式PCR擴(kuò)增VP3/VP1連接區(qū),回收目的擴(kuò)增產(chǎn)物并測序,系統(tǒng)進(jìn)化分析確定基因型別。所有臨床標(biāo)本同時(shí)進(jìn)行輪狀病毒、杯狀病毒、星狀病毒和腺病毒的酶免分析,以確定HPeV陽性標(biāo)本的合并感染情況。結(jié)合臨床資料和基因分型結(jié)果,了解每種基因型別的流行特征,以及統(tǒng)計(jì)分析HPeV的感染與臨床表征之間的相關(guān)性。 HPeV的全年檢出率為25.3%(73/289),其中95.9%(70/73)的感染病例發(fā)生在2歲以下的兒童,無性別差異,HPeV的檢出主要集中在7月-9月和11月,其中在8月份和11月份呈現(xiàn)兩個(gè)高峰流行季節(jié),而4月-5月則呈較低的流行。73例陽性標(biāo)本中56例確定了基因型別,分別為HPeV1-4型。其中HPeV1為最主要的檢出型別,流行主要集中在7月-9月之間,多數(shù)感染病例小于18月齡,無性別差異。與此同時(shí),本研究首次在國內(nèi)檢出2例較為罕見的HPeV2型。HPeV3型的檢出率為2.1%(6/289),感染患兒的平均年齡為9月齡。HPeV4型感染患兒的平均年齡12月齡,此外,核酸序列的比對(duì)顯示該基因型別具有其他基因型別所不具有的獨(dú)特的GAT (nt241-243)三核苷酸插入。64.4%(47/73)的HPeV感染患兒伴有合并感染,合并感染見于所檢出的四種基因型別。其中85.1%(40/47)的合并感染屬于雙重感染,輪狀病毒(29/47,61.7%)為最主要的合并感染病原體。在上述四種常見腹瀉病毒篩查均為陰性的患兒群體中,HPeV的檢出率為22.2%(26/117)。除了腹瀉癥狀外,嘔吐(42.3%,11/26)和呼吸道癥狀(11.5%,3/26)是HPeV單獨(dú)感染患兒最為常見的臨床表現(xiàn)。 HPeV的檢出率與以往我們關(guān)于該地區(qū)的監(jiān)測結(jié)果接近,但是流行的季節(jié)性與以往有所不同,此外,各基因型別也呈現(xiàn)出與過往不同的流行特征,表現(xiàn)為HPeV1的流行較往年提前了3個(gè)月,而在本研究中HPeV3型傾向于感染更加年幼的兒童,HPeV4型則更多的檢出于年長的兒童。本研究首次在國內(nèi)檢出了較為罕見的HPeV2型感染病例,并在HPeV4的核苷酸序列中檢出了該基因型別特有的GAT三核苷酸插入現(xiàn)象。合并感染的結(jié)果與以往的監(jiān)測結(jié)果類似,本研究的數(shù)據(jù)再次證實(shí)HPeV的感染與臨床表征之間并沒有顯著的相關(guān)性。
[Abstract]:Virus is the most important pathogen that causes acute respiratory infection and central nervous system infection in children. Although many detection techniques are used, most of these cases are still unknown. Unlike traditional methods, high throughput sequencing technology can not be used to predict the genome information of pathogens without bias. Detection of almost all nucleic acid backgrounds in clinical specimens, which can be used for detection of virus pathogens and the discovery of some new previously unknown viral pathogens. This study is intended to apply high throughput sequencing technology to respiratory specimens of healthy children and unsuspected acute viral respiratory infections in children. The cerebrospinal fluid specimens of children with acute viral central nervous system infection, which are negative for the common encephalitis related virus screening, are analyzed. By means of bioinformatics methods, the composition and differences of the virus groups in all the above specimens are understood and provided for further exploration of the disease related pathogens and the new unknown virus pathogens. At the same time, explore an effective virus detection method.
A total of 229 multiple respiratory viruses (including some common and newly discovered respiratory viruses) were screened for nasopharyngeal aspirates in children suspected of acute viral respiratory infection, 97 healthy children's nasopharyngeal swabs, and 109 common encephalitis related viruses were negative in the suspected virus. The cerebrospinal fluid specimens of the armature nervous system infected children were premixed in the way of mixing each 2-3 original specimens into 1 mixed specimens. The purified nucleic acid was extracted by 0.45/0.22 micron filter membrane filtration and DNase/RNase treatment, and then the purified nucleic acid was randomly expanded by random amplification of non dependent sequence. In addition, the amplified products were labeled with Barcode, and the same amount of mixed amplification products were constructed to construct the sequencing library. Then 454 high flux sequencing was completed. The sequencing results were analyzed by bioinformatics to determine all the virus homologous sequences in the specimens.
2642142 and 668403 sequences of respiratory tract specimens from children with acute respiratory infection and healthy children were sequenced respectively. After removing redundant sequences, low mass sequences and shielding repeated sequences, 9178 and 1205 intact Barcode sequences of non redundant viruses were obtained from two groups of children after BLASTn and BLASTx comparison. The detection sequence of children with acute respiratory infection showed different degrees of homology with 58 different viruses from 23 virus families, including vertebrate and invertebrate viruses, plant viruses and eukaryotic microorganism virus like sequences. The most frequently detected diseases include Anelloviridae, Parvoviridae, Coronavir. Idae, Paramyxoviridae, Polyomaviridae, Orthomyxoviridae and so on. The detection sequence of healthy children is homologous to the 39 virus sequences belonging to 22 families, including vertebrate and invertebrate virus, plant virus, eukaryotic microorganism virus and palaeobacteria virus. The detection sequence is homologous to the virus members from the Anelloviridae, Polyomaviridae, Caliciviridae, Herpesviridae, Virgaviridae and Circoviridae. In the detection sequence of the two groups, the partial detection sequence and the virus sequence in the database show a lower Identity value, indicating the sequence detected. It may contain some sequences from the previously unknown viral pathogens.
A total of 962920 sequences were sequenced in the cerebrospinal fluid samples. After the average reading length 312bp. was analyzed with the same bioinformatics analysis above, 1061 non redundant virus homologous sequences containing complete Barcode sequences were obtained. The BLAST alignment analysis of these non redundant sequences showed that they were with the sequence of 54 different viruses from 25 virus families. The similarity of.Anelloviridae and Parvoviridae is the most frequently detected sequence in sequence alignment. These detected sequences cover the sequence of vertebrate and invertebrate viruses, plant viruses, eukaryotic and palaeobacteria viruses, and the sequence of virus like parts of the vertebrates and vertebrates, The homologous sequences of a variety of OLV homologous sequences, such as Brevidensovirus, Chloriridovirus and Densovirus, are also detected at the same time. The same sequence is similar to that of the respiratory tract specimens, and the partial sequences only show a lower homology between the known virus sequences in the database.
By using the method of viral metagenomics, we obtained the structure and composition of the virus population in the children's respiratory and cerebrospinal fluid specimens. The results show that there are certain differences in the composition of the virus groups in different clinical specimens and in different health states. The sequence information obtained in this study is also the same. It will provide a preliminary research basis for further research and exploration of virus related diseases.
Human parechovirus (HPeV) is a kind of pathogenic microorganism which is not known and understood by clinical workers but is not rare in infantile diarrhea population. In recent years, its epidemic characteristics and its correlation with clinical diseases are concerned. As a part of regular monitoring, the purpose of this study is to understand the purpose of this study. In recent years, the prevalence of HPeV in hospitalized children with acute diarrhea under 5 years old, combined with our previous monitoring results to understand the changes in the epidemic characteristics of the pathogen in different periods of this area, in order to get a more comprehensive understanding of the prevalence of the pathogen in the diarrhoea children's body in this area.
The fecal specimens of 289 hospitalized children with acute diarrhoea collected during the whole year were screened by the real-time RT-PCR screening based on the conservative area of HPeV5'UTR. The positive specimens were amplified by nested PCR for the VP3/VP1 connection area, and the target amplified products were sequenced and sequenced. All clinical specimens were simultaneously rotavirus and goblet disease. Enzyme immunoassay for virus, stellate virus and adenovirus to determine the combined infection of HPeV positive specimens. Combined with clinical data and genotyping results, the epidemic characteristics of each genotype were understood and the correlation between HPeV infection and clinical characterization was statistically analyzed.
The annual detection rate of HPeV was 25.3% (73/289), of which 95.9% (70/73) infected cases occurred in children under 2 years of age, with no sexual difference. The detection of HPeV was mainly in July and November, in August and November, there were two peak epidemic seasons, and in April, 56 of the lower epidemic.73 positive specimens confirmed the genotype. HPeV1-4 type, respectively, HPeV1 is the most important detection type. The epidemic is mainly concentrated in July -9 months, most of the cases are less than 18 month old, and there are no sexual differences. At the same time, the detection rate of 2 cases of HPeV2 type.HPeV3 is 2.1% (6/289) for the first time in our country. The average age of the infected children is 9 month old.HPeV4. The average age of the infected children was 12 month old. In addition, the comparison of nucleic acid sequences showed that the unique GAT (nt241-243) trinucleotide (47/73) HPeV infection in children with other genotypes was associated with the combined infection, and the combined infection was found in the detected four genotypes. Among them, 85.1% (40/47) was associated with a sense of merger. 29/47,61.7% (rotavirus (29/47,61.7%) is the most common infection pathogen. In these four common children with negative diarrhea virus screening, the detection rate of HPeV is 22.2% (26/117). In addition to diarrhea symptoms, vomiting (42.3%, 11/26) and respiratory tract symptoms (11.5%, 3/26) are the most common cases of HPeV alone. Clinical manifestation.
The detection rate of HPeV is close to our previous monitoring results about the area, but the seasonal characteristics of the epidemic are different from that in the past. In addition, the genotypes also show a different epidemic characteristics, showing that the prevalence of HPeV1 is 3 months ahead of the previous year. In this study, the HPeV3 type tends to infect younger children, HPeV4 type. A more rare case of HPeV2 infection was detected in this study for the first time in China, and the GAT trinucleotide insertion of the genotype was detected in the nucleotide sequence of HPeV4. The results of the combined infection were similar to those of previous monitoring results. The data of this study confirmed the infection of HPeV again. There was no significant correlation between clinical manifestations.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R725.1

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