幽门螺杆菌外膜蛋白18识别干扰素gamma辅助幽门螺杆菌在胃部长期定植
发布时间：2018-08-28 16:39
【摘要】：目的 幽门螺杆菌(Helicobacter pylori, H. pylori)是一种单极、多鞭毛、末端钝圆、螺旋形弯曲的革兰氏阴性菌,定植于全世界约一半的人体内。在大部分带菌者体内,H. pylori感染引起的慢性胃炎是无症状的,但却被认为是十二指肠溃疡、胃溃疡、胃癌及黏膜相关淋巴组织(MALT)淋巴瘤的主要致病因素。在不使用抗生素的情况下,H. pylori能够持续定植于人体胃组织,表明宿主免疫反应无效。同时,H. pylori耐药率不断升高,多数抗生素已经无法控制H. pylori感染的蔓延,因此,对于H. pylori免疫逃逸机制的研究显得尤为重要。 H. pylori感染诱导胃窦部黏膜的慢性及活动性炎症反应,并伴随有B细胞、T细胞及中性粒细胞的浸润。虽然所有的H. pylori菌株都能够引起胃炎,但是与cagA-的菌株相比,cagA+的H. pylori感染大大提高了严重性胃炎,萎缩性胃炎及胃癌的发病率,而且cagA+的H. pylori引起更强烈的IL-8的分泌。胃上皮细胞在急慢性H. pylori感染的过程中起重要作用,H. pylori能够激活胃上皮细胞的多种信号转导通路,激活信号通路的结果之一就是产生大量的IL-8.H. pylori引起的慢性活动性胃炎的胃黏膜组织中大量中性粒细胞的浸润被认为是对H.pylori的中性粒诱导因子(尿素酶,Nap A)的应答。 IFN-γ能够诱导炎症反应,保护机体抵抗细菌感染。IFN-γ激活免疫系统的多个环节包括吞噬作用及抗原提呈,诱导抗原提呈细胞MHCⅡ的表达并激活巨噬细胞及自然杀伤细胞,因此IFN-γ在免疫反应中起重要作用。信号传导及转录激活因子1(STAT1)是IFN-γ信号通路的重要分子,IFN-γ能够激活STAT1并提高其磷酸化水平,p-STAT1激活一氧化氮合酶(iNOS)并促进一氧化氮(NO)的产生。NO作为IFN-γ信号通路的效应分子,是宿主抵抗病原茵感染的基础分子,能够抑制对数期病原菌的生长。 病原菌具有能够与宿主相接触的多种表面结构(包括菌毛,鞭毛,外膜蛋白以及多种分泌系统)用以调节细菌对宿主细胞的黏附及入侵。革兰阴性菌外膜蛋白是一种复杂的结构,主要功能是辅助细菌适应多变的外部环境。外膜蛋白能够主动的,有选择性的控制重要物质(多肽或蛋白质,核酸以及脂质、多糖等)的流入及排出。编码H. pylori外膜蛋白的基因约有33种,大多数外膜蛋白位于膜的表面,其主要功能包括对宿主细胞的粘附及摄取营养物质。 虽然H. pylori引起强烈的炎症反应但是宿主免疫系统不能够清除该菌,表明H. pylori具有免疫逃逸机制。H. pylori免疫逃逸机制包括诱导极化的免疫应答、调节吞噬作用及中性粒细胞的功能以及抑制淋巴细胞增值。研究表明,H. pylori能够结合IFN-γ并下调主要毒力因子CagA的表达。但是目前尚未有H. pylori结合IFN-γ的具体机制的相关报道,本论文通过基因芯片筛选出H. pylori外膜蛋白Omp18,并进一步证实Omp18能够结合IFN-γ辅助H. pylori长期定植,有助于提高H. pylori在NO压力下的生存力及抗吞噬作用。 方法 1.通过基因芯片方法筛选出H. pylori野生株在IFN-γ作用下发生表达变化的基因。用IFN-γ处理培养至对数期的H. pylori野生株8h,未处理组作为对照,分别进行基因芯片检测,通过比较找出IFN-γ作用下发生表达变化的基因。 2.通过Real-Time PCR法验证基因芯片结果。用IFN-γ处理培养至对数期的H.pylori野生株,分别于0h,2h,4h,8h收集菌液,提取RNA反转录为cDNA,通过Real-Time PCR检测omp18的表达。 3.检测H. pylori野生株毒力因子CagA\NapA在IFN-γ作用下的表达情况。H.pylori野生株及omp18突变株过夜培养至对数生长期,用IFN-γ处理8h,未处理组作为对照,收集菌液分别用于提取细菌总蛋白及RNA,通过western blot及Real-Time PCR检测毒力因子CagA、NapA的表达情况。 4.动物实验。将H. pylori野生株及ompl8突变株分别多次经口感染蒙古沙鼠,分别于末次感染后第2,4,6,8周脱颈处死蒙古沙鼠,取其胃窦组织进行细菌的分离培养检测H. pylori定植情况,并通过HE染色鉴定胃组织炎症状况,应用Real-Time PCR及ELISA检测胃组织炎性因子表达情况。 5.检测H. pylori野生株及ompl8突变株生存能力的差异。 (1)用硝普钠(SNP)处理培养至对数期的H. pylori野生株及omp18突变株,分别通过琼脂稀释法及荧光染色法比较H. pylori野生株及omp18突变株的生存力。 (2)将培养至对数生长期的H. pylori野生株及omp18突变株分别加入至培养巨噬细胞的孔板中,分别于第2h,6h,24h裂解巨噬细胞并将含有H. pylori的裂解液经梯度稀释后涂布至琼脂平板上,培养3-5天后计数单克隆。 6.通过免疫荧光的方法证实H. pylori外膜蛋白Omp18能够结合IFN-γ。 7.T-COFFEE软件分析Omp18,OprF及干扰素结合区域蛋白序列。 8.通过western blot比较H. pylori野生株与omp18突变株刺激后巨噬细胞p-STAT1蛋白的表达差异。 9.NO测定。将H. pylori感染后的巨噬细胞及沙鼠胃组织分泌的亚硝酸盐的含量作为NO分泌的间接指标并通过Griess反应测定。 结果 1.IFN-y刺激下H. pylori Omp18表达升高。基因芯片发现与未处理的菌株相比,经10ng/mL IFN-γ处理后H. pylori野生株Omp18表达升高。 2.T-COFFEE软件分析发现Ompl8序列与OprF序列以及干扰素gamma感受器1(IRF1)的干扰素结合域相似度很高。 3.免疫荧光证实IFN-γ能够与H. pylori Omp18结合。 4.IFN-γ下调H. pylori野生株毒力因子的表达。Western blot及Real-Time PCR发现经10ng/mL IFN-γ处理后H. pylori野生株CagA及NapA表达下降,而ompl8突变株中CagA及NapA表达上升。 5.H. pylori omp18突变株在蒙古沙鼠胃组织中存在定植缺陷。动物实验表明H.pylori野生株及ompl8突变株均可在蒙古沙鼠胃部定植；ompl8突变株在蒙古沙鼠胃组织的定植力明显低于野生株,第8周差异最明显。 6.H. pylori omp18突变株感染诱导强烈的炎症反应。与野生株感染的蒙古沙鼠相比,omp18突变株感染的蒙古沙鼠胃组织表现出更多的中性粒细胞浸润及更严重的组织损伤；Real-Time PCR及ELISA检测发现omp18突变株诱导蒙古沙鼠胃组织分泌更多的炎性因子；同样,omp18突变株感染诱导AGS细胞分泌更多IL-8,诱导巨噬细胞分泌更多MIP-2,特别是在IFN-γ存在时。 7.H. pylori omp18突变株感染上调NO表达。在10ng/mL IFN-γ作用下,H. pylori野生株而非omp18突变株能够抑制巨噬细胞p-STAT1的表达；而omp18突变株能够诱导巨噬细胞以及蒙古沙鼠胃组织NO高表达。 8.Omp18有助于提高H. pylori野生株在氧应激下的生存力及抗吞噬作用。在SNP刺激下,与H. pylori野生株相比,omp18突变株生存力急剧下降,且绝大多数突变株由正常的螺杆状变为球形；同样,omp18突变株在巨噬细胞中生存力减弱。 结论 H. pylori能够通过Omp18主动感应IFN-y的变化,优化自身基因型从而避免诱导强烈的免疫应答以期达到长期定植。另外,Omp18有助于提高H. pylori在NO压力下的生存力及抗吞噬作用,为H. pylori在宿主胃部的长期定植奠定了基础。
[Abstract]:objective
Helicobacter pylori (H. pylori) is a unipolar, multi-flagellated, obtuse-rounded, spirally curved Gram-negative bacterium that colonizes about half of the world's population. The main pathogenic factor of mucosa-associated lymphoid tissue (MALT) lymphoma. H.pylori can persist in human gastric tissues without antibiotics, indicating that the host immune response is ineffective. At the same time, H.pylori resistance rate is increasing, most antibiotics have been unable to control the spread of H.pylori infection, therefore, for H.pylori immune escape. The study of escape mechanism is particularly important.
H. pylori infection induces chronic and active inflammation of the antral mucosa with infiltration of B, T and neutrophils. Although all H. pylori strains can cause gastritis, H. pylori infection with cagA + significantly increases the incidence of severe gastritis, atrophic gastritis and gastric cancer compared with cagA - strains. Gastric epithelial cells play an important role in the process of acute and chronic H. pylori infection. H. pylori can activate a variety of signal transduction pathways in gastric epithelial cells. One of the results of activating signal pathways is the production of a large number of IL-8.H. pylori-induced chronic active gastritis gastric mucosa. Invasion of large numbers of neutrophils in tissues is thought to be a response to H.pylori's neutrophil-inducible factor (urease, Nap A).
IFN-gamma can induce inflammation and protect the body against bacterial infection. IFN-gamma activates many aspects of the immune system, including phagocytosis and antigen presentation, induces the expression of antigen-presenting cells MHC II and activates macrophages and natural killer cells. Therefore, IFN-gamma plays an important role in the immune response. Signal transduction and activator of transcription 1 (S-1) TAT1 is an important molecule in the IFN-gamma signaling pathway. IFN-gamma can activate STAT1 and increase its phosphorylation level. p-STAT1 activates nitric oxide synthase (iNOS) and promotes the production of nitric oxide (NO). As an effector molecule of the IFN-gamma signaling pathway, NO is the basic molecule of host resistance to pathogenic infection and can inhibit the growth of logarithmic pathogenic bacteria.
Pathogens have a variety of surface structures (including fimbriae, flagella, adventitia proteins and secretory systems) that can interact with host cells to regulate bacterial adhesion and invasion. Gram-negative bacteria adventitia proteins are complex structures whose main function is to assist bacteria to adapt to changeable external environments. There are about 33 genes encoding H.pylori outer membrane proteins. Most outer membrane proteins are located on the surface of the membrane. Their main functions include adhesion to host cells and uptake of nutrients.
Although H.pylori induces a strong inflammatory response, the host immune system is unable to clear the bacteria, suggesting that H.pylori has an immune escape mechanism. H.pylori immune escape mechanism includes induced polarized immune response, regulation of phagocytosis, neutrophil function and inhibition of lymphocyte proliferation. IFN-gamma also down-regulates the expression of CagA, a major virulence factor. However, no specific mechanism of H.pylori binding to IFN-gamma has been reported. In this study, the outer membrane protein Omp18 of H.pylori was screened by gene chip, and further confirmed that Omp18 can bind to IFN-gamma to assist H.pylori long-term colonization, which is helpful to improve H.pylori's survival under NO pressure. Force and anti phagocytosis.
Method
1. The genes of H. pylori wild strains were screened out by gene chip. The H. pylori wild strains were incubated with IFN-gamma for 8 hours. The genes of H. pylori wild strains were detected by gene chip and compared with the untreated ones.
2. The results of gene chip were verified by Real-Time PCR. The H.pylori wild strains were cultured in logarithmic phase by IFN-gamma treatment. The bacterial liquids were collected at 0 h, 2 h, 4 h and 8 h respectively. RNA was retrieved and transcribed into cDNA. The expression of omp18 was detected by Real-Time PCR.
3. To detect the expression of CagANapA in H. pylori wild strain under the action of IFN-gamma. H. pylori wild strain and omp18 mutant were overnight cultured to logarithmic growth stage, treated with IFN-gamma for 8 hours, and untreated as control. The bacterial liquor was collected for extracting total bacterial protein and RNA, and the virulence factors CagA, Na and Real-Time PCR were detected by Western blot and Real-Time PCR. The expression of pA.
4. Animal experiment. Mongolian gerbils were orally infected with H. pylori wild strain and ompl8 mutant for many times, and were killed at the 2nd, 4th, 6th and 8th weeks after the last infection. The gastric antrum tissues of Mongolian gerbils were isolated and cultured to detect the colonization of H. pylori, and the gastric inflammation was identified by HE staining. Real-Time PCR and ELISA were used to detect the gastric inflammation. The expression of inflammatory factors in gastric tissue was detected.
5. to detect the difference in viability between H. pylori wild strain and ompl8 mutant strain.
(1) H. pylori wild strain and omp18 mutant strain were treated with sodium nitroprusside (SNP) and cultured to logarithmic phase. The viability of H. pylori wild strain and omp18 mutant strain were compared by agar dilution and fluorescence staining respectively.
(2) H. pylori wild strain and omp18 mutant strain were added to the pore plate of cultured macrophages at logarithmic growth stage. Macrophages were lysed at 2h, 6h and 24h respectively, and the lysate containing H. pylori was coated on agar plate after gradient dilution. Monoclones were counted after 3-5 days of culture.
6. immunofluorescence assay confirmed that H. pylori outer membrane protein Omp18 could bind IFN- gamma.
7.T-COFFEE software was used to analyze Omp18, OprF and IFN binding region protein sequences.
8. The expression of p-STAT1 protein in macrophages stimulated by H.pylori wild strain and omp18 mutant was compared by Western blot.
The nitrite secreted by macrophages and gastric tissues of gerbils infected with H.pylori was used as an indirect indicator of NO secretion and determined by Griess reaction.
Result
1. The expression of H. pylori Omp18 increased under IFN-y stimulation. Compared with untreated strains, the expression of H. pylori Omp18 increased after 10 ng/mL IFN-gamma treatment.
2. T-COFFEE software analysis found that the Ompl8 sequence was highly similar to the OprF sequence and the interferon binding domain of interferon gamma receptor 1 (IRF1).
3. immunofluorescence confirmed that IFN- gamma could bind to H. pylori Omp18.
4. IFN-gamma down-regulated the expression of virulence factors in H. pylori wild strain. Western blot and Real-time PCR showed that the expression of CagA and NapA in H. pylori wild strain decreased after 10 ng/mL IFN-gamma treatment, while the expression of CagA and NapA in ompl8 mutant increased.
5. H. pylori omp18 mutant was found to be defective in the stomach of Mongolian gerbils. Animal experiments showed that both H. pylori wild strain and ompl8 mutant could be colonized in the stomach of Mongolian gerbils. The colonization ability of ompl8 mutant in the stomach of Mongolian gerbils was significantly lower than that of wild strain, and the difference was most obvious at the 8th week.
6. H. pylori omp18 mutant infection induced strong inflammation. Compared with Mongolian gerbils infected with wild strain, the gastric tissue of Mongolian gerbils infected with omp18 mutant showed more neutrophil infiltration and more serious tissue damage; Real-Time PCR and ELISA detection showed that the gastric tissue of Mongolian gerbils was secreted more by omp18 mutant. Similarly, infection with omp18 mutant induces AGS cells to secrete more IL-8 and macrophages to secrete more MIP-2, especially in the presence of IFN-gamma.
7.H.pylori omp18 mutant infection up-regulated the expression of NO.Under the effect of 10ng/mL IFN-gamma, H.pylori wild strain, not omp18 mutant, could inhibit the expression of p-STAT1 in macrophages, while omp18 mutant could induce the high expression of NO in macrophages and Mongolian gerbil gastric tissue.
8.Omp18 is helpful to improve the viability and anti-phagocytosis of H.pylori wild strain under oxygen stress.Compared with H.pylori wild strain under SNP stimulation, the viability of omp18 mutant decreased sharply, and most of the mutants changed from normal screw to sphere.Similarly, the viability of omp18 mutant in macrophages decreased.
conclusion
H.pylori can actively induce changes in IFN-y by Omp18 to optimize its genotype and avoid inducing strong immune responses in order to achieve long-term colonization.In addition, Omp18 helps to improve H.pylori's viability and anti-phagocytosis under NO stress, laying the foundation for H.pylori's long-term colonization in the stomach of the host.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R573
[Abstract]:objective
Helicobacter pylori (H. pylori) is a unipolar, multi-flagellated, obtuse-rounded, spirally curved Gram-negative bacterium that colonizes about half of the world's population. The main pathogenic factor of mucosa-associated lymphoid tissue (MALT) lymphoma. H.pylori can persist in human gastric tissues without antibiotics, indicating that the host immune response is ineffective. At the same time, H.pylori resistance rate is increasing, most antibiotics have been unable to control the spread of H.pylori infection, therefore, for H.pylori immune escape. The study of escape mechanism is particularly important.
H. pylori infection induces chronic and active inflammation of the antral mucosa with infiltration of B, T and neutrophils. Although all H. pylori strains can cause gastritis, H. pylori infection with cagA + significantly increases the incidence of severe gastritis, atrophic gastritis and gastric cancer compared with cagA - strains. Gastric epithelial cells play an important role in the process of acute and chronic H. pylori infection. H. pylori can activate a variety of signal transduction pathways in gastric epithelial cells. One of the results of activating signal pathways is the production of a large number of IL-8.H. pylori-induced chronic active gastritis gastric mucosa. Invasion of large numbers of neutrophils in tissues is thought to be a response to H.pylori's neutrophil-inducible factor (urease, Nap A).
IFN-gamma can induce inflammation and protect the body against bacterial infection. IFN-gamma activates many aspects of the immune system, including phagocytosis and antigen presentation, induces the expression of antigen-presenting cells MHC II and activates macrophages and natural killer cells. Therefore, IFN-gamma plays an important role in the immune response. Signal transduction and activator of transcription 1 (S-1) TAT1 is an important molecule in the IFN-gamma signaling pathway. IFN-gamma can activate STAT1 and increase its phosphorylation level. p-STAT1 activates nitric oxide synthase (iNOS) and promotes the production of nitric oxide (NO). As an effector molecule of the IFN-gamma signaling pathway, NO is the basic molecule of host resistance to pathogenic infection and can inhibit the growth of logarithmic pathogenic bacteria.
Pathogens have a variety of surface structures (including fimbriae, flagella, adventitia proteins and secretory systems) that can interact with host cells to regulate bacterial adhesion and invasion. Gram-negative bacteria adventitia proteins are complex structures whose main function is to assist bacteria to adapt to changeable external environments. There are about 33 genes encoding H.pylori outer membrane proteins. Most outer membrane proteins are located on the surface of the membrane. Their main functions include adhesion to host cells and uptake of nutrients.
Although H.pylori induces a strong inflammatory response, the host immune system is unable to clear the bacteria, suggesting that H.pylori has an immune escape mechanism. H.pylori immune escape mechanism includes induced polarized immune response, regulation of phagocytosis, neutrophil function and inhibition of lymphocyte proliferation. IFN-gamma also down-regulates the expression of CagA, a major virulence factor. However, no specific mechanism of H.pylori binding to IFN-gamma has been reported. In this study, the outer membrane protein Omp18 of H.pylori was screened by gene chip, and further confirmed that Omp18 can bind to IFN-gamma to assist H.pylori long-term colonization, which is helpful to improve H.pylori's survival under NO pressure. Force and anti phagocytosis.
Method
1. The genes of H. pylori wild strains were screened out by gene chip. The H. pylori wild strains were incubated with IFN-gamma for 8 hours. The genes of H. pylori wild strains were detected by gene chip and compared with the untreated ones.
2. The results of gene chip were verified by Real-Time PCR. The H.pylori wild strains were cultured in logarithmic phase by IFN-gamma treatment. The bacterial liquids were collected at 0 h, 2 h, 4 h and 8 h respectively. RNA was retrieved and transcribed into cDNA. The expression of omp18 was detected by Real-Time PCR.
3. To detect the expression of CagANapA in H. pylori wild strain under the action of IFN-gamma. H. pylori wild strain and omp18 mutant were overnight cultured to logarithmic growth stage, treated with IFN-gamma for 8 hours, and untreated as control. The bacterial liquor was collected for extracting total bacterial protein and RNA, and the virulence factors CagA, Na and Real-Time PCR were detected by Western blot and Real-Time PCR. The expression of pA.
4. Animal experiment. Mongolian gerbils were orally infected with H. pylori wild strain and ompl8 mutant for many times, and were killed at the 2nd, 4th, 6th and 8th weeks after the last infection. The gastric antrum tissues of Mongolian gerbils were isolated and cultured to detect the colonization of H. pylori, and the gastric inflammation was identified by HE staining. Real-Time PCR and ELISA were used to detect the gastric inflammation. The expression of inflammatory factors in gastric tissue was detected.
5. to detect the difference in viability between H. pylori wild strain and ompl8 mutant strain.
(1) H. pylori wild strain and omp18 mutant strain were treated with sodium nitroprusside (SNP) and cultured to logarithmic phase. The viability of H. pylori wild strain and omp18 mutant strain were compared by agar dilution and fluorescence staining respectively.
(2) H. pylori wild strain and omp18 mutant strain were added to the pore plate of cultured macrophages at logarithmic growth stage. Macrophages were lysed at 2h, 6h and 24h respectively, and the lysate containing H. pylori was coated on agar plate after gradient dilution. Monoclones were counted after 3-5 days of culture.
6. immunofluorescence assay confirmed that H. pylori outer membrane protein Omp18 could bind IFN- gamma.
7.T-COFFEE software was used to analyze Omp18, OprF and IFN binding region protein sequences.
8. The expression of p-STAT1 protein in macrophages stimulated by H.pylori wild strain and omp18 mutant was compared by Western blot.
The nitrite secreted by macrophages and gastric tissues of gerbils infected with H.pylori was used as an indirect indicator of NO secretion and determined by Griess reaction.
Result
1. The expression of H. pylori Omp18 increased under IFN-y stimulation. Compared with untreated strains, the expression of H. pylori Omp18 increased after 10 ng/mL IFN-gamma treatment.
2. T-COFFEE software analysis found that the Ompl8 sequence was highly similar to the OprF sequence and the interferon binding domain of interferon gamma receptor 1 (IRF1).
3. immunofluorescence confirmed that IFN- gamma could bind to H. pylori Omp18.
4. IFN-gamma down-regulated the expression of virulence factors in H. pylori wild strain. Western blot and Real-time PCR showed that the expression of CagA and NapA in H. pylori wild strain decreased after 10 ng/mL IFN-gamma treatment, while the expression of CagA and NapA in ompl8 mutant increased.
5. H. pylori omp18 mutant was found to be defective in the stomach of Mongolian gerbils. Animal experiments showed that both H. pylori wild strain and ompl8 mutant could be colonized in the stomach of Mongolian gerbils. The colonization ability of ompl8 mutant in the stomach of Mongolian gerbils was significantly lower than that of wild strain, and the difference was most obvious at the 8th week.
6. H. pylori omp18 mutant infection induced strong inflammation. Compared with Mongolian gerbils infected with wild strain, the gastric tissue of Mongolian gerbils infected with omp18 mutant showed more neutrophil infiltration and more serious tissue damage; Real-Time PCR and ELISA detection showed that the gastric tissue of Mongolian gerbils was secreted more by omp18 mutant. Similarly, infection with omp18 mutant induces AGS cells to secrete more IL-8 and macrophages to secrete more MIP-2, especially in the presence of IFN-gamma.
7.H.pylori omp18 mutant infection up-regulated the expression of NO.Under the effect of 10ng/mL IFN-gamma, H.pylori wild strain, not omp18 mutant, could inhibit the expression of p-STAT1 in macrophages, while omp18 mutant could induce the high expression of NO in macrophages and Mongolian gerbil gastric tissue.
8.Omp18 is helpful to improve the viability and anti-phagocytosis of H.pylori wild strain under oxygen stress.Compared with H.pylori wild strain under SNP stimulation, the viability of omp18 mutant decreased sharply, and most of the mutants changed from normal screw to sphere.Similarly, the viability of omp18 mutant in macrophages decreased.
conclusion
H.pylori can actively induce changes in IFN-y by Omp18 to optimize its genotype and avoid inducing strong immune responses in order to achieve long-term colonization.In addition, Omp18 helps to improve H.pylori's viability and anti-phagocytosis under NO stress, laying the foundation for H.pylori's long-term colonization in the stomach of the host.
【学位授予单位】：山东大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R573
【共引文献】
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8 凌峰;王晓春;陈s，
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