上海地区人甲型流感病毒基因变异与季节性流行关系的研究

发布时间：2018-07-02 22:52

本文选题：甲型流感病毒 + 基因变异　；参考：《复旦大学》2010年博士论文

【摘要】： 流感长期以来一直是威胁人类健康的重要呼吸道病原体之一,流感的基因变异及重组所导致的抗原漂移和抗原转换是流感出现流行或者暴发的基础,虽然已有很多研究对流感的基因变异进行探讨,但是对流感病毒的进化情况和流行动力学的许多方面的认识仍然是未知的,特别对流感病毒的跨时空的变异缺乏精确的测量。在北半球流感发病存在如时钟般准确的流行季节高峰,是什么因素驱使流感出现明显的季节性高峰却众说纷纭,特别是关于基因变异和流感季节性高峰间的关系研究基本缺乏。本研究采用合理的流行病学和生物信息学方法,对流感的基因变异情况和流感季节性发病高峰的关系进行探讨,主要包括以下5个方面内容： 1.在上海地区建立合适的流感监测点和网络,长期收集监测网络医院的类流感病例发病情况,利用时间序列分析流感的季节性发病高峰分布特征。结果显示：上海地区的流感监测病例每年存在2次季节高峰,两次高峰间的距离为6个月,和中国北方地区只有1次流行高峰且间隔为12个月不同。 2.从研究现场的监测系统采集标本并分离流感病毒后并按照一定条件选择甲型流感病毒株进行HA、NA和PB2基因的全基因测序。利用基于MCMC抽样技术的Bayesian分析分别完成流感病毒HA, NA和PB2基因的跨时间变异情况分析,结合已有的流行病学资料,对人甲型流感3种重要基因变异情况进行全面的分析。结果显示甲型流感2个不同亚型的基因变异速度是不一致的,总的说来,H3N2亚型进化速度比较快,而H1N1的进化速度相对较慢。在同一个亚型中,一般是HA的进化速度比NA快,PB2最慢,这和病毒为了逃避宿主的免疫清除而进行的适应性变异紧密相关。在大部分时间中,H3N2亚型基因变异的程度相对较高,而H1N1亚型的基因变异程度相对较低,即使在占据优势的2004和2005年,其变异高峰也只有H3N2最高峰的三分之一不到。这从另外一方面证实H1N1亚型保存相对稳定,不容易突破人体的免疫屏障和H3N2亚型对其的压制。病毒基因变异程度高,并不意味着其传播能力的提高,需结合基因对流感发病造成的理论感染人数数据等数据进行综合的评估才能得到更准确的结果。 3.选择典型的病毒株测试其对流感最有效药物是否出现耐受,间接证明病毒的基因变异是否有产生明显的抗原变异。发现基因变异并没有导致病毒出现抗原根本性的转变,以点突变和适应性变异为主要特点。 4.对禽类相关从业人员血清进行检测,探索某些其他宿主病毒感染人可能的途径和人群对流感的易感性情况。结果表明人群对其他宿主来源的流感病毒普遍易感,一般人群和接触人群中均存在H9亚型流感病毒HAI抗体,接触人群H9抗体阳性率是17.9%,普通人群也达到2.6%。接触人群感染H9的危险性是普通人群的3.392倍。此外两个人群的H3N2和H1N1的抗体滴度并没有差别。在大部分受调查人群都没有接种疫苗的情况下,但是抗体滴度都相对较高,特别是变异速度比较快的H3N2亚型,抗体阳性率都为30%左右。 5.探索甲型流感季节高峰分布和病毒主要基因变异间的关联情况,为流感的科学有效防治提供可靠的依据。甲型流感的基因变异在每个观察年的冬季出现一个明显的高峰,与监测病例每年2个高峰且冬春季高峰跨年不同,基因变异的高峰只有一个,且在流感监测病例的2个高峰间。结果表明,在一个相对稳定的环境中,病毒主要是在宿主的免疫压力驱动下产生适应性突变后造成一个新的流行。综合上述结果,可以认为上海地区存在流感发病的季节性高峰,流感的基因变异在短期内主要以基因的点突变和适应性变异为主,并没有出现明显的表型改变从而导致产生耐药的情形。在人群对流感普遍易感,其人口构成、生活状态和免疫水平也基本保存稳定、气候条件也没有很大的变化的情况下,流感的季节性高峰主要是受到甲型流感病毒适应性变异的影响。
[Abstract]:Influenza has long been one of the important respiratory pathogens that threaten human health. The genetic variation of influenza and the antigen shift and antigen conversion caused by recombinant human influenza are the basis of influenza epidemic or outbreak. Although many studies have discussed the genetic variation of influenza, the evolution and epidemic of influenza virus Many aspects of the dynamics are still unknown, particularly the lack of accurate measurements of the temporal and spatial variability of influenza viruses. In the northern hemisphere, the incidence of influenza, such as the clock and accurate seasonal peak, is a factor that drives the flu to appear to be seasonal. The relationship between the genetic variation of influenza and the peak of seasonal influenza was discussed with reasonable epidemiological and bioinformatics methods, including the following 5 aspects:
1. establish appropriate influenza surveillance sites and networks in Shanghai, collect and monitor influenza like cases in network hospitals for a long time and analyze the seasonal peak distribution characteristics of influenza in time series. The results show that influenza surveillance cases in Shanghai region have 2 seasonal peaks each year, and the distance between two peaks is 6 months, There are only 1 epidemic peaks in northern China and 12 months apart.
2. the whole gene sequence of HA, NA and PB2 gene was sequenced from the monitoring system of the field monitoring system and the influenza virus strain was selected according to certain conditions. The Bayesian analysis based on MCMC sampling technique was used to analyze the cross time variation of the influenza virus HA, NA and PB2 gene, combined with the existing epidemic. A comprehensive analysis of 3 important genes variation in human influenza A (influenza A) was carried out. The results showed that the rate of genetic variation in the 2 different subtypes of influenza A was inconsistent. In general, the evolution speed of the H3N2 subtype was faster and the evolutionary speed of the H1N1 was relatively slow. In the same subtype, the evolution rate of HA was generally faster than that of NA, PB2 Most slowly, it is closely related to the adaptive variation of the virus in order to escape from the immune clearance of the host. In most of the time, the H3N2 subtype gene variation is relatively high and the H1N1 subtype is relatively low in genetic variation, even in the dominant 2004 and 2005, and the peak of mutation is only 1/3 of the H3N2 peak. On the other hand, it has proved that the H1N1 subtype is relatively stable, and it is not easy to break through the human immune barrier and the suppression of the H3N2 subtype. The high degree of variation of the virus gene does not mean that the transmission ability of the virus is improved. It is necessary to combine the data of the number of people with the theory of the gene infection caused by the influenza. More accurate results.
3. select a typical virus strain to test its tolerance to the most effective influenza drugs and indirectly prove whether the genetic variation of the virus produces an obvious antigen variation. It is found that the gene mutation does not lead to a fundamental change in the antigen of the virus, with the characteristics of point mutation and adaptive mutation.
4. to detect the serum of poultry related employees and explore the possible pathways of some other host virus infection and the susceptibility to influenza. The results show that the population is generally susceptible to influenza viruses from other host sources. The H9 subtype influenza virus HAI antibody is present in the general population and the contact population, and the H9 antibody positive of the population is exposed. The sex rate was 17.9%, and the average population also reached 3.392 times the risk of 2.6%. exposure to H9 in the general population. In addition, there was no difference in the titer of antibody titers between H3N2 and H1N1 in two people. The antibody titers were relatively high in the majority of the people who were not vaccinated, especially the H3N2 subunit of H3N2 with faster mutation speed. The positive rate of antibody was about 30%.
5. explore the correlation between the seasonal peak distribution of influenza A and the main gene mutation of the virus, which provides a reliable basis for the scientific and effective prevention and control of influenza. The genetic variation of influenza A has a significant peak in winter of each observation year, 2 peaks in the monitoring case and the high cross year of winter and spring, and the high gene variation. Only one peak, and between 2 peaks of influenza surveillance cases, shows that in a relatively stable environment, the virus is mainly caused by an adaptive mutation driven by the host's immune pressure, resulting in a new epidemic.
According to the above results, it is believed that there is a seasonal peak of influenza in Shanghai. The genetic variation of influenza is mainly based on the point mutation and adaptive variation of genes in the short term, and there is no obvious phenotypic change that leads to the emergence of drug resistance. The immune level is also basically stable, and the climate conditions have not changed greatly. The seasonal peak of influenza is mainly affected by the adaptive variation of influenza A virus.
【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】：R181.3

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