進階搜尋


 
系統識別號 U0026-0812200915281897
論文名稱(中文) 幽門螺旋桿菌感染樹狀突細胞後複製進而造成的功能受損
論文名稱(英文) Helicobacter pylori infects and multiplies in bone marrow-derived dendritic cell and causes its dysfunction
校院名稱 成功大學
系所名稱(中) 基礎醫學研究所
系所名稱(英) Institute of Basic Medical Sciences
學年度 97
學期 2
出版年 98
研究生(中文) 王雅慧
研究生(英文) Ya-Hui Wang
學號 s5891126
學位類別 博士
語文別 中文
論文頁數 104頁
口試委員 指導教授-黎煥耀
口試委員-許秉寧
口試委員-王錦堂
口試委員-吳俊忠
口試委員-何漣漪
中文關鍵字 細胞自噬  幽門螺旋桿菌  樹狀突細胞  主要組織相容性複合物第二型分子 
英文關鍵字 autophagy  MHC class II  Helicobacter pylori  dendritic cells 
學科別分類
中文摘要 幽門螺旋桿菌為革蘭氏陰性、螺旋狀的微嗜氧菌,可感染人類胃部,引發胃炎、十二指腸潰瘍、消化性潰瘍或胃癌。雖被定義為細胞外細菌,但有越來越多的證據顯示幽門螺旋桿菌可藉由延緩吞噬小體的成熟而存活於吞噬細胞中。我們使用台灣幽門螺旋桿菌臨床株HP238感染不同的巨噬細胞株以及由小鼠骨髓細胞分化獲得的樹狀突細胞發現幽門螺旋桿菌可以在這些吞噬細胞內複製。臨床株HP238可以在THP-1與U937此兩種巨噬細胞株以及小鼠樹狀突細胞中複製,但無法在Raw264.7巨噬細胞株及小鼠腹腔巨噬細胞中複製。另一株臨床株HP250在THP-1細胞中也類似,但臨床株HP45A、HP45B與標準菌株J99與ATCC43504則無法在THP-1細胞中複製。幽門螺旋桿菌感染後以穿透式電子顯微鏡觀察,發現幽門螺旋桿菌感染的巨噬細胞與小鼠樹狀突細胞內細菌周圍圍繞有雙層膜結構。胞內的雙層膜結構為自噬小體的主要特徵,且以西方墨點法、LC3-II蛋白螢光染色分析均觀察到細胞自噬反應。以細胞自噬誘發或抑制性藥物處理受感染的細胞,發現幽門螺旋桿菌的清除率有相對地下降或上升的情形。這些證據顯示細胞自噬的誘發可以協助細胞清除幽門螺旋桿菌;若給予樹狀突細胞外加干擾素來增強細胞自噬,則可以協助樹狀突細胞清除此菌。另外我們也發現在vacA或是cagA基因缺失的情況之下,幽門螺旋桿菌受清除的速度會加快,顯示VacA或是CagA可能協助幽門螺旋桿菌逃脫細胞清除。
樹狀突細胞可吞噬、分解病原成抗原片段,再將之與主要組織相容性複合物第二型分子結合後以進行抗原呈獻,活化淋巴細胞。我們使用螢光染色法進行分析,以了解樹狀突細胞吞噬幽門螺旋桿菌後對抗原呈獻能力的影響,發現細菌感染樹狀突細胞後,會進入自噬小體且在後期吞噬小體(LAMP-1+ vesicle)中複製,並使主要組織相容性複合物第二型分子傳送至細胞表面的能力缺損。此現象和TLR2與TLR4訊息路徑的參與有關,在TLR4缺失的樹狀突細胞中,感染後24小時可以觀察到主要組織相容性複合物第二型分子回復表達至細胞表面,在TLR2缺失的樹狀突細胞中則延遲至48小時回復。我們也發現受感染後的樹狀突細胞難以刺激淋巴細胞增殖,但在TLR2缺失之下則可回復此功能。因此我們認為幽門螺旋桿菌的脂多醣體可能透過TLR2與TLR4訊息路徑影響樹狀突細胞呈獻抗原分子和刺激淋巴細胞的能力。受感染樹狀突細胞製造細胞激素的能力也受影響,導致IL-12減少和IL-10增加,這顯示幽門螺旋桿菌會感染樹狀突細胞,並複製,也影響其細胞激素分泌的能力。本研究顯示幽門螺旋桿菌會感染樹狀突細胞,並在細胞內複製,進而影響樹狀突細胞的功能,對於往後探討此菌在人類胃部疾病以及參與的免疫反應的機制,提供了一個重要的訊息。
英文摘要 Helicobacter pylori is a Gram-negative, spiral-shaped, microaerophilic bacterium that infects the human gastric mucosa and causes gastritis, duodenal ulcer, peptic ulcer or gastric cancer. H. pylori is generally considered as an extracellular microorganism. However, growing evidences have shown that H. pylori microorganisms can persistently survive in phagocytes, including neutrophil and macrophage. H. pylori can delay or disrupt the phagosome maturation in macrophage. We found that Taiwan clinical H. pylori isolate, HP238 could replicate in the macrophages and bone marrow derived-dendritic cells (BMDCs). The outcomes varied with the H. pylori isolates or the host cells used. Various strains of H. pylori behaved differently: HP250 replicated in THP-1 cells, but HP46A, HP46B, J99 or ATCC43504 did not. When the H. pylori-infected macrophages and BMDCs were observed with transmission electron microscope, we found that H. pylori or diving bacteria were surrounded by double membranes and form multi-layer structures within the infected cells. The double-layer membrane vesicles are characteristics of autophagosome. By using western blot analysis and LC3 punctate formation in confocal microscopic examination, we demonstrated that autophagy was induced in H. pylori-infected macrophage and BMDCs. The 3-MA, an autophagy inhibitor, inhibited the H. pylori clearance while the rapamycin, an autophagy inducer, enhanced the clearance in THP-1 cells. The IFN- treatment also enhanced the clearance in BMDCs. The VacA and CagA mutant strains are cleared quicker than wild type strain. This suggests that autophagy participate in the clearance of H. pylori and VacA or CagA might involve in this process.
Dendritic cell can phagocytose and process bacteria for peptide presentation on MHC class II molecules. To investigate the antigen-processing of H. pylori and the antigen presentation and maturation of BMDC post H. pylori infection, the endocytic trafficking of H. pylori in murine BMDCs was characterized. We found the numbers of H. pylori microorganism were increased after the entry into the LAMP1+ vacuoles after 6 and 12 h infection. This phenomenon was observed on VacA and CagA mutants as well. But, the intracellular H. pylori will be digested after 24 and 48 h infection, and the expression of MHC class II molecules on cell surface was not increased in infected BMDCs. The MHC class II molecules were trapped in H. pylori containing vesicles. However, the MHC class II surface expression can be reversed in TLR4-/- BMDC at 24 h post infection, and in TLR2-/- BMDC at 48 h post infection. Furthermore, the wild type BMDCs were difficulty prime the lymphocyte proliferation, and this dysfunction will be revered in TLR2-/- BMDC as well as the expression of MHC calss II molecules. The cytokine productions were also modulated on H. pylori-infected BMDCs, IL-12p70 cannot be detected. The LPS of H. pylori may contribute to impair the antigen presentation of BMDCs by TLR4 and TLR2-dependent signal pathway. In conclusion, H. pylori can infect and multiple within BMDCs and results in impairment of BMDC antigen presentation. This finding have great implication on the H. pylori induced responses and its associated diseases.
論文目次 考試合格證明............................................................................................................. I
總目錄………………………………………………………………………............ II
圖目錄...................................................................................................................... IV
縮寫索引................................................................................................................... VI
誌謝.......................................................................................................................... VII
中文摘要………………………………………………………………………..… IX
英文摘要………………………………………………………………………….. XI
緒論............................................................................................................................. 1
研究目標................................................................................................................... 18
材料與方法………………………………………………………………………... 19
A. 材料
1. 實驗動物.............................................................................................................19
2. 菌株……………………………………………………………………………. 19
3. 細胞株………………………………………………………………………..... 19
4. 試劑……………………………………………………………………………. 20
5. 抗體..................................................................................................................... 22
6. 塑膠、玻璃製品………………………………………………………………. 24
7. 儀器……………………………………………………………………………. 25
B. 方法
1. 菌株之培養與保養……………………………………………………………. 26
2. 細胞培養............................................................................................................. 26
3. 小鼠腹腔巨噬細胞之純化與使用……………………………………………. 27
4. 小鼠樹狀突細胞之分化與培養………………………………………………. 27
5. 細胞內活菌測量………………………………………………………………. 27
6. 免疫螢光染色…………………………………………………………………. 28
7. 細胞激素測定…………………………………………………………………. 28
8. 流式細胞儀分析法…………………………………………………………….29
9. 細胞墨點法…………………………………………………………………….29
10. 穿透式電子顯微鏡分析法…………………………………………………….30
11. 淋巴細胞增殖試驗……………………………………………………………. 30
實驗結果…………………………………………………………………………... 31
I. 幽門螺旋桿菌於巨噬細胞中存活之情形…………………………………….. 31
II. 幽門螺旋桿菌感染誘發巨噬細胞產生細胞自噬小體..................................... 32
III. VacA與CagA突變株在巨噬細胞中存活之情形…………………………... 33
IV. 幽門螺旋桿菌在小鼠樹狀突細胞質中的小體運輸.………………………... 34
V. 幽門螺旋桿菌感染誘發樹狀突細胞產生自噬小體之情形…………………. 35
VI. 幽門螺旋桿菌感染對主要組織相容性抗原第二型分子表現之影響………36
VII. 受幽門螺旋桿菌感染誘發樹狀突細胞分泌細胞激素的情形…………….. 37
VIII. TLR2與TLR4參與幽門螺旋桿菌感染所造成的功能缺失………………37
討論……………………………………………………………………………….. 40
結論……………………………………………………………………………….. 48
參考文獻………………………………………………………………………….. 50
圖…………………………………………………………………………………... 74
作者簡歷………………………………………………………………………….. 103
參考文獻 Alexander DE, Ward SL, Mizushima N, Levine B, Leib DA. Analysis of the role of autophagy in replication of herpes simplex virus in cell culture. J Virol. 81:12128-34, 2007.

Algood HM, Cover TL. Helicobacter pylori persistence: an overview of interactions between H. pylori and host immune defenses. Clin Microbiol Rev. 19:597-613, 2006.

Ait-Goughoulte M, Kanda T, Meyer K, Ryerse JS, Ray RB, Ray R. Hepatitis C virus genotype 1a growth and induction of autophagy. J Virol. 82:2241-9, 2008.

Alm RA, Ling LS, Moir DT, King BL, Brown ED, Doig PC, Smith DR, Noonan B, Guild BC, deJonge BL, Carmel G, Tummino PJ, Caruso A, Uria-Nickelsen M, Mills DM, Ives C, Gibson R, Merberg D, Mills SD, Jiang Q, Taylor DE, Vovis GF, Trust TJ. Genomic-sequence comparison of two unrelated isolates of the human gastric pathogen Helicobacter pylori. Nature. 397:176-80, 1999.

Almeida R, Silva E, Santos-Silva F, Silberg DG, Wang J, De Bolós C, David L. Expression of intestine-specific transcription factors, CDX1 and CDX2, in intestinal metaplasia and gastric carcinomas. J Pathol. 199:36-40, 2003.

Alvarez-Arellano L, Camorlinga-Ponce M, Maldonado-Bernal C, Torres J. Activation of human neutrophils with Helicobacter pylori and the role of Toll-like receptors 2 and 4 in the response. FEMS Immunol Med Microbiol. 51:473-9, 2007.

Amedei A, Cappon A, Codolo G, Cabrelle A, Polenghi A, Benagiano M, Tasca E, Azzurri A, D'Elios MM, Del Prete G, de Bernard M. The neutrophil-activating protein of Helicobacter pylori promotes Th1 immune responses. J Clin Invest. 116:1092-101, 2006.

Amer AO, Swanson MS. Autophagy is an immediate macrophage response to Legionella pneumophila. Cell Microbiol. 7:765-78, 2005.

Amieva MR, Vogelmann R, Covacci A, Tompkins LS, Nelson WJ, Falkow S. Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 300:1430-4, 2003.

Andersen-Nissen E, Smith KD, Strobe KL, Barrett SL, Cookson BT, Logan SM, Aderem A. Evasion of Toll-like receptor 5 by flagellated bacteria. Proc Natl Acad Sci U S A. 102:9247-52, 2005.

Asahi K, Fu HY, Hayashi Y, Eguchi H, Murata H, Tsujii M, Tsuji S, Tanimura H, Kawano S. Helicobacter pylori infection affects Toll-like receptor 4 expression in human gastric mucosa. Hepatogastroenterology. 54:1941-4, 2007.

Aspholm M, Olfat FO, Nordén J, Sondén B, Lundberg C, Sjöström R, Altraja S, Odenbreit S, Haas R, Wadström T, Engstrand L, Semino-Mora C, Liu H, Dubois A, Teneberg S, Arnqvist A, Borén T. SabA is the H. pylori hemagglutinin and is polymorphic in binding to sialylated glycans. PLoS Pathog. 2:e110, 2006.

Atherton JC, Cao P, Peek RM, Jr, Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. J Biol Chem. 270:17771-7, 1995.

Atherton JC, Peek RM, Jr, Tham KT, Cover TL, Blaser MJ. Clinical and pathological importance of heterogeneity in vacA, the vacuolating cytotoxin gene of Helicobacter pylori. Gastroenterology. 112:92-9, 1997.

Backert S, Selbach M. Role of type IV secretion in Helicobacter pylori pathogenesis. Cell Microbiol. 10:1573-81, 2008.

Barrera C, Ye G, Espejo R, Gunasena S, Almanza R, Leary J, Crowe S, Ernst P, Reyes VE. Expression of cathepsins B, L, S, and D by gastric epithelial cells implicates them as antigen presenting cells in local immune responses. Hum Immunol. 62:1081-91, 2001.

Barrionuevo P, Cassataro J, Delpino MV, Zwerdling A, Pasquevich KA, García Samartino C, Wallach JC, Fossati CA, Giambartolomei GH. Brucella abortus inhibits major histocompatibility complex class II expression and antigen processing through interleukin-6 secretion via Toll-like receptor 2. Infect Immun. 76:250-62, 2008.

Bartsch H, Nair J. Chronic inflammation and oxidative stress in the genesis and perpetuation of cancer: role of lipid peroxidation, DNA damage, and repair. Langenbecks Arch Surg. 391:499-510, 2006.

Basu M, Czinn SJ, Blanchard TG. Absence of catalase reduces long-term survival of Helicobacter pylori in macrophage phagosomes. Helicobacter. 9:211-6, 2004.

Bauerfeind P, Garner R, Dunn BE, Mobley HL. Synthesis and activity of Helicobacter pylori urease and catalase at low pH. Gut. 40:25-30, 1997.

Beg AA. Endogenous ligands of Toll-like receptors: implications for regulating inflammatory and immune responses. Trends Immunol. 23: 509-12, 2002.

Betten A, Bylund J, Christophe T, Boulay F, Romero A, Hellstrand K, Dahlgren C. A proinflammatory peptide from Helicobacter pylori activates monocytes to induce lymphocyte dysfunction and apoptosis. J Clin Invest. 116:1457, 2006.

Bergman M, Del Prete G, van Kooyk Y, Appelmelk B. Helicobacter pylori phase variation, immune modulation and gastric autoimmunity. Nat Rev Microbiol. 4:151-9, 2006.

Bergman MP, Engering A, Smits HH, van Vliet SJ, van Bodegraven AA, Wirth HP, Kapsenberg ML, Vandenbroucke-Grauls CM, van Kooyk Y, Appelmelk BJ. Helicobacter pylori modulates the T helper cell 1/T helper cell 2 balance through phase-variable interaction between lipopolysaccharide and DC-SIGN. J Exp Med. 200:979-90, 2004.

Berrebi D, Languepin J, Ferkdadji L, Foussat A, De Lagausie P, Paris R, Emilie D, Mougenot, JF, Cezard, JP, Navarro J, Peuchmaur M. Cytokines, chemokine receptors, and homing molecule distribution in the rectum and stomach of pediatric patients with ulcerative colitis. J Pediatr Gastroenterol Nutr. 37:300-8, 2003.

Beron W, Gutierrez MG, Rabinovitch M, Colombo MI. Coxiella burnetii localizes in a Rab7-labeled compartment with autophagic characteristics. Infect Immun. 70:5816-21, 2002.

Billard E, Dornand J, Gross A. Brucella suis prevents human dendritic cell maturation and antigen presentation through regulation of tumor necrosis factor alpha secretion. Infect Immun. 75:4980-9, 2007.

Blaser MJ. Parasitism by the slow bacterium Helicobacter pylori leads to alter gastric homeostasis and neoplasia. J Clin Invest. 94:4-8, 1994.

Chochi K, Ichikura T, Kinoshita M, Majima T, Shinomiya N, Tsujimoto H, Kawabata T, Sugasawa H, Ono S, Seki S, Mochizuki H. Helicobacter pylori augments growth of gastric cancers via the lipopolysaccharide-toll-like receptor 4 pathway whereas its lipopolysaccharide attenuates antitumor activities of human mononuclear cells. Clin Cancer Res. 14:2909-17, 2008.

Covacci A, Censini S, Bugnoli M, Petracca R, Burroni D, Macchia G, Massone A, Papini E, Xiang Z, Figura N, Rappuoli R. Molecular characterization of the 128-kDa immunodominant antigen of Helicobacter pylori associated with cytotoxicity and duodenal ulcer. Proc Natl Acad Sci U S A. 90:5791-5, 1993.

Correa P, Haenszel W, Cuello C, Zavala D, Fontham E, Zarama G, Tannenbaum S, Collazos T, Ruiz B. Gastric precancerous process in a high risk population: cohort follow-up. Cancer Res. 50:4737-40, 1990.

Cover TL, Glupczynski Y, Lage AP, Burette A, Tummuru MK, Perez-Perez GI, Blaser MJ. Serologic detection of infection with cagA+ Helicobacter pylori strains. J Clin Microbiol. 33:1496-500, 1995.

Cover TL, Tummuru MK, Cao P, Thompson SA, Blaser MJ. Divergence of genetic sequences for the vacuolating cytotoxin among Helicobacter pylori strains. J Biol Chem. 269:10566-73, 1994.

Cover TL, Krishna US, Israel DA, Peek RM Jr. Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res. 63:951-7, 2003.

Crabtree JE, Shallcross TM, Heatley RV, Wyatt JI. Mucosal tumour necrosis factor alpha and interleukin-6 in patients with Helicobacter pylori associated gastritis. Gut. 32:1473-7, 1991.

David H, Ellermann J, Uerlings I. Primary phase of hepatocytic autophagocytosis under ischaemic conditions. Exp Toxicol Pathol. 44:74-80, 1992.

Du MQ, Isaccson PG. Gastric MALT lymphoma: from aetiology to treatment. Lancet. Oncol. 3:97-104, 2002.

Evans DJ Jr, Evans DG, Takemura T, Nakano H, Lampert HC, Graham DY, Granger DN, Kvietys PR. Characterization of a Helicobacter pylori neutrophil-activating protein. Infect Immun. 63:2213-20, 1995.

Fader CM, Colombo MI. Multivesicular bodies and autophagy in erythrocyte maturation. Autophagy. 2:122-5, 2006.

Fan X, Gunasena H, Cheng Z, Espejo R, Crowe SE, Ernst PB, Reyes VE. Helicobacter pylori urease binds to class II MHC on gastric epithelial cells and induces their apoptosis. J Immunol. 165:1918-24, 2000.

Farinati F, Cardin R, Cassaro M, Bortolami M, Nitti D, Tieppo C, Zaninotto G, Rugge M. Helicobacter pylori, inflammation, oxidative damage and gastric cancer: a morphological, biological and molecular pathway. Eur J Cancer Prev. 17:195-200, 2008.

Ferrero RL. Innate immune recognition of the extracellular mucosal pathogen, Helicobacter pylori. Mol Immunol. 42:879-85, 2005.

Forestier C, Deleuil F, Lapaque N, Moreno E, Gorvel JP. Brucella abortus lipopolysaccharide in murine peritoneal macrophages acts as a down-regulator of T cell activation. J Immunol. 165:5202-10, 2000.

Geis G, Suerbaum S, Forsthoff B, Leying H, Opferkuch W. Ultrastructure and biochemical studies of the flagellar sheath of Helicobacter pylori. J Med Microbiol. 38:371-7, 1993.

Gerhard M, Lehn N, Neumayer N, Borén T, Rad R, Schepp W, Miehlke S, Classen M, Prinz C. Clinical relevance of the Helicobacter pylori gene for blood-group antigen-binding adhesin. Proc Natl Acad Sci U S A. 96:12778-83, 1999.

Gewirtz AT, Yu Y, Krishna US, Israel DA, Lyons SL, Peek RM Jr. Helicobacter pylori flagellin evades toll-like receptor 5-mediated innate immunity. J Infect Dis. 189:1914-20, 2004.

Goll R, Gruber F, Olsen T, Cui G, Raschpichler G, Buset M, Asfeldt AM, Husebekk A, Florholmen J. Helicobacter pylori stimulates a mixed adaptive immune response with a strong T-regulatory component in human gastric mucosa. Helicobacter. 12:185-92, 2007.

Gorvel JP, de Chastellier C. Bacteria spurned by self-absorbed cells. Nat Med. 11:18-9, 2005.

Grebowska A, Moran AP, Matusiak A, Bak-Romaniszyn L, Czkwianianc E, Rechciński T, Walencka M, Płaneta-Małecka I, Rudnicka W, Chmiela M. Anti-phagocytic activity of Helicobacter pylori lipopolysaccharide (LPS)--possible modulation of the innate immune response to these bacteria. Pol J Microbiol. 57:185-92, 2008.

Guiney DG, Hasegawa P, Cole SP. Helicobacter pylori preferentially induces interleukin 12 (IL-12) rather than IL-6 or IL-10 in human dendritic cells. Infect Immun. 71:4163-6, 2003.

Gutierrez MG, Master SS, Singh SB, Taylor GA, Colombo MI, Deretic V. Autophagy is a defense mechanism inhibiting BCG and Mycobacterium tuberculosis survival in infected macrophages. Cell. 119:753-66, 2004.

Gutierrez MG, Vazquez CL, Munafo DB, Zoppino FC, Beron W, Rabinovitch M, Colombo MI. Autophagy induction favours the generation and maturation of the Coxiella-replicative vacuoles. Cell Microbiol. 7:981-93, 2005.

Hafsi N, Voland P, Schwendy S, Rad R, Reindl W, Gerhard M, Prinz C. Human dendritic cells respond to Helicobacter pylori, promoting NK cell and Th1-effector responses in vitro. J Immunol. 173:1249-57, 2004.

Hatakeyama M. Helicobacter pylori and gastric carcinogenesis. J. Gastroenterol. 44:239-48, 2009.

Hernandez LD, Pypaert M, Flavell RA, Galan JE. A Salmonella protein causes macrophage cell death by inducing autophagy. J Cell Biol. 163:1123-31, 2003.

Josenhans C, Labigne A, Suerbaum S. Comparative ultrastructural and functional studies of Helicobacter pylori and Helicobacter mustelae flagellin mutants: both flagellin subunits, FlaA and FlaB, are necessary for full motility in Helicobacter species. J Bacteriol. 177:3010-20, 1995.

Kabelitz D. Expression and function of Toll-like receptors in T lymphocytes. Curr Opin Immunol. 19:39-45, 2007.

Kao JY, Rathinavelu S, Eaton KA, Bai L, Zavros Y, Takami M, Pierzchala A, Merchant JL. Helicobacter pylori-secreted factors inhibit dendritic cell IL-12 secretion: a mechanism of ineffective host defense. Am J Physiol Gastrointest Liver Physiol. 291:G73-81, 2006.

Kavermann H, Burns BP, Angermuller K, Odenbreit S, Fischer W, Melchers K, Haas R. Identification and characterization of Helicobacter pylori genes essential for gastric colonization. J Exp Med. 197:813-22, 2003.

Kawano S, Asahi K, Fu HY, Hayashi Y, Eguchi H, Murata H, Tsujii M, Tsuji S, Tanimura H, Helicobacter pylori infection affects Toll-like receptor 4 expression in human gastric mucosa. Hepatogastroenterology. 54:1941-4, 2007.

Kersulyte D, Velapatiño B, Mukhopadhyay AK, Cahuayme L, Bussalleu A, Combe J, Gilman RH, Berg DE. Cluster of type IV secretion genes in Helicobacter pylori's plasticity zone. J Bacteriol. 185:3764-72, 2003.

Kondo Y, Kanzawa T, Sawaya R, Kondo S. The role of autophagy in cancer development and response to therapy. Nat Rev Cancer. 5:726-34, 2005.

Kranzer K, Eckhardt A, Aigner M, Knoll G, Deml L, Speth C, Lehn N, Rehli M, Schneider-Brachert W. Induction of maturation and cytokine release of human dendritic cells by Helicobacter pylori. Infect Immun. 72:4416-23, 2004.

Krueger S, Hundertmark T, Kuester D, Kalinski T, Peitz U, Roessner A. Helicobacter pylori alters the distribution of ZO-1 and p120ctn in primary human gastric epithelial cells. Pathol Res Pract. 203:433-44, 2007.

Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev. 19:449-90, 2006.

Lai CH, Kuo CH, Chen YC, Chao FY, Poon SK, Chang CS, Wang WC. High prevalence of cagA- and babA2-positive Helicobacter pylori clinical isolates in Taiwan. J Clin Microbiol. 40:3860-62, 2002.

Lee A. The nature of Helicobacter pylori. Scand J Gastroenterol. 31 (supply): 5-8, 1996.

Lee H, Paik SG. Regulation of BNIP3 in normal and cancer cells. Mol Cells. 21:1-6, 2006.

Lee YR, Lei HY, Liu MT, Wang JR, Chen SH, Jiang-Shieh YF, Lin YS, Yeh TM, Liu CC, Liu HS. Autophagic machinery activated by dengue virus enhances virus replication. Virology. 374:240-8, 2008.

Lepper PM, Triantafilou M, Schumann C, Schneider EM, Triantafilou K. Lipopolysaccharides from Helicobacter pylori can act as antagonists for Toll-like receptor 4. Cell Microbiol. 7:519-28, 2005.

Levinson G, Gutman GA. Slipped-strand mispairing: a major mechanism for DNA sequence evolution. Mol. Biol. Evol. 4:203-221, 1987.

Lin CW, Wu SC, Lee SC, Cheng KS. Genetic analysis and clinical evaluation of vacuolating cytotoxin gene A and cytotoxin-associated gene A in Taiwanese Helicobacter pylori isolates from peptic ulcer patients. Scand J Infect Dis. 32:51-7, 2000.

Lozniewski A, Haristoy X, Rasko DA, Hatier R, Plénat F, Taylor DE, Angioi-Duprez K. Influence of Lewis antigen expression by Helicobacter pylori on bacterial internalization by gastric epithelial cells. Infect Immun. 71:2902-6, 2003.

Lu H, Wu JY, Beswick EJ, Ohno T, Odenbreit S, Haas R, Reyes VE, Kita M, Graham DY, Yamaoka Y. Functional and intracellular signaling differences associated with the Helicobacter pylori AlpAB adhesin from Western and East Asian strains. J Biol Chem. 282:6242-54, 2007.

Mahdavi J, Sondén B, Hurtig M, Olfat FO, Forsberg L, Roche N, Angstrom J, Larsson T, Teneberg S, Karlsson KA, Altraja S, Wadström T, Kersulyte D, Berg DE, Dubois A, Petersson C, Magnusson KE, Norberg T, Lindh F, Lundskog BB, Arnqvist A, Hammarström L, Borén T. Helicobacter pylori SabA adhesin in persistent infection and chronic inflammation. Science. 297:573-8, 2002.

Maekawa T, Kinoshita Y, Matsushima Y, Okada A, Fukui H, Waki S, Kishi K, Kawanami C, Nakata H, Hassan S, Wakatsuki Y, Ota H, Amano K, Nakao M, Chiba T. Helicobacter pylori induces proinflammatory cytokines and major histocompatibility complex class II antigen in mouse gastric epithelial cells. J Lab Clin Med. 130:442-9, 1997.

Mannick EE, Bravo LE, Zarama G, Realpe JL, Zhang XJ, Ruiz B, Fontham ET, Mera R, Miller MJ, Correa P. Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer. Res. 56:3238-43, 1996.

Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 388:394-7, 1997.

Miehlke S, Go MF, Kim JG, Graham DY, Figura N. Serologic detection of Helicobacter pylori infection with cagA-positive strains in duodenal ulcer, gastric cancer, and asymptomatic gastritis. J Gastroenterol. Suppl 10:18-21, 1998.

Mitchell P, Germain C, Fiori PL, Khamri W, Foster GR, Ghosh S, Lechler RI, Bamford KB, Lombardi G. Chronic exposure to Helicobacter pylori impairs dendritic cell function and inhibits Th1 development. Infect Immun. 75:810-9, 2007.

Mizushima T, Sugiyama T, Komatsu Y, Ishizuka J, Kato M, Asaka M. Clinical relevance of the babA2 genotype of Helicobacter pylori in Japanese clinical isolates. J Clin Microbiol. 39:2463-5, 2001.

Mobley HL, Island MD, Hausinger RP. Molecular biology of microbial ureases. Microbiol Rev. 59:451-80, 1995.

Molinari M, Salio M, Galli C, Norais N, Rappuoli R, Lanzavecchia A, Montecucco C. Selective inhibition of Ii-dependent antigen presentation by Helicobacter pylori toxin VacA. J Exp Med. 187:135-40, 1998.

Mollenhauer-Rektorschek M, Hanauer G, Sachs G, Melchers K. Expression of UreI is required for intragastric transit and colonization of gerbil gastric mucosa by Helicobacter pylori. Res Microbiol. 153:659-66, 2002.

Montecucco C, De Bernard M, Papini E, Zoratti M. Helicobacter pylori vacuolating cytotoxin: cell intoxication and anion-specific channel activity. Curr Top Microbiol Immunol. 257:113-29, 2001.

Mota LJ, Cornelis GR. The bacterial injection kit: type III secretion systems. Ann Med. 37:234-49, 2005.

Murata-Kamiya N, Kurashima Y, Teishikata Y, Yamahashi Y, Saito Y, Higashi H, Aburatani H, Akiyama T, Peek RM Jr, Azuma T, Hatakeyama M. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene. 26:4617-26, 2007.

Muotiala A, Helander IM, Pyhälä L, Kosunen TU, Moran AP. Low biological activity of Helicobacter pylori lipopolysaccharide. Infect Immun. 60:1714-6, 1992.

Münzenmaier A, Lange C, Glocker E, Covacci A, Moran A, Bereswill S, Baeuerle PA, Kist M, Pahl HL. A secreted/shed product of Helicobacter pylori activates transcription factor nuclear factor-kappa B. J Immunol. 159:6140-7, 1997.

Nakagawa I, Amano A, Mizushima N, Yamamoto A, Yamaguchi H, Kamimoto T, Nara A, Funao J, Nakata M, Tsuda K, Hamada S, Yoshimori T. Autophagy defends cells against invading group A Streptococcus. Science. 306:1037-40, 2004.

Nalini R, Thomans M. Helicobacter pylori resists phagocytosis by macrophages: quantitative assessment by confocal microscopy and fluorescence-associated cell sorting. Infect Immun. 69:2604-11, 2001.

Nilsson C, Skoglund A, Moran AP, Annuk H, Engstrand L, Normark S. Lipopolysaccharide diversity evolving in Helicobacter pylori communities through genetic modifications in fucosyltransferases. PLoS ONE. 3:e3811, 2008.

Nomura S, Kaminishi M, Sugiyama K, Oohara T, Esumi H. Clonal analysis of isolated intestinal metaplastic glands of stomach using X linked polymorphism. Gut. 42:663-8, 1998.

Obonyo M, Sabet M, Cole SP, Ebmeyer J, Uematsu S, Akira S, Guiney DG. Deficiencies of myeloid differentiation factor 88, Toll-like receptor 2 (TLR2), or TLR4 produce specific defects in macrophage cytokine secretion induced by Helicobacter pylori. Infect Immun. 75:2408-14, 2007.

Odenbreit S, Till M, Hofreuter D, Faller G, Haas R. Genetic and functional characterization of the alpAB gene locus essential for the adhesion of Helicobacter pylori to human gastric tissue. Mol Microbiol. 31:1537-48, 1999.

Ogawa M, Sasakawa C. Shigella and autophagy. Autophagy. 2:171-4, 2006.

Ogawa M, Yoshimori T, Suzuki T, Sagara H, Mizushima N, Sasakawa C. Escape of intracellular Shigella from autophagy. Science. 307:727-31, 2005.

Peck B, Ortkamp M, Diehl KD, Hundt E, Knapp B. Conservation, localization and expression of HopZ, a protein involved in adhesion of Helicobacter pylori. Nucleic Acids Res. 27:3325-33, 1999.

Perng CL, Lin HJ, Sun IC, Tseng GY, Facg. Helicobacter pylori cagA, iceA and vacA status in Taiwanese patients with peptic ulcer and gastritis. J Gastroenterol Hepatol. 18:1244-9, 2003.

Polenghi A, Bossi F, Fischetti F, Durigutto P, Cabrelle A, Tamassia N, Cassatella MA, Montecucco C, Tedesco F, de Bernard M. The neutrophil-activating protein of Helicobacter pylori crosses endothelia to promote neutrophil adhesion in vivo. J Immunol. 178:1312-20, 2007.

Poltorak A, He X, Smirnova I, Liu MY, Van Huffel C, Du X, Birdwell D, Alejos E,Silva M, Galanos C, Freudenberg M, Ricciardi-Castagnoli P, Layton B, Beutler B. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 282:2085-8, 1998.

Py BF, Lipinski MM, Yuan J. Autophagy limits Listeria monocytogenes intracellular growth in the early phase of primary infection. Autophagy. 3:117-125. 2007.

Rad R, Gerhard M, Lang R, Schöniger M, Rösch T, Schepp W, Becker I, Wagner H, Prinz C. The Helicobacter pylori blood group antigen-binding adhesin facilitates bacterial colonization and augments a nonspecific immune response. J Immunol. 168:3033-41, 2002.

Rad R, Brenner L, Krug A, Voland P, Mages J, Lang R, Schwendy S, Reindl W, Dossumbekova A, Ballhorn W, Wagner H, Schmid RM, Bauer S, Prinz C. Toll-like receptor-dependent activation of antigen-presenting cells affects adaptive immunity to Helicobacter pylori. Gastroenterology. 133:150-163, 2007.

Ramarao N, Gray-Owen SD, Backert S, Meyer TF. Helicobacter pylori inhibits phagocytosis by professional phagocytes involving type IV secretion components. Mol Microbiol. 37:1389-404, 2000.

Rittig MG, Shaw B, Letley DP, Thomas RJ, Argent RH, Atherton JC. Helicobacter pylori-induced homotypic phagosome fusion in human monocytes is independent of the bacterial vacA and cag status. Cell Microbiol. 5:887-99, 2003.

Rocha-Ramírez LM, Estrada-García I, López-Marín LM, Segura-Salinas E, Méndez-Aragón P, Van Soolingen D, Torres-González R, Chacón-Salinas R, Estrada-Parra S, Maldonado-Bernal C, López-Macías C, Isibasi A. Mycobacterium tuberculosis lipids regulate cytokines, TLR-2/4 and MHC class II expression in human macrophages. Tuberculosis (Edinb). 88:212-20, 2008.

Romano PS, Gutierrez MG, Berón W, Rabinovitch M, Colombo MI. The autophagic pathway is actively modulated by phase II Coxiella burnetii to efficiently replicate in the host cell. Cell Microbiol. 9:891-909, 2007.

Salama N, Guillemin K, McDaniel TK, Sherlock G, Tompkins L, Falkow S. A whole-genome microarray reveals genetic diversity among Helicobacter pylori strains. Proc Natl Acad Sci U S A. 97:14668-73, 2000.

Scheynius A, Engstrand L. Gastric epithelial cells in Helicobacter pylori-associated gastritis express HLA-DR but not ICAM-1. Scand J Immunol. 33:237-41, 1991.

Schmid D, Pypaert M, Munz C. Antigen-loading compartments for major histocompatibility complex class II molecules continuously receive input from autophagosomes. Immunity. 26:79-92, 2007.

Schwartz JT, Allen LA. Role of urease in megasome formation and Helicobacter pylori survival in macrophages. J Leukoc Biol. 79:1214-25. 2006.

Selbach M, Moese S, Hurwitz R, Hauck CR, Meyer TF, Backert S. The Helicobacter pylori CagA protein induces cortactin dephosphorylation and actin rearrangement by c-Src inactivation. EMBO J. 22:515-28, 2003.

Sendide K, Deghmane AE, Pechkovsky D, Av-Gay Y, Talal A, Hmama Z. Mycobacterium bovis BCG attenuates surface expression of mature class II molecules through IL-10-dependent inhibition of cathepsin S. J Immunol. 175:5324-32, 2005.

Shiratsuchi A, Watanabe I, Takeuchi O, Akira S, Nakanishi Y. Inhibitory effect of Toll-like receptor 4 on fusion between phagosomes and endosomes/lysosomes in macrophages. J Immunol. 172:2039-47, 2004.

Sheu BS, Sheu SM, Yang HB, Huang AH, Wu JJ. Host gastric Lewis expression determines the bacterial density of Helicobacter pylori in babA2 genopositive infection. Gut. 52:927-32, 2003.

Sheu SM, Sheu BS, Yang HB, Lei HY, Wu JJ. Anti-Lewis X antibody promotes Helicobacter pylori adhesion to gastric epithelial cells. Infect Immun. 75:2661-7, 2007.

Shiao YH, Rugge M, Correa P, Lehmann HP, Scheer WD. p53 alteration in gastric precancerous lesions. Am J Pathol. 144:511-7, 1994.

Sipponen P, Kimura K. Intestinal metaplasia, atrophic gastritis and stomach cancer: trends over time. Eur J Gastroenterol Hepatol. 1:S79-83, 1994.

Slomiany BL, Slomiany A. Suppression of gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide by peroxisome proliferator-activated receptor gamma activation. IUBMB Life. 53:303-8, 2002.

Smith GV, Moran AP, Bajaj-Elliott M, Farthing MJ. Induction of cyclooxygenase 2 by Escherichia coli but not Helicobacter pylori lipopolysaccharide in gastric epithelial cells in vitro. Helicobacter. 8:513-20, 2003.

Smith MF Jr, Mitchell A, Li G, Ding S, Fitzmaurice AM, Ryan K, Crowe S, Goldberg JB. Toll-like receptor (TLR) 2 and TLR5, but not TLR4, are required for Helicobacter pylori-induced NF-kappa B activation and chemokine expression by epithelial cells. J Biol Chem. 278:32552-60, 2003.

Skene C, Young A, Every A, Sutton P. Helicobacter pylori flagella: antigenic profile and protective immunity. FEMS Immunol Med Microbiol. 50:249-56, 2007.

Sultzer BM. Genetic control of leucocyte responses to endotoxin. Nature. 219:1253-4, 1968.

Szabo I, Brutsche S, Tombola F, Moschioni M, Satin B, Telford JL, Rappuoli R, Montecucco C, Papini E, Zoratti M. Formation of anion-selective channels in the cell plasma membrane by the toxin VacA of Helicobacter pylori is required for its biological activity. EMBO J. 18:5517-27, 1999.

Tabassam FH, Graham DY, Yamaoka Y. OipA plays a role in Helicobacter pylori-induced focal adhesion kinase activation and cytoskeletal re-organization. Cell Microbiol. 10:1008-20, 2008.

Taylor MP, Kirkegaard K. Modification of cellular autophagy protein LC3 by poliovirus. J Virol. 81:12543-53, 2007.

Teneberg S, H Miller-Podraza, Lampert HC, Evans DJ, Jr., Evans DG, Danielsson D, Karlsson KA. Carbohydrate binding specificity of the neutrophil-activating protein of Helicobacter pylori. J Biol Chem. 272:19067-71, 1997.

Tobian AA, Potter NS, Ramachandra L, Pai RK, Convery M, Boom WH, Harding CV. Alternate class I MHC antigen processing is inhibited by Toll-like receptor signaling pathogen-associated molecular patterns: Mycobacterium tuberculosis 19-kDa lipoprotein, CpG DNA, and lipopolysaccharide. J Immunol. 171:1413-22, 2003.

Tomb JF, White O, Kerlavage AR, Clayton RA, Sutton GG, Fleischmann RD, Ketchum KA, Klenk HP, Gill S, Dougherty BA, Nelson K, Quackenbush J, Zhou L, Kirkness EF, Peterson S, Loftus B, Richardson D, Dodson R, Khalak HG, Glodek A, McKenney K, Fitzegerald LM, Lee N, Adams MD, Hickey EK, Berg DE, Gocayne JD, Utterback TR, Peterson JD, Kelley JM, Cotton MD, Weidman JM, Fujii C, Bowman C, Watthey L, Wallin E, Hayes WS, Borodovsky M, Karp PD, Smith HO, Fraser CM, Venter JC. The complete genome sequence of the gastric pathogen Helicobacter pylori. Nature. 388:539-47, 1997.

Tsutsumi R, Higashi H, Higuchi M, Okada M, Hatakeyama M. Attenuation of Helicobacter pylori CagA x SHP-2 signaling by interaction between CagA and C-terminal Src kinase. J Biol Chem. 278:3664-70, 2003.

Uno K, Kato K, Atsumi T, Suzuki T, Yoshitake J, Morita H, Ohara S, Kotake Y, Shimosegawa T, Yoshimura T. Toll-like receptor (TLR) 2 induced through TLR4 signaling initiated by Helicobacter pylori cooperatively amplifies iNOS induction in gastric epithelial cells. Am J Physiol Gastrointest Liver Physiol. 293:G1004-12, 2007.

van Belkum A, Scherer S, van Alphen L, Verbrugh H. Short-sequence DNA repeats in prokaryotic genomes. Microbiol. Mol. Biol. Rev. 62:275-293, 1998.

Vergne I, Singh S, Roberts E, Kyei G, Master S, Harris J, de Haro S, Naylor J, Davis A, Delgado M, Deretic V. Autophagy in immune defense against Mycobacterium tuberculosis. Autophagy. 2:175-8, 2006.

Verstak B, Hertzog P, Mansell A. Toll-like receptor signalling and the clinical benefits that lie within. Inflamm Res. 56:1-10, 2007.

Viala J, Chaput C, Boneca IG, Cardona A, Girardin SE, Moran AP, Athman R, Mémet S, Huerre MR, Coyle AJ, DiStefano PS, Sansonetti PJ, Labigne A, Bertin J, Philpott DJ, Ferrero RL. Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island. Nat Immunol. 5:1166-74, 2004.

Voland P, Weeks DL, Marcus EA, Prinz C, Sachs G, Scott D. Interactions among the seven Helicobacter pylori proteins encoded by the urease gene cluster. Am J Physiol Gastrointest Liver Physiol. 284:G96-G106, 2003.

Vorobjova T, Watanabe T, Chiba T. Helicobacter pylori immunology and vaccines. Helicobacter. 13 Suppl 1:18-22, 2008.

Walz A, Odenbreit S, Mahdavi J, Borén T, Ruhl S. Identification and characterization of binding properties of Helicobacter pylori by glycoconjugate arrays. Glycobiology. 15:700-8, 2005.

Wang HJ, Kuo CH, Yeh AA, Chang PC, Wang WC. Vacuolating toxin production in clinical isolates of Helicobacter pylori with different vacA genotypes. J Infect Dis. 178:207-12, 1998.

Warren JR. Helicobacter: the ease and difficulty of a new discovery (Nobel lecture). ChemMedChem. 1:672-85, 2006.

Weeks DL, Eskandari S, Scott DR, Sachs G. A H+-gated urea channel: the link between Helicobacter pylori urease and gastric colonization. Science. 287:482-85, 2000.

Willhite DC, Blanke SR. Helicobacter pylori vacuolating cytotoxin enters cells, localizes to the mitochondria, and induces mitochondrial membrane permeability changes correlated to toxin channel activity. Cell Microbiol. 6:143-54, 2004.

Wong J, Zhang J, Si X, Gao G, Mao I, McManus BM, Luo H. Autophagosome supports coxsackievirus B3 replication in host cells. J Virol. 82:9143-53, 2008.

Wotherspoon AC, Dogan A, Du MQ. Mucosa-associated lymphoid tissue lymphoma. Curr Opin Hematol. 9:50-5, 2002.

Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 338:1175-6, 1991.

Wu JJ, Sheu BS, Huang AH, Lin ST, Yang HB. Characterization of flgK gene and FlgK protein required for H. pylori colonization--from cloning to clinical relevance. World J. Gastroenterol. 12:3989-93, 2003.

Yakabi K, Mimura H, Iwabuchi H, Ro S, Kamiichi H, Miura S, Nakamura T. Neutrophil-derived hydroxyl radicals mediate interleukin-8-induced increases in tetragastrin-stimulated acid secretion in rats. Dig Dis Sci. 48:1081-7, 2003.

Yang JC, Wang TH, Wang HJ, Kuo CH, Wang JT, Wang WC. Genetic analysis of the cytotoxin-associated gene and the vacuolating toxin gene in Helicobacter pylori strains isolated from Taiwanese patients. Am J Gastroenterol. 92:1316-21, 1997.

Yap GS, Ling Y, Zhao Y. Autophagic elimination of intracellular parasites: convergent induction by IFN-gamma and CD40 ligation ? Autophagy. 3:163-5, 2007.

Ye H, Liu H, Attygalle A, Wotherspoon AC, Nicholson AG, Charlotte F, Leblond V, Speight P, Goodlad J, Lavergne-Slove A, Martin-Subero JI, Siebert R, Dogan A, Isaacson PG, Du MQ. Variable frequencies of t(11;18)(q21;q21) in MALT lymphomas of different sites: significant association with CagA strains of H. pylori in gastric MALT lymphoma. Blood. 102:1012-8, 2003.

Yokota S, Ohnishi T, Muroi M, Tanamoto K, Fujii N, Amano K. Highly-purified Helicobacter pylori LPS preparations induce weak inflammatory reactions and utilize Toll-like receptor 2 complex but not Toll-like receptor 4 complex. FEMS Immunol Med Microbiol. 51:140-8, 2007.

Yoshimori T. Autophagy vs. Group A Streptococcus. Autophagy. 2:154-5, 2006.

Yuan JP, Li T, Chen HB, Li ZH, Yang GZ, Hu BY, Shi XD, Tong SQ, Li YX, Guo XK. Analysis of gene expression profile in gastric cancer cells stimulated with Helicobacter pylori isogenic strains. J Med Microbiol. 53:965-74, 2004.

Zhao Y, Yokota K, Ayada K, Yamamoto Y, Okada T, Shen L, Oguma K. Helicobacter pylori heat-shock protein 60 induces interleukin-8 via a Toll-like receptor (TLR)2 and mitogen-activated protein (MAP) kinase pathway in human monocytes. J Med Microbiol. 56:154-64, 2007.

Zheng PY, Jones NL. Helicobacter pylori strains expressing the vacuolating cytotoxin interrupt phagosome maturation in macrophages by recruiting and retaining TACO (coronin 1) protein. Cell Microbiol. 5:25-40, 2003.
論文全文使用權限
  • 同意授權校內瀏覽/列印電子全文服務,於2012-08-05起公開。
  • 同意授權校外瀏覽/列印電子全文服務,於2014-08-05起公開。


  • 如您有疑問,請聯絡圖書館
    聯絡電話:(06)2757575#65773
    聯絡E-mail:etds@email.ncku.edu.tw