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
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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。
Influenza is a highly contagious acute respiratory disease which was caused by influenza virus. Because of high genetic variation of the virus, it infected the population again and again with high incidence. Antigenic evolution map and genetic evolution map were used to visualize antigenic and genetic evolution of human influenza A/H1N1 and A/H3N2 viruses in Shanghai area in recent years. Potential immunodominant positions of human influenza A/H1N1 viruses were identified and bioinformatics models for predicting antigenic variants of human influenza A/H1N1 viruses were proposed.
The details as follow:
1. Antigenic evolution map and genetic evolution map of human influenza A/H1N1 and A/H3N2 viruses in Shanghai area in recent years were constructed. The results showed that strains of influenza A/H3N2 viruses from 2007 to 2008 were gathered together according to the year in the antigenic evolution map and genetic evolution map. There existed cross protection between some strains from 2007 and 2008. The mutation at the amino acid position 194 makes vaccine may not provide a effective protective immunity. The results also showed that strains of influenza A/H1N1 viruses from 2005 to 2008 were gathered together according to the year in the antigenic evolution map and genetic evolution map. The mutation at the amino acid position 140 may be responsiable for the antigenic variation of influenza A/H1N1 viruses in Shanghai area in recent years. There existed cross protection between some strains, which shows that influenza A/H1N1 viruses evolve relatively slowly in Shanghai area in recent years. The cross protection between A/Shanghai/MH79/2008 and A/Brisbane/59/2007 was feeble, which should arouse our attention.
Antigenic prediction models of human influenza A/H3N2 viruses were implemented to predict antigenic distances based on the differences of amino acid sequences. Antigenic evolution map of human influenza A/H3N2 viruses in Shanghai area over the years was constructed. The results showed that the characteristics of antigenic evolution and genetic evolution were generally similar.
Antigenic evolution map and genetic evolution map of human influenza A/H1N1 viruses in the world over the years were constructed. The results showed that there exist some regularity in the evolution and some strains were interspersed. The results also showed the genetic evolution was continuous and the antigenic evolution was puctuated. The mutation at the amino acid position 54,127,193 may be responsiable for the antigenic gap.
2. Statistical models for predicting antigentic variants of human influenza A/H1N1 viruses were studied. SVM-RFE(linear), SVM-RFE(RBF), Random forest were used for variable selection. SVM, Random forest, RidgePLS were used as prediction models. Agreement rate, sensitivity, specificity were calculated for evaluating the qualitative performance of the models. The results showed that Random forest was the best model for predicting antigentic variants of human influenza A/H1N1 viruses. The number of variables for prediction models was chosen, which is 30. The agreement rate for SVM-RFE(linear)/RF, SVM-RFE(RBF)/RF, RF/RF were 88.05%,88.05%,87.66%.
Therefore,23 positions (position 36,43,54,69,71,73,80,96,121,125,127, 128,140,165,169,189,192,193,204,251,270,271 and 282) were identified as potential immunodominant positions of human influenza A/H1N1 viruses.
3. Comparative study on genetic evolution of hemagglutinin between novel influenza A (H1N1) virus and influenza A virus subtype H1 from China. The results showed that there were distant evolutionary relationships between novel influenza A (H1N1) virus HA gene and human influenza A virus subtype H1 HA gene from China, influenza vaccine. At the gene level in China population immunity and vaccine might not provide protection against novel influenza A (H1N1) virus. There was still a little evolutionary distance between novel influenza A (H1N1) virus HA gene and swine influenza A virus subtype H1 HA gene from China. There was no evidence that novel influenza A (H1N1) virus might originate in China.
While carrying out the above work, antigenic and genetic evolution of human influenza A/H1N1 and A/H3N2 viruses in Shanghai area in recent years were intuitively understood. The genetic evolution and antigenic variation rule of influenza A viruses were explored. Valuable clues were provided for the prevention and control of influenza. Meanwhile, identifying potential immunodominant positions can assist the annual selection of influenza vaccine strains. The prediction models for antigentic variants of human influenza A/H1N1 viruses may further improve the selection of vaccine strains.
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。
Influenza is a highly contagious acute respiratory disease which was caused by influenza virus. Because of high genetic variation of the virus, it infected the population again and again with high incidence. Antigenic evolution map and genetic evolution map were used to visualize antigenic and genetic evolution of human influenza A/H1N1 and A/H3N2 viruses in Shanghai area in recent years. Potential immunodominant positions of human influenza A/H1N1 viruses were identified and bioinformatics models for predicting antigenic variants of human influenza A/H1N1 viruses were proposed.
The details as follow:
1. Antigenic evolution map and genetic evolution map of human influenza A/H1N1 and A/H3N2 viruses in Shanghai area in recent years were constructed. The results showed that strains of influenza A/H3N2 viruses from 2007 to 2008 were gathered together according to the year in the antigenic evolution map and genetic evolution map. There existed cross protection between some strains from 2007 and 2008. The mutation at the amino acid position 194 makes vaccine may not provide a effective protective immunity. The results also showed that strains of influenza A/H1N1 viruses from 2005 to 2008 were gathered together according to the year in the antigenic evolution map and genetic evolution map. The mutation at the amino acid position 140 may be responsiable for the antigenic variation of influenza A/H1N1 viruses in Shanghai area in recent years. There existed cross protection between some strains, which shows that influenza A/H1N1 viruses evolve relatively slowly in Shanghai area in recent years. The cross protection between A/Shanghai/MH79/2008 and A/Brisbane/59/2007 was feeble, which should arouse our attention.
Antigenic prediction models of human influenza A/H3N2 viruses were implemented to predict antigenic distances based on the differences of amino acid sequences. Antigenic evolution map of human influenza A/H3N2 viruses in Shanghai area over the years was constructed. The results showed that the characteristics of antigenic evolution and genetic evolution were generally similar.
Antigenic evolution map and genetic evolution map of human influenza A/H1N1 viruses in the world over the years were constructed. The results showed that there exist some regularity in the evolution and some strains were interspersed. The results also showed the genetic evolution was continuous and the antigenic evolution was puctuated. The mutation at the amino acid position 54,127,193 may be responsiable for the antigenic gap.
2. Statistical models for predicting antigentic variants of human influenza A/H1N1 viruses were studied. SVM-RFE(linear), SVM-RFE(RBF), Random forest were used for variable selection. SVM, Random forest, RidgePLS were used as prediction models. Agreement rate, sensitivity, specificity were calculated for evaluating the qualitative performance of the models. The results showed that Random forest was the best model for predicting antigentic variants of human influenza A/H1N1 viruses. The number of variables for prediction models was chosen, which is 30. The agreement rate for SVM-RFE(linear)/RF, SVM-RFE(RBF)/RF, RF/RF were 88.05%,88.05%,87.66%.
Therefore,23 positions (position 36,43,54,69,71,73,80,96,121,125,127, 128,140,165,169,189,192,193,204,251,270,271 and 282) were identified as potential immunodominant positions of human influenza A/H1N1 viruses.
3. Comparative study on genetic evolution of hemagglutinin between novel influenza A (H1N1) virus and influenza A virus subtype H1 from China. The results showed that there were distant evolutionary relationships between novel influenza A (H1N1) virus HA gene and human influenza A virus subtype H1 HA gene from China, influenza vaccine. At the gene level in China population immunity and vaccine might not provide protection against novel influenza A (H1N1) virus. There was still a little evolutionary distance between novel influenza A (H1N1) virus HA gene and swine influenza A virus subtype H1 HA gene from China. There was no evidence that novel influenza A (H1N1) virus might originate in China.
While carrying out the above work, antigenic and genetic evolution of human influenza A/H1N1 and A/H3N2 viruses in Shanghai area in recent years were intuitively understood. The genetic evolution and antigenic variation rule of influenza A viruses were explored. Valuable clues were provided for the prevention and control of influenza. Meanwhile, identifying potential immunodominant positions can assist the annual selection of influenza vaccine strains. The prediction models for antigentic variants of human influenza A/H1N1 viruses may further improve the selection of vaccine strains.
引文
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