本文選題：鼠疫耶爾森氏菌 + RovM�。� 參考：《中國人民解放軍軍事醫(yī)學(xué)科學(xué)院》2016年博士論文

【摘要】：鼠疫耶爾森氏菌是(Yersinia pestis,以下簡稱“鼠疫菌”)是引發(fā)烈性傳染病鼠疫的病原菌,是一種革蘭氏染色陰性的短小桿菌。而且,鼠疫菌在不同的培養(yǎng)條件或宿主環(huán)境下會呈現(xiàn)不同的形態(tài)。鼠疫菌染色體基因組大小約為4.65 Mb,包含約4000個(gè)基因。大多數(shù)的鼠疫菌菌株都包含3種質(zhì)粒:p PCP1,p CD1和p MT1,3種質(zhì)粒上包含有大量重要的毒力因子,對于鼠疫菌在宿主體內(nèi)生存、傳播以及致病有著重要意義。鼠疫菌進(jìn)入人體后,感染初期會在幾天內(nèi)迅速擴(kuò)散至人體的淋巴結(jié)形成腺鼠疫(bubonic plague);一旦進(jìn)入血液經(jīng)大量繁殖后容易引發(fā)敗血癥鼠疫(septicemic plague),并進(jìn)一步擴(kuò)散至脾、肝、肺等器官和組織;最終,一部分患者會發(fā)展為肺鼠疫(pneumonic plague),病原菌可以直接通過空氣傳播給其他人,易傳播且致死率高。鼠疫菌引發(fā)的烈性傳染病曾在世界范圍內(nèi)引發(fā)3次大流行,給人類帶來了深重的災(zāi)難,并在一定程度上影響了各民族的政治、經(jīng)濟(jì)和文化。而且,近些年來世界衛(wèi)生組織(WHO)將鼠疫列為重新抬頭的傳染病。鼠疫防治的研究工作仍然顯得十分重要。鼠疫菌由其祖先假結(jié)核耶爾森氏菌(Yersinia pseudotuberculosis,以下簡稱“假結(jié)核菌”)進(jìn)化而來,然而完全區(qū)別于假結(jié)核菌的傳播方式,在自然界中,鼠疫菌通過節(jié)肢動物跳蚤的叮咬在宿主動物間進(jìn)行循環(huán)傳播,攜帶病原菌的跳蚤偶然間叮咬到人類會引發(fā)人間鼠疫。鼠疫菌在跳蚤體內(nèi)傳播時(shí),會形成致密的生物被膜堵塞跳蚤的前胃,形成所謂的“菌栓”,使得跳蚤吸食的血液無法進(jìn)入胃內(nèi)消化,跳蚤時(shí)刻處于饑餓狀態(tài),反復(fù)叮咬宿主從而促進(jìn)了鼠疫菌的傳播。因此,鼠疫菌生物被膜的產(chǎn)生對于其經(jīng)蚤傳播的能力是具有重要意義的。鼠疫菌擁有復(fù)雜而精確的調(diào)控網(wǎng)絡(luò)控制著各個(gè)生物被膜形成決定性因子以及毒力因子的激活和抑制,這其中各級調(diào)控子的協(xié)同作用對于鼠疫菌的致病和傳播有著重要意義。目前的研究表明,許多重要的調(diào)控子以及它們調(diào)控的靶標(biāo)基因在鼠疫菌生物被膜形成以及病原菌致病性中扮演著重要角色。鼠疫菌中hms HFRS操縱子坐落于染色體上的pgm位點(diǎn)內(nèi),負(fù)責(zé)合成和運(yùn)輸多聚β-1,6-N-乙酰-D-氨基葡糖(poly-β-1,6-N-acetylglucosamine exopolysaccharide)類似的多糖化合物,是生物被膜基質(zhì)的主要成分,與鼠疫菌菌落能否被剛果紅染料染色有直接關(guān)系。環(huán)二鳥苷單磷酸(c-di-GMP)是一個(gè)在細(xì)菌內(nèi)廣泛存在的第二信使分子,影響細(xì)菌毒力因子的表達(dá)和生物被膜形成。在鼠疫菌內(nèi),Hms T和Hms D是僅有的兩個(gè)鳥苷酸環(huán)化酶能夠催化c-di-GMP的合成,從而促進(jìn)生物被膜的形成。然而,Hms P是鼠疫菌中唯一催化降解c-di-GMP的磷酸二酯酶,從而抑制鼠疫菌生物被膜的產(chǎn)生。在革蘭氏陰性菌中,脂多糖(Lipopolysaccharide)是構(gòu)成外膜必不可少的主要成分。一般來說,脂多糖由三部分組成:脂質(zhì)A,核心多糖(Kdo)和O抗原,而鼠疫菌的脂多糖僅由脂質(zhì)A在糖基轉(zhuǎn)移酶的催化下與Kdo連接。在鼠疫菌中,waa A,waa E和coa D構(gòu)成一個(gè)三基因的操縱子waa AE-coa D。waa A編碼的糖基轉(zhuǎn)移酶催化Kdo連接到脂質(zhì)A上,而waa A缺失后的鼠疫菌也表現(xiàn)出明顯的生物被膜形成缺陷。waa E編碼的蛋白對于核心多糖鏈內(nèi)庚糖的修飾起到關(guān)鍵作用,而研究表明waa E缺失后體外培養(yǎng)細(xì)菌時(shí)生物被膜形成約有40%左右的降低。這說明了鼠疫菌生物被膜的形成和脂多糖的合成有著重要聯(lián)系。在鼠疫菌中,p H6抗原是重要的黏附因子以及毒力因子。p H6抗原的合成和分泌需要兩個(gè)相鄰的操縱子基因簇的參與,即psa ABC和psa EF。psa EF可以編碼調(diào)控子蛋白促進(jìn)psa ABC的表達(dá)。重要的毒力調(diào)控子Rov A和Pho P可以通過直接結(jié)合psa ABC和psa EF的啟動子區(qū)結(jié)構(gòu),分別激活和抑制它們的表達(dá)。p H6抗原可以通過介導(dǎo)鼠疫菌黏附到肺泡上皮細(xì)胞,對于鼠疫菌引發(fā)小鼠腺鼠疫和肺鼠疫的發(fā)生都有重要的貢獻(xiàn)。Rov A是Mar R/Sly A家族的調(diào)控子,影響著許多細(xì)菌大量毒力基因的表達(dá),在三種致病型耶爾森氏菌的毒力基因調(diào)控中都扮演重要角色。許多Mar R家族的轉(zhuǎn)錄調(diào)控子,例如表皮葡萄球菌(Staphylococcus epidermidis)的Tca R,屎腸球菌(Enterococcus faecium)的Asr R,變異鏈球菌(Streptococcus mutans)的Rca R以及金黃色葡萄球菌(Staphylococcus aureus)的Sar Z/Sar A等,都有研究報(bào)道影響細(xì)菌生物被膜的形成,然而Rov A對于鼠疫菌生物被膜形成的調(diào)控機(jī)制還是未知的。Rov M是Lys R家族的一個(gè)轉(zhuǎn)錄調(diào)控子,它首次被發(fā)現(xiàn)是在假結(jié)核菌中,研究表明Rov M可以直接結(jié)合到rov A基因的啟動子區(qū)并抑制其轉(zhuǎn)錄,而且Rov M影響假結(jié)核菌的侵襲能力、毒力及運(yùn)動性等。許多Lys R家族的轉(zhuǎn)錄調(diào)控子,例如菊歐文氏菌(Erwinia chrysanthemi)的Pec T,胡蘿卜軟腐歐文氏菌(Erwinia carotovora)以及大腸桿菌(Escherichia coli)的Lrh A,都在細(xì)菌毒力及生物被膜基因調(diào)控方面影響重大。那么,Rov M在鼠疫菌毒力及生物被膜形成的基因調(diào)控網(wǎng)絡(luò)中又扮演怎樣的角色呢?本研究中,以Rov M和Rov A兩個(gè)調(diào)控子作為主要的研究對象,通過生物被膜形成檢測的相關(guān)表型實(shí)驗(yàn)如:結(jié)晶紫染色半定量實(shí)驗(yàn)、線蟲蟲卵發(fā)育實(shí)驗(yàn)、菌落表面形態(tài)觀察等實(shí)驗(yàn)方法探究Rov M和Rov A對鼠疫菌生物被膜形成的影響。結(jié)果表明:Rov M能夠促進(jìn)鼠疫菌生物被膜的形成,而Rov A卻抑制鼠疫菌生物被膜的形成。通過檢測并比較鼠疫菌不同菌株之間細(xì)菌胞內(nèi)c-di-GMP的含量探究Rov M和Rov A是否影響第二信使分子c-di-GMP的合成。結(jié)果表明:Rov M顯著地激活c-di-GMP的合成,而Rov A卻強(qiáng)烈地抑制c-di-GMP的合成。通過皮下感染以及靜脈感染兩種方式給小鼠注射鼠疫菌,繪制小鼠生存曲線來探究Rov M對鼠疫菌毒力的影響。結(jié)果表明:Rov M抑制鼠疫菌的毒力。在獲得了表型實(shí)驗(yàn)結(jié)果后,進(jìn)一步通過精細(xì)的基因調(diào)控實(shí)驗(yàn)如:引物延伸實(shí)驗(yàn)、實(shí)時(shí)定量熒光PCR實(shí)驗(yàn)、Lac Z報(bào)告基因融合實(shí)驗(yàn)以及凝膠阻滯實(shí)驗(yàn)等方法探究Rov M和Rov A對鼠疫菌生物被膜形成以及毒力相關(guān)的靶基因和調(diào)控子基因調(diào)控的分子機(jī)制。結(jié)果表明,Rov M通過激活hms HFRS、hms T、hms CDE的表達(dá),并同時(shí)抑制hms P的表達(dá)促進(jìn)鼠疫菌生物被膜的形成。然而,Rov M間接地抑制YPO1635-pho PQ-YPO1632的表達(dá),卻不影響waa AE-coa D、pho PQ-YPO1632和fur的表達(dá)。Rov A通過抑制hms T、waa AE-coa D、YPO1635-pho PQ-YPO1632和pho PQ-YPO1632的表達(dá)阻礙鼠疫菌生物被膜的形成。然而,Rov A卻不影響hms HFRS、hms CDE、hms P、fur和rov M的表達(dá)。并且,Rov M通過直接抑制rov A的表達(dá),且同時(shí)間接抑制psa ABC和psa EF的表達(dá)來抑制鼠疫菌毒力。同時(shí),Rov M可以激活自身的表達(dá),且在26°C下高表達(dá)而37°C下低表達(dá)。我們匯總本研究中的實(shí)驗(yàn)結(jié)果以及前期的研究成果,大膽的提出了Rov M和Rov A在鼠疫菌致病和傳播中可能存在的調(diào)控通路。在跳蚤體內(nèi)環(huán)境溫度(26°C)下,Rov M處于激活狀態(tài),它可以通過調(diào)控生物被膜形成相關(guān)決定性因子來促進(jìn)鼠疫菌生物被膜的形成,并且同時(shí)抑制Rov A的表達(dá),使得Rov A作用的大量毒力因子處于被抑制狀態(tài),從而有利于增強(qiáng)鼠疫菌經(jīng)蚤傳播的能力。當(dāng)鼠疫菌由跳蚤傳播到哺乳動物體內(nèi)后,其生存環(huán)境由26°C轉(zhuǎn)變?yōu)?7°C,此時(shí)Rov M的表達(dá)明顯降低,導(dǎo)致生物被膜形成的相關(guān)決定性因子處于抑制狀態(tài),而原本表達(dá)處于抑制狀態(tài)的Rov A得到激活,通過調(diào)控大量的毒力因子來增強(qiáng)鼠疫菌的致病性。因此,我們可以看出Rov M和Rov A在鼠疫菌調(diào)控網(wǎng)絡(luò)中的重要地位,Rov M和Rov A分別通過激活和抑制鼠疫菌生物被膜的形成,并同時(shí)分別抑制和激活鼠疫菌的毒力來影響鼠疫菌經(jīng)跳蚤的傳播能力以及對哺乳動物或人類的致病性。當(dāng)生長環(huán)境溫度由26°C轉(zhuǎn)變?yōu)?7°C時(shí),假結(jié)核菌中的Rov M表達(dá)水平無明顯變化,而鼠疫菌中Rov M的表達(dá)水平卻顯著降低,這可能是由假結(jié)核菌進(jìn)化到鼠疫菌過程中的一個(gè)適應(yīng)性變化。
[Abstract]:The plague Jerson Prand (Yersinia pestis, hereinafter referred to as "Yersinia pestis") is the pathogenic bacteria causing the strong infectious disease of the plague, and is a gram-negative bacilli. Moreover, the Yersinia pestis will present different forms in different culture conditions or host environment. The genome size of the pestis is about 4.65 Mb, including about 40. 00 genes. Most of the strains of Yersinia pestis contain 3 plasmids: P PCP1, P CD1 and P MT1,3 contain a large number of important virulence factors, which are important for the survival, transmission and pathogenesis of Yersinia pestis in the host. Plague (bubonic plague); once the blood is brought into the blood, it can easily cause the septicemia plague (septicemic plague), and further spread to the spleen, liver, lung and other organs and tissues; finally, a part of the patients will develop into the lung plague (pneumonic plague), the pathogen can be transmitted directly through the air to other people, easy to spread and high lethal rate. The strong infectious disease caused by Phytophthora has triggered 3 pandemics worldwide, which has brought serious disasters to human beings, and to some extent affected the politics, economy and culture of all ethnic groups. Moreover, in recent years, the WHO (WHO) has listed the plague as a resurgence of the infectious disease. The research on the prevention and control of plague still appears to be very important. Yersinia pestis is evolved from its ancestor false tuberculosis Jerson Prand (Yersinia pseudotuberculosis, hereinafter referred to as "pseudo tuberculosis"), but it is completely different from the mode of transmission of pseudo tuberculosis bacteria. In nature, Yersinia pestis is circulated through the bite of the arthropod flea in the host animal, and the flea of the pathogen is accidental. In the flea body, Yersinia pestis will form a dense biological membrane that clog the flea's front stomach, and form a so-called "fungus bolt", which makes the flea sucking blood unable to enter the stomach, the flea is at the moment of starvation, repeatedly bites the host and promotes the spread of the Yersinia pestis. Therefore, the rat The production of the biofilm of the Phytophthora is of great significance to its ability to spread through the fleas. Yersinia pestis has a complex and accurate control network that controls the decisive factors of the biofilm formation and the activation and inhibition of the virulence factors. The synergism of the regulators at all levels has important implications for the pathogenesis and spread of the Yersinia pestis. The current research shows that many important regulators and their target genes play an important role in the formation of Yersinia pestis biofilm and pathogenicity of the pathogen. The HMS HFRS operon in Yersinia pestis is located in the PGM site on the chromosome and is responsible for the synthesis and transport of poly beta -1,6-N- acetyl -D- glucosamine (poly- beta -1,6-N). -acetylglucosamine exopolysaccharide) a similar polysaccharide compound, the main component of the biofilm matrix, is directly related to whether the bacterial colony of Yersinia pestis can be dyed by Congo red dye. C-di-GMP is a widely existing second messenger in bacteria, affecting the expression of bacterial virulence factors and biofilm. Formation. In Yersinia pestis, Hms T and Hms D are the only two guanosine cyclase catalyzing the synthesis of c-di-GMP, thus promoting the formation of biofilm. However, Hms P is the only phosphodiesterase that catalyzes the degradation of c-di-GMP in Yersinia pestis, thus inhibiting the production of the biofilm of the Yersinia pestis. In Gram-negative bacteria, the lipopolysaccharide (Lipopolysacch) Aride) is an essential component of the outer membrane. Generally speaking, lipopolysaccharide consists of three parts: lipid A, core polysaccharide (Kdo) and O antigen, while LPS are connected to Kdo with the lipid A only under the catalysis of glycosyltransferase. In Yersinia pestis, WAA A, WAA E and COA D constitute a operon encoding of the three gene. The glycosyltransferase catalyzes Kdo to connect to the lipid A, and the Yersinia pestis after the deletion of WAA A also shows a distinct biofilm formation defect, the protein encoded by.Waa E plays a key role in the modification of the core polysaccharide chain, and the study shows that the biofilm formation is about 40% reduced when the WAA E is missing in vitro. There is an important link between the formation of the biofilm of Yersinia pestis and the synthesis of lipopolysaccharide. In Yersinia pestis, the synthesis and secretion of P H6 antigen, an important adhesion factor and the.P H6 antigen of virulence factor, requires the participation of two adjacent operon genes, that is, PSA ABC and PSA EF.psa EF can promote the expression of PSA ABC by encoding the regulatory subproteins. Important virulence regulators, Rov A and Pho P, can activate and inhibit their expression of.P H6 antigen by directly binding to the promoter region of PSA ABC and PSA EF, and can be used to mediate the adhesion of Yersinia pestis to alveolar epithelial cells. Family regulator, affecting the expression of a large number of bacterial virulence genes, plays an important role in the regulation of three pathogenic Jerson Prand's virulence genes. Many transcriptional regulators of the Mar R family, such as Tca R of Staphylococcus epidermidis (Staphylococcus epidermidis), Asr R for Enterococcus faecium (Enterococcus faecium), and variant chain balls The Rca R of Streptococcus mutans and Sar Z/Sar A of Staphylococcus aureus (Staphylococcus aureus) have been reported to affect the formation of bacterial biofilm. However, Rov A on the regulation mechanism of the biofilm formation of Yersinia pestis is an unknown transcriptional regulator. It was first found to be false. In tuberculosis, studies have shown that Rov M can directly bind to the promoter region of the ROV A gene and inhibit its transcription, and Rov M affects the invasiveness, virulence and motility of the Mycobacterium tuberculosis. Many Lys R family transcriptional regulators, such as the Pec T of the chrysanthemum (Erwinia Chrysanthemi), and the soft rot of carrots. And Lrh A of Escherichia coli (Escherichia coli) are all important in the effects of bacterial virulence and biofilm gene regulation. Then, what is the role of Rov M in the virulence of Yersinia pestis and the gene regulatory network formed by biofilm? In this study, the two regulators of Rov M and Rov A were used as the main research objects, through biological being The related phenotypic experiments of membrane formation detection, such as the semi quantitative experiment of crystal violet staining, the egg development experiment of nematode worm, and the morphology observation of the colony surface, explored the effect of Rov M and Rov A on the formation of the biofilm of Yersinia pestis. The results showed that Rov M could promote the formation of the biofilm of Yersinia pestis, while Rov A inhibited the shape of the biofilm of Yersinia pestis. Explore whether Rov M and Rov A affect the synthesis of second messenger c-di-GMP by detecting and comparing the intracellular c-di-GMP content of bacteria between the different strains of Yersinia. The results show that Rov M activates the synthesis of c-di-GMP significantly, while Rov A strongly inhibits the synthesis of c-di-GMP. Two ways are given by subcutaneous infection and venous infection. Mice injected with Yersinia pestis and plotted the survival curve of mice to explore the effect of Rov M on the virulence of Yersinia pestis. The results showed that Rov M inhibited the virulence of Yersinia pestis. After obtaining the results of the phenotypic experiment, the fine gene regulation experiments, such as primer extension experiment, real-time quantitative fluorescence PCR experiment, Lac Z report gene fusion experiment and gel resistance, were further studied. The molecular mechanism of Rov M and Rov A on the formation of Yersinia pestis biofilm and the regulation of virulence related target genes and regulatory subgenes was investigated. The results showed that Rov M expressed the expression of HMS HFRS, HMS T, HMS CDE, and inhibited the formation of the Yersinia pestis biofilm at the same time. The expression of -pho PQ-YPO1632 does not affect WAA AE-coa D, Pho PQ-YPO1632 and fur's expression.Rov A through inhibition of HMS T, which obstruct the formation of the membrane of the Yersinia pestis. The expression of ROV A and the inhibition of the expression of PSA ABC and PSA EF to inhibit the virulence of Yersinia pestis. At the same time, Rov M can activate its own expression and low expression under 26 degree C and low expression under 37 degree C. The possible regulatory pathway. Under the environment temperature of the flea (26 C), Rov M is in the active state. It can promote the formation of Yersinia pestis biofilm by regulating the biofilm formation, and inhibit the expression of Rov A at the same time, so that a large number of virulence factors of Rov A are in a state of inhibition, which is beneficial to it. Increasing the ability of Yersinia pestis to spread through fleas. When the Yersinia pestis is transmitted to the mammalian body, the survival environment changes from 26 C to 37 C, and the expression of Rov M decreases obviously, resulting in the inhibition of the related decisive factors of the biofilm formation, and the Rov A in the original expression at the inhibitory state is activated by the regulation of a large number of factors. The virulence of Yersinia pestis is enhanced by the virulence factors. Therefore, we can see the important position of Rov M and Rov A in the control network of Yersinia pestis. Rov M and Rov A inhibit and activate the virulence of Yersinia pestis by activating and inhibiting the formation of the biofilm of Yersinia pestis, respectively. The pathogenicity of mammalian and human beings. When the temperature of the growth environment changed from 26 C to 37 C, the expression level of Rov M in the Mycobacterium tuberculosis was not obviously changed, but the expression level of Rov M in Yersinia pestis was significantly reduced, which may be a suitable change in the process of evolution from pseudo tuberculosis bacteria to Yersinia pestis.

【學(xué)位授予單位】：中國人民解放軍軍事醫(yī)學(xué)科學(xué)院
【學(xué)位級別】：博士
【學(xué)位授予年份】：2016
【分類號】：R378

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