本文選題：豬鏈球菌 + 腦微血管內皮細胞　； 參考：《中國人民解放軍軍事醫(yī)學科學院》2011年博士論文

【摘要】：豬鏈球菌病是重要的新發(fā)傳染病,1998年和2005年先后兩次在我國江蘇和四川爆發(fā)流行,造成200多人感染,50多人死亡,具有較高的病死率和病殘率。腦膜炎為豬鏈球菌感染的主要臨床癥狀。目前,豬鏈球菌致腦膜炎的致病機制還不完全清楚。一般認為,豬鏈球菌致腦膜炎過程是多步驟的,其中關鍵環(huán)節(jié)是:豬鏈球菌如何以較低水平的菌量從粘膜上皮進入血液;豬鏈球菌如何實現(xiàn)血中存活,造成菌血癥;豬鏈球菌如何穿過血腦屏障進入中樞神經(jīng)系統(tǒng)。 豬鏈球菌與腦微血管內皮細胞相互作用的過程是豬鏈球菌穿過血腦屏障的重要過程。目前,對豬鏈球菌與腦微血管內皮細胞的相互作用特征有了一定的了解,如豬鏈球菌能粘附豬腦微血管內皮細胞(porcine brain microvascular endothelial cells, pBMEC)和人腦微血管內皮細胞(human brain microvascular endothelial cells, hBMEC),但不能侵襲hBMEC;豬鏈球菌能刺激BMEC細胞分泌細胞因子等。但有關豬鏈球菌與BMEC細胞相互作用的細胞和分子機制還不完全清楚。 因此,本研究擬從三個方面研究豬鏈球菌與hBMEC細胞的相互作用。即:豬鏈球菌如何調節(jié)自身,調控特定的毒力因子應對同hBMEC細胞的接觸;豬鏈球菌感染對hBMEC細胞基因轉錄的影響以及豬溶血素對hBMEC細胞骨架的影響。 第一部分:豬鏈球菌與hBMEC接觸后,自身基因表達譜變化情況。 本部分選用豬鏈球菌DNA芯片,研究與hBMEC細胞接觸后的豬鏈球菌全基因表達譜的變化。研究發(fā)現(xiàn):在與hBMEC接觸1 h后,豬鏈球菌有219個基因轉錄發(fā)生改變(其中131個基因上調,88個基因下調),與hBMEC接觸3 h后,豬鏈球菌有175個基因轉錄發(fā)生改變(其中123個基因上調,52個基因下調)。根據(jù)豬鏈球菌05ZY基因組的注釋信息,對所有表達發(fā)生改變的基因進行COG分類。COG分類顯示在編碼基因翻譯、氨基酸運輸、能量產(chǎn)生、細胞周期調控、細胞壁合成及脂類運輸相關的基因中,表達上調的基因數(shù)目多于表達下調的基因數(shù)目;而在編碼核苷酸運輸和碳水化合物運輸相關的基因中,表達下調的基因數(shù)目多于表達上調的基因數(shù)目。 進一步的分析發(fā)現(xiàn):細胞接觸后,與豬鏈球菌莢膜(capsule, CPS)合成有關的基因表達上調。透射電子顯微鏡觀察發(fā)現(xiàn),與細胞接觸后,豬鏈球菌莢膜明顯增厚,證明豬鏈球菌莢膜合成相關基因在豬鏈球菌與細胞接觸后表達上調。除上調CPS合成相關基因外,與hBMEC接觸后,豬鏈球菌還上調了epf、mrp、ofs等毒力基因的表達,但下調了ADS和sly等毒力基因的表達。另外,與hBMEC接觸后,豬鏈球菌上調細胞壁合成有關的基因,細胞壁蛋白基因如sao、SSU05_0272等,菌毛蛋白基因如sfp1,sfp2等以及與LTA丙氨�；揎椨嘘P的基因如dltB等的表達。此外,與hBMEC細胞接觸后,豬鏈球菌上調參與脂類合成的基因,參與基因復制、轉錄特別是蛋白合成的基因,以及編碼ATP合成酶F1F0的基因如atpC,atpD,atpA,atpH,atpF等的表達,使得代謝活動增加。同時,豬鏈球菌還上調細胞分裂相關基因的表達,使得細胞周期加快。 在分析芯片數(shù)據(jù)的基礎上,我們研究了豬鏈球菌與細胞接觸后莢膜增厚的分子機制。實驗結果表明:細胞接觸后豬鏈球菌莢膜的增厚,同雙組分系統(tǒng)2148/2149和Rgg有關,而同covR無關。具體機制為:豬鏈球菌在與hBMEC細胞接觸后,Rgg能通過某種機制感知細胞接觸信號,并將其傳遞給2148/2149基因,后者通過某種機制上調了CPS基因的表達。盡管covR能負調節(jié)CPS基因的表達,但與細胞接觸后,存在某種未知的機制阻斷covR對莢膜多糖合成相關基因的調控。 通過對與hBMEC接觸后豬鏈球菌基因表達譜變化的分析,我們推測豬鏈球菌基因表達的改變,可能有助于豬鏈球菌穿過血腦屏障。首先,增厚的莢膜和丙氨�；腖TA有助于豬鏈球菌抵抗血中吞噬細胞的清除和陽離子抗菌肽的殺傷。而且,莢膜自身還能以TLR-2和MyD88非依賴的方式誘發(fā)MCP-1的釋放。而MCP-1能下調緊密連接蛋白如ZO-1,occludin等在BMEC細胞中的表達并改變其在細胞間的分布,破壞血腦屏障的完整性。其次,豬鏈球菌上調編碼菌毛蛋白的基因、細胞壁蛋白的基因和細胞壁合成相關的基因的表達。這些上調表達的基因有助于增強豬鏈球菌與hBMEC細胞受體的識別,提高豬鏈球菌與hBMEC細胞的粘附,有助于豬鏈球菌刺激hBMEC細胞分泌細胞因子。再者,豬鏈球菌上調細胞周期相關基因和代謝、蛋白翻譯相關基因的表達。這些上調的基因,能加快豬鏈球菌的分裂,有助于豬鏈球菌在hBMEC細胞外的增殖。 第二部分:豬鏈球菌感染對hBMEC細胞基因表達的影響。 豬鏈球菌野生型261菌株和2148/2149基因敲除突變體分別以1:1的感染復數(shù)感染hBMEC細胞系hCMEC/D3細胞,以未感染的細胞為陰性對照,4 h后分別提取各組hCMEC/D3細胞的總RNA,逆轉錄和熒光標記后,同高密度的人全基因表達譜芯片(Agilent SurePrint G3 Human GE 8×60K)雜交。 芯片數(shù)據(jù)分析時,我們選擇q-value(%)≤5,同時差異倍數(shù)大于1.5倍的基因作為差異表達的基因。研究發(fā)現(xiàn),相比未感染組細胞,261菌株感染組細胞有2780個差異表達基因,其中446個基因上調表達,2334個基因下調表達。相比未感染組細胞,2148/2149突變體感染組細胞有2926個差異表達的基因,其中611個基因上調表達,2315個基因下調表達。而261菌株感染組和2148/2149突變體感染組的hCMEC/D3細胞表達譜之間未有差異顯著的基因。 進一步的分析發(fā)現(xiàn):在豬鏈球菌261菌株和2148/2149突變體感染4 h后,hCMEC/D3細胞大量上調編碼細胞因子如IL-1?,IL-6,IL-11,GM-CSF和趨化因子IL-8,MCP-1,CXCL1,CXCL2等基因的表達,上調細胞粘附蛋白如selectin E,ICAM-4等基因的表達,同時下調緊密連接相關蛋白如ZO-1,claudin 5的表達。此外,編碼細胞表面抗原的基因如CD34,CD59,CD93,CD83和CD274的表達也發(fā)生改變。 通過對豬鏈球菌感染后hCMEC/D3細胞基因表達譜數(shù)據(jù)的分析,結合目前豬鏈球菌與hBMEC細胞相互作用的研究進展,我們推測豬鏈球菌可能通過腦微血管內皮細胞間隙的方式穿過血腦屏障。首先,豬鏈球菌對hBMEC粘附率很低,且無侵襲能力,因此豬鏈球菌直接穿過hBMEC細胞進入中樞神經(jīng)系統(tǒng)的可能性基本可以排除。其次,豬鏈球菌感染后,hBMEC細胞編碼細胞因子、趨化因子和細胞粘附蛋白的基因表達上調。這些上調表達的分子在招募和粘附中性白細胞和單核細胞方面有重要作用,而中性白細胞和單核細胞粘附內皮細胞后,能激活內皮細胞信號通路,調節(jié)內皮細胞緊密連接的分布,增大細胞間的通透性。再者,豬鏈球菌感染后,hBMEC細胞下調ZO-1,Claudin 5,par-6等基因的表達,而這些蛋白在維持內皮細胞間的緊密連接中有重要作用。 第三部分:豬溶血素對hBMEC細胞骨架的影響。 熒光顯微鏡觀察發(fā)現(xiàn):亞裂解濃度的豬鏈球菌上清和SLY蛋白能重塑hBMEC的細胞骨架,形成應力纖維、絲狀偽足和片狀偽足。SLY蛋白對hBMEC細胞骨架的重塑表現(xiàn)為膽固醇依賴性。與不同濃度的膽固醇預孵育后,SLY蛋白重塑細胞骨架的活性被部分或完全抑制,而用M?CD對hBMEC細胞表面的膽固醇進行預去除,同樣能抑制豬鏈球菌上清和SLY對細胞骨架的重塑。 為了研究SLY蛋白重塑hBMEC細胞骨架的分子機制,我們檢測了hBMEC細胞裂解液中GTPase激活情況,研究發(fā)現(xiàn)豬鏈球菌上清和SLY均能激活hBMEC的RhoA和Rac1,且表現(xiàn)為時間依賴性,10 min時激活效應達到最大,但豬鏈球菌上清和SLY蛋白重塑hBMEC細胞骨架時沒有激活Cdc42。 總之,本研究從病原體和宿主細胞的反應性兩方面,研究了豬鏈球菌與hBMEC的相互作用。病原體方面:與hBMEC接觸后,豬鏈球菌通過雙組分系統(tǒng)Rgg和2148/2149上調莢膜合成相關基因的表達,增厚莢膜。此外,豬鏈球菌上調脂磷壁酸丙氨�；揎椣嚓P的基因。增厚的莢膜和丙氨�；腖TA有助于豬鏈球菌抵抗吞噬細胞和陽離子抗菌肽的殺傷。另外,豬鏈球菌還上調表達編碼菌毛蛋白的基因、細胞壁合成相關的基因以及細胞壁蛋白的基因,這有助于重塑豬鏈球菌的表面。豬鏈球菌表面蛋白表達量的上調,有助于豬鏈球菌與hBMEC的接觸,有助于豬鏈球菌刺激宿主細胞分泌細胞因子并激活其信號通路。此外,豬鏈球菌還上調細胞分裂相關基因的表達,加快細胞周期,這些變化有助于豬鏈球菌在細胞表面的增殖。宿主細胞方面:豬鏈球菌感染后,hBMEC細胞大量上調編碼細胞因子、趨化因子及細胞粘附蛋白基因的表達,下調編碼緊密連接相關蛋白基因的表達,同時改變細胞表面抗原基因表達。這些變化有助于提高腦微血管內皮細胞間的通透性。此外,豬鏈球菌上清和豬溶血素還能通過激活RhoA和Rac1重塑hBMEC細胞的細胞骨架,形成應力纖維、絲狀偽足和片狀偽足。由于肌動蛋白同緊密連接分子相連,細胞骨架的重塑造成緊密連接蛋白的重新分布,增大細胞間的間隙。我們推測這些變化有利于豬鏈球菌從腦微血管內皮細胞間隙穿過血腦屏障。
[Abstract]:Streptococcus suis disease (Streptococcus suis) is an important new infectious disease. It broke out in Jiangsu and Sichuan two times in China in 1998 and 2005, resulting in infection of more than 200 people, more than 50 deaths, high mortality and morbidity. Meningitis is the main clinical symptom of Streptococcus suis infection. The pathogenesis of meningitis caused by Streptococcus suis is not completely clear at present. It is generally believed that the process of meningitis induced by Streptococcus suis is a multistep process, and the key link is how Streptococcus suis enters the blood from the mucosal epithelium at a lower level of bacteria, how Streptococcus suis can survive in the blood, cause bacteremia, and how Streptococcus suis enters the central nervous system through the blood brain barrier.
The interaction between Streptococcus suis and cerebral microvascular endothelial cells is an important process of Streptococcus suis passing through the blood brain barrier. At present, the interaction characteristics of Streptococcus suis and cerebral microvascular endothelial cells have some understanding, for example, Streptococcus suis can adhere to porcine brain microvascular endothelial cells. PBMEC) and human brain microvascular endothelial cells (human brain microvascular endothelial cells, hBMEC), but not hBMEC, Streptococcus suis can stimulate the secretion of cytokines in BMEC cells, but the cell and molecular mechanisms of the interaction between Streptococcus suis and BMEC cells are not completely clear.
Therefore, this study intends to study the interaction between Streptococcus suis and hBMEC cells from three aspects: how Streptococcus suis regulates itself, regulates specific virulence factors to deal with hBMEC cells, the effect of Streptococcus suis infection on the gene transcription of hBMEC cells and the effect of pig hemolysin on the cytoskeleton of hBMEC.
Part one: the change of gene expression profile in Streptococcus suis after contact with hBMEC.
In this part, Streptococcus suis DNA chip was used to study the whole gene expression profiles of Streptococcus suis after contact with hBMEC cells. It was found that after 1 h contact with hBMEC, Streptococcus suis had 219 gene transcriptional changes (131 of them up, 88 genes down). After 3 h contact with hBMEC, there were 175 gene transcriptional changes in Streptococcus suis. Change (123 of these genes up, 52 genes down). According to the annotation information of the 05ZY genome of Streptococcus suis, the COG classification of all the genes that have changed is classified by.COG classification in the encoding gene translation, amino acid transport, energy production, cell cycle regulation, cell wall synthesis, and lipid transport related genes. The number of down regulated genes was more than the number of genes expressed. In genes encoding nucleotide transport and carbohydrate transport, the number of down regulated genes was more than the number of genes up - regulated.
Further analysis showed that after cell contact, the gene expression related to the synthesis of capsule (CPS) was up-regulated. Transmission electron microscopy showed that after contact with the cells, the capsule of Streptococcus suis was thickened obviously. It was proved that the gene of Streptococcus suis was up regulated by Streptococcus suis after contact with the cells. In addition to the up regulation of CPS In contact with hBMEC, Streptococcus suis also up-regulated the expression of EPF, MRP, ofs and other virulence genes, but down regulated the expression of virulence genes such as ADS and sly. In addition, Streptococcus suis up-regulated the genes related to cell wall synthesis, cell wall protein genes such as Sao, SSU05_0272, and pilin protein genes such as sfp1, SFP2 and so on. In addition to the expression of LTA propanylated modification related genes such as dltB, in addition, after contact with hBMEC cells, Streptococcus suis up-regulated genes involved in lipid synthesis, participated in gene replication, transcriptional in particular protein synthesis genes, and the expression of the genes encoding ATP synthase F1F0, such as atpC, atpD, atpA, atpH, atpF, etc., to increase metabolic activity. Streptococcus suis also up-regulated the expression of cell division related genes and accelerated cell cycle.
On the basis of the analysis of the chip data, we studied the molecular mechanism of the capsule thickening of Streptococcus suis after contact with the cells. The experimental results showed that the thickening of the capsule of Streptococcus suis after contact was related to the two component system 2148/2149 and Rgg, but not with covR. The specific mechanism is that after contact with hBMEC cells, the Streptococcus suis can pass through some sort. The mechanism perceiving the cell contact signal and transferring it to the 2148/2149 gene, the latter up-regulated the expression of the CPS gene through some mechanism. Although covR can negatively regulate the expression of CPS gene, there is a certain unknown mechanism that blocks the regulation of covR on the related basis of the capsule polysaccharide synthesis after contact with the cells.
By analyzing the gene expression profiles of Streptococcus suis after contact with hBMEC, we speculate that the changes in gene expression of Streptococcus suis may help Streptococcus suis to pass through the blood brain barrier. First, the thickened capsule and propionylated LTA can help Streptococcus suis to resist the clearance of phagocytes in blood and the killing of cationic antimicrobial peptides. The membrane itself can also induce the release of MCP-1 in a non dependent manner of TLR-2 and MyD88. And MCP-1 can down regulate the expression of tight connexin such as ZO-1, occludin and so on in BMEC cells and change its distribution in the cell and destroy the integrity of the blood brain barrier. Secondly, Streptococcus suis is up regulation of the gene of protein hair protein, gene and fine of cell wall protein. These up-regulated genes help to enhance the recognition of Streptococcus suis and hBMEC cell receptors, increase the adhesion of Streptococcus suis to hBMEC cells and stimulate Streptococcus suis to stimulate the secretion of cytokines in hBMEC cells. Furthermore, Streptococcus suis is up regulation of cell cycle related genes and metabolism, and related to protein translation These up-regulated genes can accelerate the division of Streptococcus suis and contribute to the proliferation of Streptococcus suis in hBMEC cells.
The second part: the effect of Streptococcus suis infection on the gene expression of hBMEC cells.
Streptococcus suis wild type 261 and 2148/2149 gene knockout mutants infect hBMEC cell line hCMEC/D3 cells with 1:1 infection complex number respectively, and the uninfected cells were negative control. The total RNA of hCMEC/D3 cells in each group was extracted after 4 h. After reverse transcription and fluorescence labeling, the same high density human whole gene expression spectrum chip (Agilent SurePrint) G3 Human GE 8 x 60K) hybridization.
In the analysis of chip data, we chose Q-value (%) (%) less than 5 and 1.5 times more than 1.5 times as differentially expressed genes. It was found that there were 2780 differentially expressed genes in the infected cells of 261 strains compared to those in the uninfected group, of which 446 genes were up-regulated and 2334 genes were downregulated. Compared with the uninfected group, 2148/2149 There were 2926 differentially expressed genes in the mutant infection group, of which 611 genes were up-regulated and 2315 genes were down regulated. There was no significant difference in the hCMEC/D3 cell expression profiles between the 261 infection group and the 2148/2149 mutant infection group.
Further analysis showed that after Streptococcus suis 261 and 2148/2149 mutants were infected with 4 h, hCMEC/D3 cells increased the expression of encoding cytokines such as IL-1?, IL-6, IL-11, GM-CSF and chemokine IL-8, MCP-1, CXCL1, CXCL2 and so on, up regulation of the expression of cell adhesion proteins such as selectin, and down regulated closely connected phase In addition, the expression of genes encoding cell surface antigens, such as CD34, CD59, CD93, CD83 and CD274, also changed, such as ZO-1, claudin 5.
Through the analysis of the gene expression profiles of hCMEC/D3 cells after Streptococcus suis infection and the research progress of the interaction between Streptococcus suis and hBMEC cells, we speculate that Streptococcus suis may pass through the blood brain barrier through the intercellular space of the cerebral microvascular endothelial cells. First, the adhesion rate of Streptococcus suis to hBMEC is very low and has no invasion ability. Therefore, the possibility of Streptococcus suis directly through hBMEC cells into the central nervous system can be eliminated. Secondly, after Streptococcus suis infection, hBMEC cells encode cytokines, chemokines and cell adhesion proteins. These up-regulated molecules are heavy in the recruitment and adhesion of neutrophils and mononuclear cells. When the neutrophils and mononuclear cells adhere to the endothelial cells, it can activate the endothelial cell signaling pathway, regulate the distribution of the endothelial cells tightly connected, and increase the permeability of the cells. Furthermore, after Streptococcus suis infection, hBMEC cells downregulate the expression of ZO-1, Claudin 5, Par-6 and other basic factors, and these proteins are tight between the endothelial cells. There is an important role in dense connections.
The third part: the effect of porcine hemolysin on hBMEC cytoskeleton.
The fluorescence microscopy showed that the sublysing concentration of Streptococcus suis supernatant and SLY protein could reshape the cytoskeleton of hBMEC and form stress fibers. The remolding of hBMEC cytoskeleton by filamentous and flaky pseudo foot.SLY protein was cholesterol dependent. After incubating with different concentrations of cholesterol, the activity of the remolded cytoskeleton of the SLY protein was found. Partial or complete inhibition, the removal of cholesterol on the surface of hBMEC cells by M? CD can also inhibit the reconstitution of cytoskeleton by supernatants of Streptococcus suis and SLY.
In order to study the molecular mechanism of SLY protein remolding hBMEC cytoskeleton, we detected the activation of GTPase in hBMEC cell lysate. The study found that Streptococcus suis supernatant and SLY could activate hBMEC RhoA and Rac1, and were time dependent, and the activation effect reached the maximum at 10 min, but Streptococcus suis supernatant and SLY protein reshaped hBMEC cells. Cdc42. does not activate the skeleton
In this study, the interaction between Streptococcus suis and hBMEC was studied from two aspects of the reactivity of the pathogen and host cell. In the aspect of pathogen: Streptococcus suis is up regulation of the expression of the related genes in the capsule synthesis and the thickening capsule through the dual component system Rgg and 2148/2149. In addition, Streptococcus suis is up regulation of lipophosphoric acid propanolylation. Decorrelating genes. Thickened capsule and propionylated LTA can help Streptococcus suis to resist the killing of phagocytes and cationic antimicrobial peptides. In addition, Streptococcus suis also up-regulated genes encoding pili protein, cell wall synthesis related genes and cell wall protein genes, which helps to reshape the surface of Streptococcus suis. The up-regulated expression of the surface protein of the bacteria contributes to the contact of Streptococcus suis with hBMEC, which helps to stimulate the secretion of cytokines and activate its signaling pathway by Streptococcus suis. In addition, Streptococcus suis also up-regulated the expression of cell division related genes and accelerated the cell cycle. These changes contribute to the proliferation of Streptococcus suis on the cell surface. Main cell side: after Streptococcus suis infection, hBMEC cells up regulate the expression of encode cytokines, chemokines and cell adhesion protein genes, down regulate the expression of closely linked protein genes and change the expression of cell surface antigen gene. These changes help to improve the permeability of cerebral microvascular endothelial cells. Streptococcus suis supernatant and pig hemolysin can also remould the cytoskeleton of hBMEC cells by activating RhoA and Rac1 to form stress fibers, filamentous and flaky pseudo feet. The redistribution of close connexin resulting from the remolding of the cytoskeleton caused by actin is connected to the close connexion molecules, and the intercellular space is increased. It helps Streptococcus suis cross the blood-brain barrier from the gap of brain microvascular endothelial cells.
【學位授予單位】：中國人民解放軍軍事醫(yī)學科學院
【學位級別】：博士
【學位授予年份】：2011
【分類號】：R363

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