本文選題：糖綴合物疫苗 + E.coli�。� 參考：《山東大學(xué)》2016年博士論文

【摘要】：大腸桿菌(E. coli) O157:H7是嚴(yán)重的腸道致病菌,通常引起腹瀉、出血性結(jié)腸炎、溶血性尿毒癥等。傳統(tǒng)的抗生素治療會(huì)引起腸道內(nèi)E. coli 0157:H7細(xì)胞裂解并向腸道黏膜釋放志賀樣毒素等,有加重病情的風(fēng)險(xiǎn)。疫苗作為替代手段,對(duì)預(yù)防E. coli 0157:H7的感染具有重要意義。O-抗原或O-PS,作為脂多糖的重要組成部分,暴露在細(xì)菌外表面,是機(jī)體免疫系統(tǒng)識(shí)別的重要靶點(diǎn)。O-PS是不依賴于T細(xì)胞的抗原。O-PS免疫機(jī)體主要產(chǎn)生抗O-PS的IgM抗體,幾乎不產(chǎn)生IgG抗體以及T細(xì)胞記憶,需要按期重復(fù)接種來維持免疫力,并且不能在免疫系統(tǒng)發(fā)育不完全的小于2周歲的嬰幼兒、免疫力低下的老年人等人群中產(chǎn)生足夠的免疫力。通過將O-PS連接到載體蛋白上,形成的糖綴合物是依賴于T細(xì)胞的抗原。糖綴合物免疫機(jī)體產(chǎn)生的抗O-PS抗體從IgM向IgG、IgA等轉(zhuǎn)換,并產(chǎn)生T細(xì)胞記憶,不僅能在健康成年人體內(nèi)產(chǎn)生持久的免疫力,而且針對(duì)嬰幼兒、免疫力底下的老年人同樣有效。糖綴合物疫苗,公認(rèn)為是最有效和最安全的抗菌疫苗之一。為了有效預(yù)防E.coli 0157:H7的感染,本論文針對(duì)E. coli O157:H7的O-PS進(jìn)行了糖綴合物疫苗的生物法合成及免疫學(xué)研究。本論文分為三部分研究?jī)?nèi)容。第一部分是生物法合成糖綴合物疫苗(第二章)；第二部分是糖綴合物疫苗O-PS-MBP的免疫學(xué)評(píng)價(jià)(第三章)；第三部分是載體蛋白及其不同位置多肽對(duì)糖綴合物疫苗抗多糖IgG滴度和亞型的影響(第四章)。第一部分：糖綴合物疫苗的合成通常采用化學(xué)法。但是化學(xué)法存在著生產(chǎn)成本高、質(zhì)量難以控制、容易有批次間的差異等局限性。本部分我們采用基于空腸彎曲菌(C. jejuni)N-糖基化系統(tǒng)的體內(nèi)酶法合成糖綴合物疫苗。糖基轉(zhuǎn)移酶Pg1B是C.jejuni的關(guān)鍵酶,負(fù)責(zé)將糖鏈從類萜類脂載體連接到載體蛋白的氨基酸序列D/E-X-N-Y-S/T (X, Y≠P)的天冬酰胺(N)殘基上。利用來自C. jejuni的N-糖基化系統(tǒng)和E. coli O-PS合成途徑比較相似的特點(diǎn),將C. jejuni N-糖基化系統(tǒng)的關(guān)鍵酶Pg1B的基因、E. coli O157:H7O-PS合成基因、載體蛋白(麥芽糖結(jié)合蛋白MBP、CRM197或AcrA)合成基因?qū)氲角贸腔D(zhuǎn)移酶基因waal的宿主菌E. coliW3110中,從而建立E. coli的N-糖基化系統(tǒng)。利用E.coli糖基化系統(tǒng)生產(chǎn)糖綴合物疫苗,具有構(gòu)建方式靈活、一次發(fā)酵、純化條件簡(jiǎn)單、成本低的特點(diǎn),滿足大規(guī)模制備的要求。同時(shí),利用E.coli N-糖基化系統(tǒng)生產(chǎn)的糖綴合物疫苗糖基化位點(diǎn)、糖鏈長(zhǎng)度等明確并可控,且生產(chǎn)批次之間沒有差異,滿足作為疫苗的質(zhì)量要求。然后通過對(duì)重組菌的誘導(dǎo)、蛋白的表達(dá)和純化,得到的糖綴合物經(jīng)過定性分析(包括考馬斯亮藍(lán)染色檢測(cè)western blot檢測(cè)、MALDI-TOF檢測(cè)、糖組成分析),得到了3個(gè)連有E. coli 0157:H7 O-PS的、載體蛋白不同的糖綴合物O-PS-MBP、O-PS-CRM、O-PS-AcrA。又通過定量分析得知,O-PS-MBP、O-PS-CRM、 O-PS-AcrA的得率約為0.5-1 mg/L(蛋白定量),且O-PS-MBP和O-PS-CRM的糖基化比例比O-PS-AcrA更高。利用E. coli N-糖基化系統(tǒng)生產(chǎn)糖綴合物O-PS-MBP、O-PS-CRM、O-PS-AcrA,開辟了一條合成E. coli O157:H7疫苗的新途徑,具有廣闊的應(yīng)用前景。第二部分：適應(yīng)性免疫應(yīng)答分為體液免疫和細(xì)胞免疫。之前報(bào)道的抗E. coli 0151:H7的糖綴合物疫苗O-PS-rEPA和O-PS-Stx,更多關(guān)注的是其產(chǎn)生抗E. coli O157:H7多糖抗體的能力,即體液免疫。幾乎沒有文獻(xiàn)報(bào)道糖綴合物疫苗刺激機(jī)體產(chǎn)生的細(xì)胞免疫,包括T細(xì)胞的增殖和分化、細(xì)胞因子的分泌等。現(xiàn)在,有越來越多的研究表明細(xì)胞免疫在抗菌感染的重要作用,而且其作用時(shí)間比抗體更加持久。目前的嬰幼兒計(jì)劃免疫中有很多疫苗是糖綴合物疫苗。然而,同時(shí)或先后免疫接種多種糖綴合物疫苗時(shí),如果載體蛋白相同,可能會(huì)引起免疫抑制等負(fù)面作用。面對(duì)日益增多的新型的糖綴合物疫苗,除了廣泛應(yīng)用的載體蛋白外,急需尋找和開發(fā)新的載體蛋白。目前,探索新型載體蛋白主要集中在尋找含有T細(xì)胞表位的蛋白、有Toll樣受體特性的蛋白等。最近,人們開始關(guān)注MBP在免疫學(xué)上的價(jià)值和應(yīng)用。一些具有抗腫瘤、抗菌或抗寄生蟲的活性蛋白在和MBP融合表達(dá)后活性明顯提高。研究證明MBP有TLR4激動(dòng)劑的性質(zhì),可促進(jìn)Thl細(xì)胞的活化,并有激活樹突狀細(xì)胞和腹腔巨噬細(xì)胞、促進(jìn)脾臟淋巴細(xì)胞的增殖等作用。然而,目前還沒有文獻(xiàn)報(bào)道MBP作為糖綴合物疫苗的載體蛋白以及MBP對(duì)糖綴合物疫苗的免疫增強(qiáng)作用。本部分,我們用以MBP作為載體蛋白的糖綴合物O-PS-MBP免疫BALB/c小鼠,檢測(cè)O-PS-MBP激活的體液免疫和細(xì)胞免疫。體液免疫方面,O-PS-MBP激活小鼠產(chǎn)生了抗E. coli O157:H7多糖的血清IgG、IgM和腸道IgA。并且,O-PS-MBP免疫血清在補(bǔ)體環(huán)境中可以有效殺死E. coli O157:H7。細(xì)胞免疫方面,O-PS-MBP促進(jìn)脾臟淋巴CD4+T細(xì)胞、CD8+T細(xì)胞的增殖。此外通過分析得出,O-PS-MBP免疫血清中IFN-γ、抗E. coli 0157:H7多糖IgG2a含量較高,說明O-PS-MBP刺激小鼠機(jī)體偏向Thl型免疫應(yīng)答。進(jìn)一步地,通過ELISPOT分析發(fā)現(xiàn),MBP無論是單獨(dú)免疫還是以糖綴合物的形式免疫,都能刺激機(jī)體產(chǎn)生IFN-y,抑制產(chǎn)生IL-4,說明載體蛋白MBP使O-PS-MBP偏向Thl型細(xì)胞免疫應(yīng)答,有很好的免疫增強(qiáng)作用。以MBP作為糖綴合物疫苗的載體蛋白具有廣闊的應(yīng)用前景。第三部分：糖綴合物疫苗激活機(jī)體產(chǎn)生抗多糖抗體,并通過多糖抗體介導(dǎo)的調(diào)理素或補(bǔ)體作用吞噬病菌,達(dá)到清除病菌、保護(hù)機(jī)體的作用。糖綴合物疫苗產(chǎn)生的抗多糖IgG抗體是體液免疫應(yīng)答的重要組成部分,IgG抗體滴度的高低直接決定著糖綴合物疫苗的免疫效果。IgG根據(jù)其結(jié)構(gòu)特點(diǎn),可分為不同的亞型,包括IgG1、 IgG2、IgG3等。不同的IgG亞型有不同的功能和特點(diǎn)。同時(shí),IgG亞型分布反應(yīng)了Th細(xì)胞免疫應(yīng)答的方向(Thl或Th2)。研究糖綴合物疫苗引起的IgG亞型的分布或Th細(xì)胞分化的方向,對(duì)評(píng)價(jià)糖綴合物疫苗免疫機(jī)制和效果有重要意義。本部分,我們通過多肽免疫小鼠實(shí)驗(yàn)和不同載體蛋白的糖綴合物疫苗免疫小鼠實(shí)驗(yàn),探討了載體蛋白及其不同位置多肽對(duì)糖綴合物疫苗抗多糖IgG滴度和亞型的影響。首先是載體蛋白及其不同位置多肽對(duì)糖綴合物疫苗抗多糖IgG滴度的影響。通過ELISA檢測(cè)3個(gè)載體蛋白不同的糖綴合物疫苗O-PS-MBP、O-PS-CRM、O-PS-AcrA分別免疫小鼠后的血清,結(jié)果發(fā)現(xiàn)載體蛋白不同的糖綴合物疫苗產(chǎn)生的抗多糖IgG滴度不同。此外,有文獻(xiàn)報(bào)道,載體蛋白對(duì)糖綴合物疫苗抗多糖抗體有促進(jìn)和抑制作用。然而,臨床結(jié)果沒有規(guī)律可循,也沒有明確的機(jī)制去解釋這種現(xiàn)象。通過以載體蛋白MBP上3個(gè)不同位置的多肽分別前免疫,以O(shè)-PS-MBP后免疫,檢測(cè)多肽對(duì)O-PS-MBP抗多糖抗體的促進(jìn)或抑制作用。結(jié)果發(fā)現(xiàn)載體蛋白MBP中靠近糖基化位點(diǎn)或者糖基化位點(diǎn)處的多肽,相比遠(yuǎn)離糖基化位點(diǎn)的多肽,對(duì)糖綴合物疫苗O-PS-MBP產(chǎn)生抗E. coli O157:H7多糖IgG有明顯促進(jìn)作用。因此,載體蛋白的促進(jìn)或抑制作用和糖綴合物疫苗的糖基化位點(diǎn)的多少有密切關(guān)系。后免疫的糖綴合物疫苗的糖基化位點(diǎn)越多,靠近糖基化位點(diǎn)的或糖基化位點(diǎn)處的多肽就越多,越會(huì)發(fā)生促進(jìn)現(xiàn)象；相反,糖基化位點(diǎn)越少,靠近糖基化位點(diǎn)的或糖基化位點(diǎn)處的多肽就越少,越會(huì)發(fā)生抑制現(xiàn)象。其次是檢測(cè)載體蛋白及其不同位置多肽對(duì)糖綴合物疫苗抗多糖抗體IgG亞型的影響。盡管糖綴合物疫苗的抗多糖IgG亞型分布與抗載體蛋白IgG亞型分布不一致,但是通過比較MBP和O-PS-MBP免疫血清中抗不同位置多肽的IgG亞型發(fā)現(xiàn),與MBP相比,O-PS-MBP抗靠近糖基化位點(diǎn)的或糖基化位點(diǎn)處的多肽的IgG2a顯著降低,而免疫O-PS-MBP產(chǎn)生的抗多糖抗體以IgG2a為主。由于靠近糖基化位點(diǎn)的或糖基化位點(diǎn)處的多肽包含有糖綴合物降解形成的寡糖-多肽中的部分多肽,由此,我們可以推斷得出,寡糖-多肽中的抗多肽的IgG亞型分布和抗寡糖的IgG亞型分布是一致的。綜上所述,寡糖-多肽的多肽可促進(jìn)糖綴合物疫苗中抗多糖抗體IgG的產(chǎn)生并且影響抗多糖抗體的IgG亞型分布。因此,通過改變糖綴合物疫苗的糖基化位點(diǎn)的個(gè)數(shù)或改變糖基化位點(diǎn)的位置,可控制糖綴合物疫苗抗多糖IgG的滴度和亞型分布。總之,本論文通過建立E. coli N-糖基化系統(tǒng)為生產(chǎn)糖綴合物疫苗開辟了新的途徑。合成的糖綴合物疫苗能夠有效地激活機(jī)體產(chǎn)生適應(yīng)性免疫應(yīng)答,保護(hù)機(jī)體免受E. coli O157:H7感染。此外,本文著重分析了載體蛋白對(duì)糖綴合物疫苗免疫活性的影響,并闡述了MBP作為載體蛋白的免疫增強(qiáng)作用,為理性地選擇載體蛋白和研究糖綴合物疫苗免疫機(jī)制有一定的意義。
[Abstract]:E. coli (E.) is a serious intestinal pathogenic bacteria, which usually causes diarrhea, hemorrhagic colitis, hemolytic uremia, etc. traditional antibiotic therapy can cause the lysis of E. coli 0157:H7 cells in the intestine and release Shiga like toxin to the intestinal mucosa, and the risk of adding serious illness. The vaccine is used as a substitute for the prevention of E. coli 015. The infection of 7:H7 is of great significance.O- antigen or O-PS. As an important component of lipopolysaccharide, it is exposed to the outer surface of the bacteria. It is an important target for the identification of the immune system..O-PS is an antigen that does not depend on the antigen of T cells to produce the anti O-PS IgM antibody, and does not produce the IgG antibody and T cell memory. It needs to be repeated on time. Inoculation to maintain immunity, and not to produce sufficient immunity in the immune system that is less than 2 years old, the aged people of less than 2 years old, the aged people with low immunity. The glycoconjugate formed by connecting to the carrier protein is an antigen dependent on the T cell. The anti O-PS antibody produced by the glycoconjugate immune body from the Ig M to IgG, IgA and so on, and produce T cell memory, not only can produce persistent immunity in healthy adults, but also be effective for infants and young people under immune system. Glycoconjugate vaccine is recognized as one of the most effective and safest antibacterial vaccines. This paper aims at the effective prevention of E.coli 0157:H7 infection. This paper aims at E. C. The biosynthesis and immunology of the glycoconjugate vaccine was carried out by the O-PS of Oli O157:H7. This paper is divided into three parts. The first part is the biosynthesis of conjugate vaccine (second chapters) by biological method; the second part is the immunological evaluation of the glycoconjugate vaccine O-PS-MBP (third chapter); the third part is the carrier protein and its different location. The effect of polypeptide on the anti polysaccharide IgG titer and subtype of glycoconjugate vaccine (fourth chapter). Part 1: synthesis of glycoconjugate vaccine is usually used chemical method. But chemical method has the limitation of high production cost, difficult quality control, easy to have difference between batch and so on. In this part, we use C. jejuni based N- glycosyl group. Glycosyltransferase Pg1B is the key enzyme of C.jejuni in vivo. Glycosyltransferase is the key enzyme to connect the sugar chain from the class terpene like carrier to the amino acid sequence of the carrier protein D/E-X-N-Y-S/T (X, Y P) on the asparagine (N) residue. It is similar to the N- glycosylation system from C. jejuni and the E. coli synthesis pathway. The gene of the key enzyme of the C. jejuni N- glycosylation system, the E. coli O157:H7O-PS synthesis gene, the carrier protein (maltose binding protein MBP, CRM197 or AcrA), was introduced into the host strain of the host bacterium that knockout glycosyltransferase gene, and the glycosylation system was built. The production of glycoconjugate vaccine has the characteristics of flexible construction, single fermentation, simple purification conditions and low cost, which meets the requirements of large scale preparation. At the same time, the glycosylation site of glycoconjugate vaccines produced by E.coli N- glycosylation system, sugar chain length and so on are clear and controllable, and there is no difference between production batches to meet the vaccine. Quality requirements. Then through the induction of recombinant bacteria, protein expression and purification, the glycoconjugate obtained by the qualitative analysis (including Coomassie brilliant blue staining detection Western blot detection, MALDI-TOF detection, sugar composition analysis), obtained 3 E. coli 0157:H7 O-PS, the carrier protein of different glycoconjugate O-PS-MBP, O-PS-CRM, O-PS-Acr. A. also found that the yield of O-PS-MBP, O-PS-CRM, and O-PS-AcrA was about 0.5-1 mg/L (protein quantitative), and that the ratio of glycosylation of O-PS-MBP and O-PS-CRM was higher than O-PS-AcrA. The new way to produce conjugate vaccines was opened with E. coli N- glycosylation system. The second part: the second part: the adaptive immune response is divided into humoral immunity and cell immunity. The previous reported glycoconjugate vaccines against E. coli 0151:H7, O-PS-rEPA and O-PS-Stx, are more concerned with the ability to produce anti E. coli O157:H7 polysaccharide antibodies, that is, humoral immunity. Few literature reports on the glycoconjugate vaccine stimulator The cell immunity produced by the body, including the proliferation and differentiation of T cells, the secretion of cytokines, and so on. Now, more and more studies have shown that cellular immunity plays an important role in antibacterial infection, and its action time is more lasting than antibody. When immunized with a variety of glycoconjugate vaccines, if the carrier protein is the same, it may cause negative effects, such as immunosuppression. Facing the increasing number of new glycoconjugate vaccines, in addition to the widely used carrier protein, it is urgent to find and develop new carrier proteins. At present, new carrier proteins are mainly focused on the search for T cells. Protein of the epitopes, proteins with Toll like receptor properties. Recently, people began to pay attention to the immunological value and application of MBP. Some active proteins with anti tumor, antibacterial, or anti parasites have been significantly improved after the fusion and expression of MBP. The study shows that MBP has the properties of TLR4 agonists, which can promote the activation of Thl cells and have the activation tree. The protrusion and peritoneal macrophages promote the proliferation of splenic lymphocytes. However, there has not been a report of MBP as a carrier protein of glycoconjugate vaccine and the immune enhancement effect of MBP on glycoconjugate vaccine. In this part, we immunized BALB/c mice with the glycoconjugate of MBP as a carrier protein to detect O-P S-MBP activates humoral and cellular immunity. In humoral immunity, O-PS-MBP activates the serum IgG, IgM and intestinal IgA. against E. coli O157:H7 polysaccharide in mice, and O-PS-MBP immune sera can effectively kill E. coli O157:H7. cell immunity in the complement environment, promote the proliferation of spleen lymphoid cells and proliferate cells. In addition, the analysis showed that the content of IFN- gamma in O-PS-MBP immune sera and the IgG2a content of anti E. coli 0157:H7 polysaccharide was higher, which indicated that O-PS-MBP stimulated the Thl immune response in mice. Further, the ELISPOT analysis showed that MBP, either alone or in the form of glycoconjugate, could stimulate the organism to produce IFN-y and inhibit the production of IL. -4, which indicates that the carrier protein MBP makes O-PS-MBP biased toward Thl cell immune response and has a good immune enhancement. The carrier protein of MBP as a glycoconjugate vaccine has a broad application prospect. The third part: glycoconjugate vaccine activates the body to produce anti polysaccharide antibody, and phagocytosis through the action of the peptide or complement mediated by polysaccharide antibody. The anti polysaccharide IgG antibody produced by the glycoconjugate vaccine is an important part of the humoral immune response. The titer of IgG antibody directly determines the immune effect of the glycoconjugate vaccine.IgG, according to its structural characteristics, it can be divided into different subtypes, including IgG1, IgG2, IgG3 and so on. Different IgG subtypes. There are different functions and characteristics. At the same time, the distribution of IgG subtypes reacts with the direction of Th cell immune response (Thl or Th2). The study of the distribution of IgG subtypes caused by glycoconjugate vaccines or the direction of Th cell differentiation is of great significance for evaluating the immune mechanism and effect of glycoconjugate vaccines. The effect of carrier protein and its different position peptides on the titer and subtype of polysaccharide IgG in glycoconjugate vaccine was investigated with the glycoconjugate vaccine of the carrier protein. First, the effect of the carrier protein and its different position peptides on the anti polysaccharide IgG titer of the glycoconjugate vaccine. The different sugars of 3 carrier proteins were detected by ELISA. The conjugate vaccine O-PS-MBP, O-PS-CRM, and O-PS-AcrA immunized the serum of the mice respectively. The results showed that the anti polysaccharide IgG titer of the glycoconjugate vaccine was different. In addition, it was reported that the carrier protein could promote and inhibit the polysaccharide conjugate vaccine against polysaccharide antibody. However, the clinical results were not regularly followed, nor were the clinical results. There is a clear mechanism to explain this phenomenon. By immunization with 3 different locations on the carrier protein MBP and after O-PS-MBP immunization, the peptide's promoting or inhibiting effect on O-PS-MBP anti polysaccharide antibody is detected. The results show that the polypeptide in the carrier protein MBP near the glycosylation site or glycosylation site is far from the glycosylation. The polypeptide of the site has a significant effect on the production of anti E. coli O157:H7 polysaccharide IgG by the glycoconjugate vaccine O-PS-MBP. Therefore, the promotion or inhibition of the carrier protein is closely related to the glycosylation site of the glycoconjugate vaccine. The more glycosylation sites in the immunized glycoconjugate vaccines are near the glycosylation site or glycosylation site. The more peptides at the site, the more promoting phenomenon; on the contrary, the less the glycosylation site, the less the polypeptide near the glycosylation site or the glycosylation site, the more inhibition occurs. Secondly, the effect of the carrier protein and its different position peptides on the glycoconjugate vaccine against the polysaccharide antibody IgG subtype of the glycoconjugate vaccine. The distribution of the anti polysaccharide IgG subtype of the vaccine was not consistent with the distribution of the anti carrier protein IgG subtype, but by comparing the IgG subtypes of the MBP and O-PS-MBP immunized serum against different positions of polypeptide, the IgG2a of O-PS-MBP near the glycosylation site or the glycosylation site decreased significantly compared with MBP, and the anti polysaccharide produced by immune O-PS-MBP was produced. The antibody is dominated by IgG2a. Since the peptide near the glycosylation site or at the glycosylation site contains some polypeptides from oligosaccharides and peptides formed by glycoconjugate degradation, we can deduce that the distribution of IgG subtypes of anti peptides in oligosaccharide peptides and the distribution of anti oligosaccharide IgG subtypes are consistent. To sum up, oligosaccharide polypeptide Polypeptide can promote the production of anti polysaccharide antibody IgG in glycoconjugate vaccine and influence the distribution of IgG subtype of anti polysaccharide antibody. Therefore, by changing the number of glycosylation sites or changing the location of glycosylation sites in glycoconjugate vaccines, the titer and subtype distribution of polysaccharide conjugate vaccine against polysaccharide IgG can be controlled. The E. coli N- glycosylation system opens a new way for the production of glycoconjugate vaccines. The synthesized glycoconjugate vaccine can effectively activate the organism to produce adaptive immune response and protect the body from E. coli O157:H7 infection. In addition, the effect of the carrier protein on the immune activity of glycoconjugate vaccine is analyzed in this paper, and MBP is described in this paper. It is of great significance to rationally select carrier protein and study the immune mechanism of glycoconjugate vaccine for the enhancement of immune function of the carrier protein.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2016
【分類號(hào)】：R392

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