本文選題：甲型流感病毒 + 基因變異　； 參考：《復(fù)旦大學(xué)》2010年博士論文

【摘要】： 流感長期以來一直是威脅人類健康的重要呼吸道病原體之一,流感的基因變異及重組所導(dǎo)致的抗原漂移和抗原轉(zhuǎn)換是流感出現(xiàn)流行或者暴發(fā)的基礎(chǔ),雖然已有很多研究對流感的基因變異進行探討,但是對流感病毒的進化情況和流行動力學(xué)的許多方面的認(rèn)識仍然是未知的,特別對流感病毒的跨時空的變異缺乏精確的測量。在北半球流感發(fā)病存在如時鐘般準(zhǔn)確的流行季節(jié)高峰,是什么因素驅(qū)使流感出現(xiàn)明顯的季節(jié)性高峰卻眾說紛紜,特別是關(guān)于基因變異和流感季節(jié)性高峰間的關(guān)系研究基本缺乏。本研究采用合理的流行病學(xué)和生物信息學(xué)方法,對流感的基因變異情況和流感季節(jié)性發(fā)病高峰的關(guān)系進行探討,主要包括以下5個方面內(nèi)容： 1.在上海地區(qū)建立合適的流感監(jiān)測點和網(wǎng)絡(luò),長期收集監(jiān)測網(wǎng)絡(luò)醫(yī)院的類流感病例發(fā)病情況,利用時間序列分析流感的季節(jié)性發(fā)病高峰分布特征。結(jié)果顯示：上海地區(qū)的流感監(jiān)測病例每年存在2次季節(jié)高峰,兩次高峰間的距離為6個月,和中國北方地區(qū)只有1次流行高峰且間隔為12個月不同。 2.從研究現(xiàn)場的監(jiān)測系統(tǒng)采集標(biāo)本并分離流感病毒后并按照一定條件選擇甲型流感病毒株進行HA、NA和PB2基因的全基因測序。利用基于MCMC抽樣技術(shù)的Bayesian分析分別完成流感病毒HA, NA和PB2基因的跨時間變異情況分析,結(jié)合已有的流行病學(xué)資料,對人甲型流感3種重要基因變異情況進行全面的分析。結(jié)果顯示甲型流感2個不同亞型的基因變異速度是不一致的,總的說來,H3N2亞型進化速度比較快,而H1N1的進化速度相對較慢。在同一個亞型中,一般是HA的進化速度比NA快,PB2最慢,這和病毒為了逃避宿主的免疫清除而進行的適應(yīng)性變異緊密相關(guān)。在大部分時間中,H3N2亞型基因變異的程度相對較高,而H1N1亞型的基因變異程度相對較低,即使在占據(jù)優(yōu)勢的2004和2005年,其變異高峰也只有H3N2最高峰的三分之一不到。這從另外一方面證實H1N1亞型保存相對穩(wěn)定,不容易突破人體的免疫屏障和H3N2亞型對其的壓制。病毒基因變異程度高,并不意味著其傳播能力的提高,需結(jié)合基因?qū)α鞲邪l(fā)病造成的理論感染人數(shù)數(shù)據(jù)等數(shù)據(jù)進行綜合的評估才能得到更準(zhǔn)確的結(jié)果。 3.選擇典型的病毒株測試其對流感最有效藥物是否出現(xiàn)耐受,間接證明病毒的基因變異是否有產(chǎn)生明顯的抗原變異。發(fā)現(xiàn)基因變異并沒有導(dǎo)致病毒出現(xiàn)抗原根本性的轉(zhuǎn)變,以點突變和適應(yīng)性變異為主要特點。 4.對禽類相關(guān)從業(yè)人員血清進行檢測,探索某些其他宿主病毒感染人可能的途徑和人群對流感的易感性情況。結(jié)果表明人群對其他宿主來源的流感病毒普遍易感,一般人群和接觸人群中均存在H9亞型流感病毒HAI抗體,接觸人群H9抗體陽性率是17.9%,普通人群也達到2.6%。接觸人群感染H9的危險性是普通人群的3.392倍。此外兩個人群的H3N2和H1N1的抗體滴度并沒有差別。在大部分受調(diào)查人群都沒有接種疫苗的情況下,但是抗體滴度都相對較高,特別是變異速度比較快的H3N2亞型,抗體陽性率都為30%左右。 5.探索甲型流感季節(jié)高峰分布和病毒主要基因變異間的關(guān)聯(lián)情況,為流感的科學(xué)有效防治提供可靠的依據(jù)。甲型流感的基因變異在每個觀察年的冬季出現(xiàn)一個明顯的高峰,與監(jiān)測病例每年2個高峰且冬春季高峰跨年不同,基因變異的高峰只有一個,且在流感監(jiān)測病例的2個高峰間。結(jié)果表明,在一個相對穩(wěn)定的環(huán)境中,病毒主要是在宿主的免疫壓力驅(qū)動下產(chǎn)生適應(yīng)性突變后造成一個新的流行。 綜合上述結(jié)果,可以認(rèn)為上海地區(qū)存在流感發(fā)病的季節(jié)性高峰,流感的基因變異在短期內(nèi)主要以基因的點突變和適應(yīng)性變異為主,并沒有出現(xiàn)明顯的表型改變從而導(dǎo)致產(chǎn)生耐藥的情形。在人群對流感普遍易感,其人口構(gòu)成、生活狀態(tài)和免疫水平也基本保存穩(wěn)定、氣候條件也沒有很大的變化的情況下,流感的季節(jié)性高峰主要是受到甲型流感病毒適應(yīng)性變異的影響。
[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.
【學(xué)位授予單位】：復(fù)旦大學(xué)
【學(xué)位級別】：博士
【學(xué)位授予年份】：2010
【分類號】：R181.3

【參考文獻】

相關(guān)期刊論文 前6條

1 梁慶,李景東,陳煜生,yね窳，

本文編號：2091208