上海地区人群甲型流感HA抗原进化与基因进化关系研究及H1N1流感潜在免疫显性位点的筛选
发布时间：2019-07-04 11:31
【摘要】： 流感是由流感病毒引起的具有高度传染性的一种急性呼吸道疾病,由于它的传播速度比较快,且流感病毒容易发生变异,所以每年都会造成不同规模的流感流行。本研究首先借助近几年对上海地区的流感监测信息通过构建抗原进化图谱和基因进化图谱呈现上海地区近年人群甲型H3N2和H1N1亚型流感病毒的抗原进化和基因进化特点,并深入探讨了其差异的原因。同时我们筛选出了人群甲型H1N1亚型流感病毒HA1片段的潜在免疫显性位点并建立了其抗原变异预测模型,主要内容和研究结果如下： 1.为研究上海地区近年来人群甲型H3N2和H1N1亚型流感病毒血凝素抗原进化和基因进化的特点,并深入探讨其抗原变异的规律,我们构建了相应的抗原进化图谱和基因进化图谱。结果显示上海地区2007-2008年甲型H3N2亚型流感病毒的抗原进化和基因进化基本上按各年份有聚集趋势,大体来说比较相似。2007和2008年的部分病毒株之间存在着抗原交叉,可能会有交叉保护。2008年上海流行株和现在的疫苗株A/Brisbane/10/2007虽然HA1基因上变异不大,但在可能的潜在免疫显性位点194处发生了变异,所以现行疫苗株可能对上海地区人群不能提供足够有效的免疫保护。研究结果同时显示上海地区2005-2008年甲型流感病毒H1N1亚型的抗原进化图谱和基因进化图谱大体上都是按各年份聚集。我们发现140位点的变异可能是近年上海地区H1N1亚型流感病毒抗原进化的主要原因。虽有一定进化,但是部分病毒株彼此存在抗原交叉保护说明这几年H1N1进化还是比较缓慢。而对于病毒株A/Shanghai/MH79/2008由于疫苗株A/Brisbane/59/2007不能对其形成有效保护,应该对它以后在上海的流行要提高警惕。 为研究上海地区历年人群甲型H3N2亚型流感病毒的抗原进化和基因进化特点,我们根据H3N2抗原变异预测模型用基因序列数据预测了其抗原进化图谱,同时我们也构建了其HA1基因进化图谱。结果显示抗原进化和基因进化特点比较相似,都按年份呈现一定的规律性。 为研究全球历年人群甲型H1N1亚型流感病毒血凝素抗原进化和基因进化特点,我们构建了其抗原进化图谱和基因进化图谱。结果都显示各年份进化呈现一定的规律性,但各年份之间交叉比较明显,同时看出其基因进化呈现连续进化的过程,而抗原进化是个跳跃进化的过程,在氨基酸位点N54K、T127N、H193R处的变异可能是抗原进化跳跃最主要的原因。 2.我们重点研究了筛选人群甲型H1N1亚型流感病毒HA1片段潜在免疫显性位点的方法并建立其抗原变异预测模型。采用了SVM-RFE(linear)、SVM-RFE(RBF)以及随机森林模型作为筛选位点的方法,同时用支持向量机、随机森林模型和Ridge偏最小二乘回归作为预测模型,共10种组合方法,通过重复抽样技术在相同条件下比较了10种组合方法的预测效果,用验证分类误差、特异度和灵敏度作为预测效果好坏的评价指标。研究发现随机森林模型作为预测模型比其它预测模型的效果都要好,所以选用随机森林模型作为H1N1亚型流感病毒抗原变异的预测模型。随后确定了纳入模型的变量个数为30,此时SVM-RFE(linear)/RF、SVM-RFE(RBF)/RF和RF/RF的预测一致率分别为88.05%、88.05%和87.66%,预测效果都比较好。 本研究筛选出了人群甲型H1N1亚型流感病毒HA1片段的23个潜在免疫显性位点,分别是36,43,54,69,71,73,80,96,121,125,127,128,140,165,169,189,192,193,204,251,270,271,282,其中有10个属于抗原决定簇区域。我们识别出了上海H1N1亚型流感病毒抗原进化图谱中两簇差异最重要的位点140。同样全球历年人群甲型H1N1亚型流感病毒抗原进化图谱中两大类间发生变异的位点N54K、T127N、H193R也属于我们筛选出的23个潜在免疫显性位点,进一步映证了我们的研究结果可靠。 3.比较研究了新甲型H1N1流感病毒和中国分离的甲型H1亚型流感病毒HA基因序列,构建了其基因进化图谱。结果显示中国流行的人甲型H1亚型流感病毒以及WHO近年推荐的疫苗株和目前流行的新甲型H1N1流感病毒在HA基因进化上相距很远,从基因层面上提示我国人群既往免疫和疫苗可能不能提供有效保护。此外,新甲型H1N1流感和中国猪甲型H1亚型流感病毒在HA基因进化上仍然存在有一定的距离,表明这次始于北美的新甲型H1N1流感并不是来自于中国。 通过本研究,对上海地区近年来人群甲型流感病毒的抗原进化和基因进化过程有了直观的理解,同时深入了解了其抗原变异和基因变异的规律,为防控流感提供了有价值的线索。另外,筛选出的人群甲型H1N1亚型流感病毒HA1片段的潜在免疫显性位点为WHO选择流感疫苗和H1N1亚型流感病毒的进化研究提供了科学依据。我们建立的H1N1抗原变异预测模型可在不进行HI试验的情况下预测抗原变异情况,节省了大量的人力、物力和时间,提高了WHO选择流感疫苗株的效率。
文内图片：
图片说明：抗原进化图谱
[Abstract]:Influenza is a highly contagious, acute respiratory disease caused by the influenza virus, because it is fast in speed and the influenza virus is susceptible to variation, so each year will result in a different scale of influenza. In this study, the evolution and genetic evolution of influenza A (H3N2) and H1N1 (H1N1) virus in Shanghai in recent years were presented by means of the evolution of the antigen and the evolution of the gene, and the reason of the difference was also discussed. At the same time, we screened the potential immunodominant site of the HA1 fragment of the human influenza A (H1N1) subtype influenza virus and established its antigen variation prediction model. The main contents and the results of the study are as follows: 1. To study the characteristics of the evolution and gene evolution of the hemagglutinin antigen of influenza A (H3N2) and H1N1 (H1N1) influenza virus in Shanghai in recent years, and to probe into the law of its antigenic variation, we constructed the corresponding antigen evolutionary map and gene. The results show that the antigenic evolution and gene evolution of the influenza A H3N2 subtype influenza virus in Shanghai in 2007-2008 are basically similar in all years, and there is an anti-virus strain between 2007 and 2008. The original crossover may have cross-protection. In 2008, the Shanghai epidemic and the present vaccine strain A/ Bridlane/10/2007, while the HA1 gene was not large, but at the possible potential immunodominant site 194, the current vaccine strain may not provide enough effective immunity to the population in the Shanghai area The results of the study also show that the antigenic evolution and genetic evolution of the H1N1 subtype of the influenza A virus in Shanghai in 2005-2008 are generally in the following year. We found that the mutation of the 140 site may be the main cause of the evolution of the H1N1 influenza virus antigen in Shanghai in recent years. For reasons, there is some evolution, but some of the virus strains have an antigen cross-protection to each other, indicating whether the H1N1 evolution or the ratio in the past few years The virus strain A/ Shanhai/ MH79/2008 cannot be effectively protected by the vaccine strain A/ Bridane/59/2007, and it should be mentioned later in Shanghai In order to study the antigenic evolution and genetic evolution of the influenza A H3N2 subtype influenza virus in the Han population in Shanghai, we used the gene sequence data of the H3N2 antigen variant prediction model to predict its antigen evolution map, and we also constructed the HA. The results showed that the evolution of the antigen and the character of the evolution of the gene were similar, both in the same year. In order to study the evolution of the hemagglutinin antigen and the genetic evolution of the influenza A (H1N1) influenza virus in the global years, we constructed the antigen. The results show that the evolution of the evolution shows a certain regularity, but the cross-correlation between the different years is obvious, and the evolution of the gene is a process of continuous evolution, and the evolution of the antigen is a process of jumping and evolution, in the amino acid position. The variation at points N54K, T127N, H193R may be anti- 2. We focus on the potential immunodominant sites of the HA1 fragment of the influenza A (H1N1) influenza virus in the screening population. Based on the method of SVM-RFE (linear), SVM-RFE (RBF) and random forest model as the screening site, SVM-RFE (linear), SVM-RFE (RBF) and random forest model are used as the screening site, and the support vector machine, the random forest model and the Ridge partial least-squares regression are used. As a prediction model, a total of 10 combination methods were used, and the prediction effect of 10 combinations was compared under the same conditions by the repeated sampling technique, and the error, specificity and spirit of the method were used to verify the classification error. In this paper, the random forest model is selected as the H1N1 (H1N1) model as the prediction model, and the effect of the model is better than that of other prediction models. The prediction model of the variant of influenza virus antigen was determined. The number of variables included in the model was 30. At this time, the consistent rate of SVM-RFE (linear)/ RF, SVM-RFE (RBF)/ RF and RF/ RF was 88.05%, 88.05%, respectively. In this study,23 potential immunodominant sites,36,43,54,69,71,73,80,96,121,125,127,128,140,165,169,189,192,193,204,251,270,271, 282,10 of which belong to the region of the antigenic determinant. We identified the anti-influenza virus of the Shanghai H1N1 subtype. The most important sites of the two clusters in the original evolutionary map are the two major sites in the evolution of the influenza A (H1N1) influenza virus antigen in the same global calendar year. The mutation sites, N54K, T127N, and H193R, also belong to the 23 potential immunogens that we screened. The results of this study are more reliable.3. A comparison of the new influenza A (H1N1) virus and the Chinese-isolated influenza A (H1) The results show that the influenza A H1 subtype influenza virus in China and the vaccine strain recommended by WHO in recent years and the new influenza A (H1N1) virus in recent years are far from the evolution of the HA gene, from the gene level It is suggested that the prior immunization and the vaccine of the Chinese population may not provide effective protection. In addition, the new influenza A (H1N1) and the influenza A H1 subtype of the Chinese swine still have a certain distance in the evolution of the HA gene, indicating that this The new H1N1 influenza, which started in North America, is not from China. By this study, the evolution of the antigen and the evolution of the gene of the influenza A virus in the population in Shanghai in recent years have a visual understanding, and at the same time, it is well understood The law of antigenic variation and gene mutation provides a valuable clue for the prevention and control of influenza. In addition, the potential immunodominant position of the HA1 fragment of the influenza A/ H1N1 subtype influenza virus of the selected population is the WHO choice. The evolutionary study of the influenza vaccine and the H1N1 subtype of influenza virus provides a scientific basis. The model of the H1N1 antigen variation established by us can predict the variation of the antigen without the HI test and save the large amount.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R392.1
本文编号：2509883
文内图片：
图片说明：抗原进化图谱
[Abstract]:Influenza is a highly contagious, acute respiratory disease caused by the influenza virus, because it is fast in speed and the influenza virus is susceptible to variation, so each year will result in a different scale of influenza. In this study, the evolution and genetic evolution of influenza A (H3N2) and H1N1 (H1N1) virus in Shanghai in recent years were presented by means of the evolution of the antigen and the evolution of the gene, and the reason of the difference was also discussed. At the same time, we screened the potential immunodominant site of the HA1 fragment of the human influenza A (H1N1) subtype influenza virus and established its antigen variation prediction model. The main contents and the results of the study are as follows: 1. To study the characteristics of the evolution and gene evolution of the hemagglutinin antigen of influenza A (H3N2) and H1N1 (H1N1) influenza virus in Shanghai in recent years, and to probe into the law of its antigenic variation, we constructed the corresponding antigen evolutionary map and gene. The results show that the antigenic evolution and gene evolution of the influenza A H3N2 subtype influenza virus in Shanghai in 2007-2008 are basically similar in all years, and there is an anti-virus strain between 2007 and 2008. The original crossover may have cross-protection. In 2008, the Shanghai epidemic and the present vaccine strain A/ Bridlane/10/2007, while the HA1 gene was not large, but at the possible potential immunodominant site 194, the current vaccine strain may not provide enough effective immunity to the population in the Shanghai area The results of the study also show that the antigenic evolution and genetic evolution of the H1N1 subtype of the influenza A virus in Shanghai in 2005-2008 are generally in the following year. We found that the mutation of the 140 site may be the main cause of the evolution of the H1N1 influenza virus antigen in Shanghai in recent years. For reasons, there is some evolution, but some of the virus strains have an antigen cross-protection to each other, indicating whether the H1N1 evolution or the ratio in the past few years The virus strain A/ Shanhai/ MH79/2008 cannot be effectively protected by the vaccine strain A/ Bridane/59/2007, and it should be mentioned later in Shanghai In order to study the antigenic evolution and genetic evolution of the influenza A H3N2 subtype influenza virus in the Han population in Shanghai, we used the gene sequence data of the H3N2 antigen variant prediction model to predict its antigen evolution map, and we also constructed the HA. The results showed that the evolution of the antigen and the character of the evolution of the gene were similar, both in the same year. In order to study the evolution of the hemagglutinin antigen and the genetic evolution of the influenza A (H1N1) influenza virus in the global years, we constructed the antigen. The results show that the evolution of the evolution shows a certain regularity, but the cross-correlation between the different years is obvious, and the evolution of the gene is a process of continuous evolution, and the evolution of the antigen is a process of jumping and evolution, in the amino acid position. The variation at points N54K, T127N, H193R may be anti- 2. We focus on the potential immunodominant sites of the HA1 fragment of the influenza A (H1N1) influenza virus in the screening population. Based on the method of SVM-RFE (linear), SVM-RFE (RBF) and random forest model as the screening site, SVM-RFE (linear), SVM-RFE (RBF) and random forest model are used as the screening site, and the support vector machine, the random forest model and the Ridge partial least-squares regression are used. As a prediction model, a total of 10 combination methods were used, and the prediction effect of 10 combinations was compared under the same conditions by the repeated sampling technique, and the error, specificity and spirit of the method were used to verify the classification error. In this paper, the random forest model is selected as the H1N1 (H1N1) model as the prediction model, and the effect of the model is better than that of other prediction models. The prediction model of the variant of influenza virus antigen was determined. The number of variables included in the model was 30. At this time, the consistent rate of SVM-RFE (linear)/ RF, SVM-RFE (RBF)/ RF and RF/ RF was 88.05%, 88.05%, respectively. In this study,23 potential immunodominant sites,36,43,54,69,71,73,80,96,121,125,127,128,140,165,169,189,192,193,204,251,270,271, 282,10 of which belong to the region of the antigenic determinant. We identified the anti-influenza virus of the Shanghai H1N1 subtype. The most important sites of the two clusters in the original evolutionary map are the two major sites in the evolution of the influenza A (H1N1) influenza virus antigen in the same global calendar year. The mutation sites, N54K, T127N, and H193R, also belong to the 23 potential immunogens that we screened. The results of this study are more reliable.3. A comparison of the new influenza A (H1N1) virus and the Chinese-isolated influenza A (H1) The results show that the influenza A H1 subtype influenza virus in China and the vaccine strain recommended by WHO in recent years and the new influenza A (H1N1) virus in recent years are far from the evolution of the HA gene, from the gene level It is suggested that the prior immunization and the vaccine of the Chinese population may not provide effective protection. In addition, the new influenza A (H1N1) and the influenza A H1 subtype of the Chinese swine still have a certain distance in the evolution of the HA gene, indicating that this The new H1N1 influenza, which started in North America, is not from China. By this study, the evolution of the antigen and the evolution of the gene of the influenza A virus in the population in Shanghai in recent years have a visual understanding, and at the same time, it is well understood The law of antigenic variation and gene mutation provides a valuable clue for the prevention and control of influenza. In addition, the potential immunodominant position of the HA1 fragment of the influenza A/ H1N1 subtype influenza virus of the selected population is the WHO choice. The evolutionary study of the influenza vaccine and the H1N1 subtype of influenza virus provides a scientific basis. The model of the H1N1 antigen variation established by us can predict the variation of the antigen without the HI test and save the large amount.
【学位授予单位】：复旦大学
【学位级别】：博士
【学位授予年份】：2010
【分类号】：R392.1
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