山東省霍亂弧菌的時(shí)空分布及變化
發(fā)布時(shí)間：2018-08-08 21:36
【摘要】：[研究背景] 霍亂(Cholera)是一古老的急性腸道傳染病,全球發(fā)生的七次霍亂大流行都嚴(yán)重危害著人們的生命和健康,特別是對于發(fā)展中國家而言更是重大的公共衛(wèi)生問題�；魜y的病原體霍亂弧菌(Vibrio cholerae, V. cholerae)是一革蘭氏陰性弧菌,可分為200多個血清型,其中O1群和O139群是兩種最為重要的能引起嚴(yán)重臨床癥狀且能引起霍亂暴發(fā)流行的血清型,O1群主要包括小川型(Ogawa)和稻葉型(Inaba)兩種血清型以及古典型(Classical biotype)和El Tor型(El Tor biotype)兩種生物型。 在全球前六次的霍亂大流行中,病原體主要是O1群古典型霍亂弧菌,而自1961年起第七次霍亂流行中,O1群El Tor型取代了古典型成為優(yōu)勢菌型,并與1964年傳入中國廣東,同年在山東檢出,此后波及全省各地區(qū)。1992年,O139群霍亂弧菌作為新的血清型在印度出現(xiàn)并迅速向鄰國引起暴發(fā)疫情,第二年在中國新疆出現(xiàn)了O13群霍亂病例,進(jìn)而于1997年在煙臺萊陽檢出山東省首株O139群霍亂弧菌。自1964年以來,霍亂疫情在山東省一直沒有間斷,經(jīng)歷了多次暴發(fā)流行且累及各個地區(qū),血清型也經(jīng)過了O1群小川型、O1群稻葉型和O139群多次變化。 由于歷史原因,1964～1975年期間霍亂疫情報(bào)告工作不完善,有關(guān)的霍亂疫情報(bào)告及記錄均為空白。本研究對山東省自1976年至今霍亂疫情流行病學(xué)特征及不同時(shí)間和地區(qū)代表菌株的毒力基因、脈沖場凝膠電泳(Pulsed Field Gel Electrophoresis, PFGE)基因分型等分子流行病學(xué)研究能夠細(xì)致的分析霍亂在局部地區(qū)的流行特征時(shí)空變異規(guī)律,對霍亂疫情的防控有著更加現(xiàn)實(shí)的指導(dǎo)意義,同時(shí)山東霍亂的流行特征也能反映全國乃至全球的態(tài)勢,對大范圍的研究有著補(bǔ)充作用。 [研究目的] 1、系統(tǒng)分析山東省霍亂疫情的時(shí)間、地區(qū)、人群等三間分布流行病學(xué)特征； 2、細(xì)致了解山東省霍亂弧菌血清型、毒力基因及PFGE基因分型的時(shí)空分布及變化規(guī)律,同時(shí)探討三者之間的關(guān)系； 3、初步建立山東省霍亂弧菌的PFGE基因分型數(shù)據(jù)庫,便于以后霍亂疫情的溯源及比對分析。 [研究方法] 1、流行病學(xué)資料整理：對山東省自1976年以來登記的所有霍亂疫情菌株血清型、分離時(shí)間、分離地點(diǎn)、病人臨床資料、流行強(qiáng)度等流行病學(xué)資料進(jìn)行整理。 2、菌株選擇及復(fù)核：根據(jù)流行病資料選取時(shí)間和空間兩個維度的代表菌株,按照以暴發(fā)為主、兼顧散發(fā)的原則選取代表菌株,同時(shí)增菌分離培養(yǎng)及血清凝集和生化鑒定。 3、脈沖場凝膠電泳(PFGE)分型：按照PulseNet霍亂弧菌PFGE分型的標(biāo)準(zhǔn)方案進(jìn)行操作,細(xì)菌裂解時(shí)間為1h,Not酶切時(shí)間為4h,電泳條件Blockl初始和最終轉(zhuǎn)換時(shí)間為2s和10s,電泳時(shí)間為13h,Block2中時(shí)間分別為20s、25s和6h。 4、毒力基因檢測：提取代表菌株核酸,PCR檢測ctxAB、 tcpA、 tcp1、toxR、 rtxA和hlyA等6種毒力基因。 5、數(shù)據(jù)分析：利用SAS9.1軟件對山東省霍亂弧菌血清型毒力基因的分布差異等分類數(shù)據(jù)進(jìn)行卡方檢驗(yàn)；利用Bionumerics6.0軟件對代表菌株的PFGE條帶進(jìn)行聚類分析,結(jié)合流行病學(xué)資料分析時(shí)空變化規(guī)律。 [結(jié)果] 1、流行病學(xué)特征： (1)自1976年以來,山東省各地區(qū)均有霍亂疫情出現(xiàn),其中魯西南和魯北地區(qū)最為嚴(yán)重,魯中地區(qū)患者相對較少； (2)自1976年以來,山東省霍亂病例幾乎每年均有出現(xiàn),其中在1983年～1984年和1994年出現(xiàn)了兩個流行高峰； (3)從1976年至今山東省霍亂疫情分離菌株依次經(jīng)歷了小川型、稻葉型、和0139群的更替變遷過程； (4)小川型霍亂弧菌疫情主要集中在魯北地區(qū),而稻葉型霍亂弧菌則主要集中在魯西南地區(qū)； (5)01群霍亂疫情患者年齡分布較為均勻,而0139群霍亂患者多為老年人。 2、毒力基因分布： (1)毒力基因hlyA和toxR,rtxA在環(huán)境株和臨床分離株陽性率均接近100%,而臨床分離株rtxAB、 tcp I和tcpA三種毒力基因的陽性率則遠(yuǎn)高于環(huán)境分離株； (2)臨床分離株ctxAB、 tcp I和tcpA三種毒力基因的陽性率有隨時(shí)間上升的趨勢,但2000年之后優(yōu)勢菌群0139群霍亂弧菌毒力基因的攜帶率有所降低； (3)毒力基因tcp I和tcpA表達(dá)較為一致,且在暴發(fā)疫情分離株的陽性率高于散發(fā)疫情菌株,而ctxAB沒有明顯差異。 3、PFGE基因分型： (1)250株代表菌株整體上主要聚為PⅠ、PⅡ、PⅢ和PⅣ4類,前3類和血清血型相吻合,依次為臨床分離株O1群稻葉型、0139群和01群小川型,而PⅣ主要為毒力基因缺失的菌株,來源及血清型較為混雜； (2)PⅠ可進(jìn)一步聚類為PⅠa和PⅠb亞類,其中PⅠa主要為1980年～1983年魯西南地區(qū)菌株,PⅠb主要為2001年魯中和魯北地區(qū)菌株；PⅡ可分為PⅡa和PⅡb亞類,PⅡa為2009年之前的0139群菌株,PⅡb為2013年濟(jì)寧霍亂疫情菌株；PⅢ可分為PⅢa、PⅢb和PⅢc亞類,其中PⅢa為1998年～1999年分散全省的菌株形成的亞類,PⅢb為1986年～1997年主要分布于魯東和魯北地區(qū)菌株形成的亞類,PⅢc主要是1978年濟(jì)寧和日照分離菌株；PⅣ類的菌株來源較為混亂,但毒力基因缺失為其共同特征； (3)250株霍亂弧菌形成了179個PFGE型,在每個亞類中均存在多菌株形成的同一PFGE型別,這主要見于三種情況：①來自同一霍亂暴發(fā)疫情；②不同時(shí)間相同地域的霍亂疫情；③同一時(shí)間相近地域的霍亂疫情。 [結(jié)論] 1、在第七次全球霍亂大流行中,山東省霍亂疫情持續(xù)存在了半個世紀(jì),流行強(qiáng)度發(fā)生著變化,不同年份和地區(qū)的優(yōu)勢血清型出現(xiàn)多次更替； 2、山東省臨床分離的霍亂弧菌多為產(chǎn)毒株,且毒力基因ctxAB、 tcp I和tcpA的陽性率存在時(shí)間和地區(qū)差異。而毒力基因缺失的臨床分離株,可能與hlyA、toxR和rtxA等其他較為保守的毒力基因有關(guān)；另外,相對于ctxAB, tcp I和tcpA對霍亂疫情的流行強(qiáng)度可能更為重要； 3、PFGE基因分型更深入地顯示了山東省霍亂弧菌在不同的時(shí)間和地區(qū)細(xì)微變化,與血清型和毒力基因均存在密切的關(guān)系,其聚類的基因相似性可為霍亂疫情傳統(tǒng)流行病學(xué)關(guān)聯(lián)提供線索。
[Abstract]:[research background]
Cholera (Cholera) is an ancient and acute intestinal infectious disease. Seven cholera pandemics worldwide are seriously endangering people's lives and health, especially for developing countries. The pathogen of Cholera (Vibrio cholerae, V. cholerae) is a gram-negative Vibrio, which can be divided into 2 More than 00 serotypes, of which the O1 group and the O139 group are the two most important serotypes that can cause serious clinical symptoms and cause cholera outbreak. The O1 group mainly includes two serotypes of the Sichuan type (Ogawa) and the rice leaf type (Inaba), and the two biological forms of the classical (Classical biotype) and El Tor (El Tor biotype).
Among the first six cholera pandemics worldwide, the main pathogen is the O1 group of the classical Vibrio cholerae, and in the seventh cholera epidemic in 1961, the O1 group El Tor replaced the classical type as the dominant bacteria type, and was introduced into Guangdong in China in 1964, and was detected in the same year in the same year in all regions of the province, and the O139 group of Vibrio cholerae is a new one. The serotype appeared in India and caused a rapid outbreak to neighbouring countries. Second years in Xinjiang, China, a group of O13 cholera appeared in Xinjiang, China, and the first O139 group of Vibrio cholerae was detected in Shandong Province in Laiyang, Yantai in 1997. Since 1964, the cholera epidemic has not been interrupted in Shandong Province. It also passed through O1 group of Ogawa type, O1 group rice leaf type and O139 group.
Due to historical reasons, the report and record of cholera epidemic situation in 1964~1975 years were not perfect, and the reports and records of cholera epidemic were blank. The epidemiological characteristics of cholera epidemic in Shandong province and the virulence genes of different time and regional representative strains from 1976 to date in Shandong Province, pulse field gel electrophoresis (Pulsed Field Gel Electrophoresis, PF) GE) molecular epidemiological studies, such as genotyping, can carefully analyze the temporal and spatial variability of cholera epidemic in local areas, and have more practical guiding significance for the prevention and control of cholera epidemic. Meanwhile, the epidemic characteristics of cholera in Shandong can also reflect the national and global situation, and have a complementary role to the wide range of research.
[research purposes]
1, we systematically analyzed the epidemiological characteristics of three cholera outbreaks in Shandong province.
2. To understand the temporal and spatial distribution and variation of serotypes, virulence genes and PFGE genotypes of Vibrio cholerae in Shandong Province, and to explore the relationship among them.
3, PFGE genotyping database of Vibrio cholerae in Shandong province was initially established to facilitate tracing and comparative analysis of cholera epidemic situation.
[research methods]
1, epidemiological data were arranged: the epidemiological data of all cholera epidemic strains, such as serotype, separation time, separation place, clinical data and epidemic intensity of all cholera epidemic strains registered since 1976 in Shandong Province, were collected.
2, the selection and reexamination of the strains: according to the epidemiological data to select the representative strains of the two dimensions of time and space, according to the outbreak of the strain mainly, taking into account the principle of sporadic selection of the representative strains, at the same time, increase the isolation and culture and serum agglutination and biochemical identification.
3, pulse field gel electrophoresis (PFGE) typing: according to the standard scheme of PulseNet cholera vibrio PFGE typing, the time of bacterial cracking is 1H, the time of Not enzyme cutting is 4h, the initial and final conversion time of Blockl is 2S and 10s, and the time of electrophoresis is 13h.
4, virulence gene detection: extract the nucleic acid of the representative strain, and detect 6 virulence genes such as ctxAB, tcpA, TCP1, toxR, rtxA and hlyA by PCR.
5, data analysis: using SAS9.1 software to carry out a chi square test on the distribution difference of Vibrio cholerae serotype virulence genes in Shandong Province, and using Bionumerics6.0 software to cluster analysis on the PFGE bands of the representative strains and analyze the temporal and spatial variation rules according to the epidemiological data.
[results]
1, epidemiological characteristics:
(1) Since 1976, cholera epidemics have occurred in all regions of Shandong Province, the most serious in the southwest and north of Shandong Province, and relatively few patients in the central part of Shandong Province.
(2) Since 1976, cholera cases have occurred almost every year in Shandong Province, with two epidemic peaks from 1983 to 1984 and 1994.
(3) From 1976 to now, strains isolated from cholera epidemic situation in Shandong Province have undergone successive changes of Ogawa type, rice leaf type and 0139 group.
(4) the outbreak of Vibrio cholerae in Ogawa is mainly concentrated in the north of Shandong Province, while the rice leaf type Vibrio cholerae is mainly concentrated in Southwest Shandong.
(5) the age distribution of 01 groups of cholera patients is more homogeneous, while the 0139 group of cholera patients are mostly elderly people.
2, the distribution of virulence genes:
(1) the positive rates of virulence genes hlyA and toxR, rtxA in both environmental and clinical isolates were close to 100%, while the positive rates of three virulence genes of rtxAB, TCP I and tcpA in clinical isolates were much higher than those of environmental isolates.
(2) the positive rates of three virulence genes of clinical isolates ctxAB, TCP I and tcpA were increasing with time, but the carrying rate of Vibrio cholerae virulence genes of 0139 groups of dominant groups decreased after 2000.
(3) The expression of virulence genes TCP I and tcpA was consistent, and the positive rate of isolates in outbreak was higher than that in sporadic outbreak, but there was no significant difference in ctxAB.
3, PFGE genotyping:
(1) the 250 representative strains were mainly composed of P I, P II, P III and P IV 4. The first 3 types were in accordance with the serum blood groups, which were followed by the clinical isolates of O1 group rice leaf type, 0139 group and 01 group of small Sichuan type, while P IV was mainly a strain of virulence gene deletion, and the source and serotype were mixed;
(2) P I can be further clustered into P I a and P I B subclass, in which P I a mainly is from 1980 to 1983 in southwestern Shandong Province, P I B is mainly in 2001 of Shandong and Northern Shandong Province; P II can be divided into P A and subordinate class of 2009. III C subclass, of which P III A is a subclass of strain formation in the province from 1998 to 1999, P III B is a subclass of strains formed mainly from 1986 to 1997 in Shandong and Northern Shandong, P III C is mainly in 1978 Jining and sunshine isolates, and P IV strains are more chaotic, but the loss of virulence genes is the common characteristic.
(3) 250 strains of Vibrio cholerae formed 179 PFGE types, and there were the same PFGE types of multiple strains in each subclass. This was mainly seen in three cases: (1) from the same cholera outbreak; (2) the cholera epidemic in the same region at different time; and the cholera epidemic in the same area at the same time.
[Conclusion]
1, in the seventh global cholera pandemic, the cholera epidemic in Shandong lasted for half a century, the intensity of the epidemic changed, and the dominant serotypes in different years and regions had been replaced by many times.
2, the clinical isolates of Vibrio cholerae in Shandong province are mostly strains of Vibrio cholerae, and the positive rates of virulence genes ctxAB, TCP I and tcpA have time and regional differences. However, the clinical isolates with the lack of virulence genes may be related to other more conservative virulence genes such as hlyA, toxR and rtxA, and TCP I and tcpA are prevalent in cholera epidemic relative to ctxAB. Strength may be more important.
3, the PFGE genotyping shows the subtle changes in the time and area of Vibrio cholerae in Shandong province. There is a close relationship with the serotypes and virulence genes. The genetic similarity of the cluster can provide clues for the traditional epidemiological association of cholera epidemic.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R516.5
本文編號：2173105
[Abstract]:[research background]
Cholera (Cholera) is an ancient and acute intestinal infectious disease. Seven cholera pandemics worldwide are seriously endangering people's lives and health, especially for developing countries. The pathogen of Cholera (Vibrio cholerae, V. cholerae) is a gram-negative Vibrio, which can be divided into 2 More than 00 serotypes, of which the O1 group and the O139 group are the two most important serotypes that can cause serious clinical symptoms and cause cholera outbreak. The O1 group mainly includes two serotypes of the Sichuan type (Ogawa) and the rice leaf type (Inaba), and the two biological forms of the classical (Classical biotype) and El Tor (El Tor biotype).
Among the first six cholera pandemics worldwide, the main pathogen is the O1 group of the classical Vibrio cholerae, and in the seventh cholera epidemic in 1961, the O1 group El Tor replaced the classical type as the dominant bacteria type, and was introduced into Guangdong in China in 1964, and was detected in the same year in the same year in all regions of the province, and the O139 group of Vibrio cholerae is a new one. The serotype appeared in India and caused a rapid outbreak to neighbouring countries. Second years in Xinjiang, China, a group of O13 cholera appeared in Xinjiang, China, and the first O139 group of Vibrio cholerae was detected in Shandong Province in Laiyang, Yantai in 1997. Since 1964, the cholera epidemic has not been interrupted in Shandong Province. It also passed through O1 group of Ogawa type, O1 group rice leaf type and O139 group.
Due to historical reasons, the report and record of cholera epidemic situation in 1964~1975 years were not perfect, and the reports and records of cholera epidemic were blank. The epidemiological characteristics of cholera epidemic in Shandong province and the virulence genes of different time and regional representative strains from 1976 to date in Shandong Province, pulse field gel electrophoresis (Pulsed Field Gel Electrophoresis, PF) GE) molecular epidemiological studies, such as genotyping, can carefully analyze the temporal and spatial variability of cholera epidemic in local areas, and have more practical guiding significance for the prevention and control of cholera epidemic. Meanwhile, the epidemic characteristics of cholera in Shandong can also reflect the national and global situation, and have a complementary role to the wide range of research.
[research purposes]
1, we systematically analyzed the epidemiological characteristics of three cholera outbreaks in Shandong province.
2. To understand the temporal and spatial distribution and variation of serotypes, virulence genes and PFGE genotypes of Vibrio cholerae in Shandong Province, and to explore the relationship among them.
3, PFGE genotyping database of Vibrio cholerae in Shandong province was initially established to facilitate tracing and comparative analysis of cholera epidemic situation.
[research methods]
1, epidemiological data were arranged: the epidemiological data of all cholera epidemic strains, such as serotype, separation time, separation place, clinical data and epidemic intensity of all cholera epidemic strains registered since 1976 in Shandong Province, were collected.
2, the selection and reexamination of the strains: according to the epidemiological data to select the representative strains of the two dimensions of time and space, according to the outbreak of the strain mainly, taking into account the principle of sporadic selection of the representative strains, at the same time, increase the isolation and culture and serum agglutination and biochemical identification.
3, pulse field gel electrophoresis (PFGE) typing: according to the standard scheme of PulseNet cholera vibrio PFGE typing, the time of bacterial cracking is 1H, the time of Not enzyme cutting is 4h, the initial and final conversion time of Blockl is 2S and 10s, and the time of electrophoresis is 13h.
4, virulence gene detection: extract the nucleic acid of the representative strain, and detect 6 virulence genes such as ctxAB, tcpA, TCP1, toxR, rtxA and hlyA by PCR.
5, data analysis: using SAS9.1 software to carry out a chi square test on the distribution difference of Vibrio cholerae serotype virulence genes in Shandong Province, and using Bionumerics6.0 software to cluster analysis on the PFGE bands of the representative strains and analyze the temporal and spatial variation rules according to the epidemiological data.
[results]
1, epidemiological characteristics:
(1) Since 1976, cholera epidemics have occurred in all regions of Shandong Province, the most serious in the southwest and north of Shandong Province, and relatively few patients in the central part of Shandong Province.
(2) Since 1976, cholera cases have occurred almost every year in Shandong Province, with two epidemic peaks from 1983 to 1984 and 1994.
(3) From 1976 to now, strains isolated from cholera epidemic situation in Shandong Province have undergone successive changes of Ogawa type, rice leaf type and 0139 group.
(4) the outbreak of Vibrio cholerae in Ogawa is mainly concentrated in the north of Shandong Province, while the rice leaf type Vibrio cholerae is mainly concentrated in Southwest Shandong.
(5) the age distribution of 01 groups of cholera patients is more homogeneous, while the 0139 group of cholera patients are mostly elderly people.
2, the distribution of virulence genes:
(1) the positive rates of virulence genes hlyA and toxR, rtxA in both environmental and clinical isolates were close to 100%, while the positive rates of three virulence genes of rtxAB, TCP I and tcpA in clinical isolates were much higher than those of environmental isolates.
(2) the positive rates of three virulence genes of clinical isolates ctxAB, TCP I and tcpA were increasing with time, but the carrying rate of Vibrio cholerae virulence genes of 0139 groups of dominant groups decreased after 2000.
(3) The expression of virulence genes TCP I and tcpA was consistent, and the positive rate of isolates in outbreak was higher than that in sporadic outbreak, but there was no significant difference in ctxAB.
3, PFGE genotyping:
(1) the 250 representative strains were mainly composed of P I, P II, P III and P IV 4. The first 3 types were in accordance with the serum blood groups, which were followed by the clinical isolates of O1 group rice leaf type, 0139 group and 01 group of small Sichuan type, while P IV was mainly a strain of virulence gene deletion, and the source and serotype were mixed;
(2) P I can be further clustered into P I a and P I B subclass, in which P I a mainly is from 1980 to 1983 in southwestern Shandong Province, P I B is mainly in 2001 of Shandong and Northern Shandong Province; P II can be divided into P A and subordinate class of 2009. III C subclass, of which P III A is a subclass of strain formation in the province from 1998 to 1999, P III B is a subclass of strains formed mainly from 1986 to 1997 in Shandong and Northern Shandong, P III C is mainly in 1978 Jining and sunshine isolates, and P IV strains are more chaotic, but the loss of virulence genes is the common characteristic.
(3) 250 strains of Vibrio cholerae formed 179 PFGE types, and there were the same PFGE types of multiple strains in each subclass. This was mainly seen in three cases: (1) from the same cholera outbreak; (2) the cholera epidemic in the same region at different time; and the cholera epidemic in the same area at the same time.
[Conclusion]
1, in the seventh global cholera pandemic, the cholera epidemic in Shandong lasted for half a century, the intensity of the epidemic changed, and the dominant serotypes in different years and regions had been replaced by many times.
2, the clinical isolates of Vibrio cholerae in Shandong province are mostly strains of Vibrio cholerae, and the positive rates of virulence genes ctxAB, TCP I and tcpA have time and regional differences. However, the clinical isolates with the lack of virulence genes may be related to other more conservative virulence genes such as hlyA, toxR and rtxA, and TCP I and tcpA are prevalent in cholera epidemic relative to ctxAB. Strength may be more important.
3, the PFGE genotyping shows the subtle changes in the time and area of Vibrio cholerae in Shandong province. There is a close relationship with the serotypes and virulence genes. The genetic similarity of the cluster can provide clues for the traditional epidemiological association of cholera epidemic.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2014
【分類號】：R516.5
【參考文獻(xiàn)】
相關(guān)期刊論文 前10條
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