克雷白氏肺炎桿菌 (Klebsiella pneumoniae) 為格蘭氏陰性腸內桿菌科 (Enterobacteriacea) 的細菌，經常引起社群及院內感染。在台灣，此菌的感染好發於糖尿病患，易併發多種臨床症狀，包括原發性肺炎、化膿性肝膿瘍 (pyogenic liver abscess)、腦膜炎 (meningitis) 以及轉移性眼內炎 (metastatic endophthalmitis) 及其高致死率，故 K. pneumoniae 引發糖尿病患肝膿瘍已成為國內重要的感染症。K. pneumoniae 的致病毒力因子包括莢膜 (capsule)、脂多醣體 (lipopolysaccharide, LPS) 等多種，但何者為主要致病因子仍不清楚。另一方面，糖尿病較易受 K. pneumoniae 感染而引發肝膿瘍之宿主成因亦仍需進一步確認。為研究糖尿病宿主之相關致病因素，我們對糖尿病人或建立糖尿病鼠的先天性免疫力，及肝臟對感染之反應進行研究。實驗發現糖尿病人的嗜中性細胞和巨噬細胞吞噬 K. pneumoniae 的能力相對地比非糖尿病人的低。檢測免疫細胞移行的能力，發現糖尿鼠的免疫細胞移行能力較正常鼠弱，且細胞的死亡率較高。比較 K. pneumoniae 感染小鼠的存活率，糖尿鼠感染 K. pneumoniae 後其死亡率較正常鼠高。另一方面，糖尿鼠經莢膜黏性較低或不具黏性的 K. pneumoniae 菌株感染後，肝細胞間隙有變大的現象，然而莢膜黏性高者感染後，糖尿鼠肝組織則呈現空洞狀，此現象未見於正常鼠肝細胞中。進一步比較小鼠肝臟細胞訊息傳遞路徑活化的差異，發現小鼠灌食感染 K. pneumoniae 後，糖尿鼠肝細胞 caspase 3 活性增加。有趣地，糖尿鼠肝細胞 Erk 及 p38 的活化程度高於正常鼠之肝細胞。而不論是否有 K. pneumoniae 的感染，正常鼠之內質網壓力反應 (unfolded protein responses, UPR) 的程度較高於糖尿鼠，且也發現肝臟有細胞自噬 (autophagy) 發生。以人類肝癌細胞株 Hep G2 及 BALB/c 肝細胞株 (BNL) 觀察 K. pneumoniae 引發細胞凋亡的情形，發現與活菌共同培養下，Hep G2 及 BNL 細胞內 DNA 片段化程度增加，但若以去莢膜的 K. pneumoniae 感染細胞，則不會造成細胞的凋亡，所以 K. pneumoniae 所引起的肝細胞凋亡，莢膜可能扮演了某種角色。綜合以上的結果，我們認為除了 K. pneumoniae 所擁有之特定致病因子外，糖尿病引發免疫低下與肝細胞低應變能力亦是導致 K. pneumoniae 引發肝膿瘍的原因。

Klebsiella pneumoniae, an important pathogen belonging to Gram-negative Enterobacteriaceae, usually causes community- and hospital-acquired infections. In Taiwan, diabetic patients have an increased susceptibility to K. pneumoniae infections combined with several clinical syndromes, including primary pneumonia, pyogenic liver abscess, meningitis and metastatic endophthalmitis, and their high mortalities, K. pneumoniae-induced liver abscess in diabetic patients become an important infectious disease in Taiwan. The virulence factors of K. pneumoniae identified include capsule, lipopolysaccharide (LPS) et al., however, the dominant pathogenic factor(s) was (were) still unclear. On the other hand, the host factors involved in pathogenesis of K. pneumoniae-induced liver abscess associated with diabetes mellitus also remain to be clarified. For studying the host effect(s) of diabetes on K. pneumoniae-induced liver abscess, we evaluated the innate immune activities of diabetes mellitus patients or diabetic mice and evaluated the responses of liver tissue to K. pneumoniae infection. Our results indicated the abilities of phagocytosis of neutrophils and macrophages from diabetic patients decreased. The migration capabilities and survival rates of both immune cells from diabetic mice were also less than those obtained from non-diabetic mice. Comparing the survival rates, K. pneumoniae-infected diabetic mice had a higher fatality rate with K. pneumoniae-infection than control non-diabetic mice. After infected with K. pneumoniae with viscoid capsule, the interspace between the hepatocytes of diabetic mice were formed as cleft, however, hyper-mucoid K. pneumoniae caused lots of vacuoles within hepatic tissues in diabetic mice but not non-diabetic groups. Furthermore, we evaluated the activities of intracellular signal pathways in hepatic tissues. After oral administration with K. pneumoniae, caspase 3 activity was detected in liver samples from K. pneumoniae-infected diabetic mice but not other groups. Interestingly, activities of Erk and p38 were more higher in hepatic tissues from diabetic mice than those samples from non-diabetic mice. Whether mice were K. pneumoniae-infected, unfolded protein responses (UPR) in liver samples of non-diabetic mice were more active than in diabetic mouse livers, and the autophagy were also be deteted in diabetic mouse liver tissues. To evaluate the direct cytopathic effects of K. pneumoniae in vitro, HepG2 or BNL cells were cocultured with K. pneumoniae and the apoptosis of these cells were the determined. Our results indicated that the DNA framgmentation increased in a dose dependent manner by live but not dead microorganisms. We proposed that capsule maybe play a role in hepatic cytopathy. Taken together, except specific virulent factors of K. pneumoniae, the immunocompromise and low stress-defenses in diabetes mellitus may also result in K. pneumoniae-induced liver abscess.

中文摘要……………………………………………………………………………I
英文摘要……………………………………………………………………………II
目錄………………………………………………………………………………IV
表目錄……………………………………………………………………………VII
圖目錄……………………………………………………………………………VIII
縮寫及簡稱………………………………………………………………………Х
第一章 緒論…………………………………………………………………………1
第一節 糖尿病…………………………………………………………………1
1-1 定義與分類……………………………………………………………1-3
1-2 糖尿病對感染的感受性………………………………………………3-5
1-3 糖尿病的免疫防禦功能………………………………………………5-6
1-4 糖尿病的動物模型……………………………………………………6-7
第二節 克雷白氏肺炎桿菌………………………………………………………7
2-1 微生物學特性……………………………………………………………7
2-2 感染途徑與臨床表徵…………………………………………………7-8
2-3 與克雷白氏肺炎桿菌致病相關的毒力因子及其致病機轉…………8-12
第三節 糖尿病與克雷白氏肺炎桿菌的相關性……………………………12-13
第四節 細胞凋亡、內質網壓力反應及自噬的介紹…………………………13-14
第五節 研究目的…………………………………………………………………15
第二章 材料與方法…………………………………………………………………16
第一節 克雷白氏肺炎桿菌的製備………………………………………………16
1. 實驗菌株…………………………………………………………………16
2. Tetracyclin agar plate配製……………………………………………17
3. 菌株培養及菌株生長曲線的測定………………………………………18
4. 製作螢光菌：pGFPuvTc 質體轉染入克雷白氏肺炎桿菌…………18-19
5. 克雷白氏肺炎桿菌死菌的製作…………………………………………19
6. 去莢膜克雷白氏肺炎桿菌的製作………………………………………19
第一部份 糖尿病患免疫能力評估實驗架構………………………………20
1-1 病人血液來源………………………………………………………20
1-2 血液中嗜中性白血球及巨噬細胞的分離…………………………21
1-3 非糖尿病人及糖尿病人血液中嗜中性白血球及巨噬細胞的吞噬能力……………………………………………………………………22
第二部份 實驗動物架構………………………………………………………23
2-1 實驗動物………………………………………………………………24
2-2 糖尿病動物模式的建立…………………………………………24-25
2-3 小鼠免疫細胞轉移腹腔的能力…………………………………26-27
2-4 小鼠灌食克雷白氏肺炎桿菌的感染模式……………………………27
2-5 小鼠灌食感染克雷白氏肺炎桿菌後的採集血液和肝脾檢體………28
2-6 小鼠各主要器官中克雷白氏肺炎桿菌菌量的測定……………28-29
2-7 小鼠肝組織冷凍切片…………………………………………………29
2-8 小鼠肝組織石臘切片及蘇木紫與伊紅染色法…………………29-30
2-9 蛋白質電泳………………………………………………………31-35
2-10 西方墨點轉漬反應 (Western blot, WB)…………………………36-39
2-11 酵素免疫分析法 (Enzyme-linked immunoassay, ELISA)………39-40
第三部份 細胞實驗架構………………………………………………………41
3-1 實驗細胞株……………………………………………………………42
3-2 人類肝癌細胞 (Hep G2) 及 BALB/c 正常肝細胞株 (BALB/c normal liver cell, BNL) 的培養……………………………………………42-43
3-3 DNA萃取及瓊膠電泳偵測凋亡…………………………………43-45
第三章 實驗結果……………………………………………………………………46
第一部份 糖尿病鼠與糖尿病人之先天性免疫能力的評估…………………46
1-1 建立糖尿病實驗動物與評估血糖值及體重變化……………………46
1-2 克雷白氏肺炎桿菌死菌誘發免疫細胞移行能力之評估………46-48
1-3 非糖尿病人和糖尿病人血球細胞吞噬的能力…………………..…49
第二部份 建立小鼠感染克雷白氏肺炎桿菌的模式………………..………50
2-1 小鼠灌食感染克雷白氏肺炎桿菌後的存活率………………………50
2-2 小鼠灌食感染克雷白氏肺炎桿菌後血液及肝脾的細菌培養………51
2-3 小鼠腹腔注射克雷白氏肺炎桿菌死菌後灌洗液中細胞激素的含
量……………………………………..………………………51-52
2-4 小鼠肝臟組織石臘切片染色後的病理特徵…………………………52
2-5 小鼠灌食感染克雷白氏肺炎桿菌後肝組織冷凍切片…………52-53
2-6 克雷白氏肺炎桿菌感染小鼠後肝功能指數的變化…………………53
2-7 小鼠肝臟組織細胞凋亡的情形……………………..……………53-54
2-8 小鼠肝臟組織 MAP Kinase 的訊息傳遞……………………………54
2-9 小鼠肝臟組織內質網壓力的程度……………………………...54-55
2-10 小鼠肝臟組織細胞自噬的情形………………………………………55
第三部份 建立細胞感染克雷白氏肺炎桿菌的模式…………………………55
3-1 以克雷白氏肺炎桿菌感染人類肝癌細胞株 Hep G2 和BALB/c正常
肝細胞株 (BNL)………………………………………………….55-56
3-2 以克雷白氏肺炎桿菌誘發Hep G2和BNL細胞凋亡的情形………56
綜合討論…………………………………………………………………………57-63
參考文獻…………………………………………………………………………64-71

表目錄
表一、K. pneumoniae的來源及特徵………………………………………………16
表二、非糖尿病人及糖尿病人的病史………………………………………………72

圖目錄
圖一、正常小鼠和糖尿鼠的血糖及體重變化……………………………………73
圖二、比較正常鼠及糖尿鼠腹腔注射 K. pneumoniae 死菌後脾臟腫大情形…74
圖三、比較正常鼠及糖尿鼠腹腔注射 K. pneumoniae 死菌後腹腔灌洗液中細胞的存活率……………………………………………………………………75
圖四、比較正常鼠及糖尿鼠腹腔注射 K. pneumoniae 死菌後免疫細胞移行至腹腔的能力……………………………………………………………………76
圖五、比較非糖尿病人與糖尿病人血球細胞吞噬的情形………………………77
圖六、比較正常鼠及糖尿鼠灌食感染 K. pneumoniae 後小鼠的存活率………78
圖七、正常鼠及糖尿鼠灌食感染 K. pneumoniae 後血液和器官的菌量………79
圖八、比較正常鼠及糖尿鼠腹腔注射 K. pneumoniae 死菌後灌洗液中細胞激素的含量………………………………………………………………………80
圖九、正常鼠及糖尿鼠感染 K. pneumoniae 後肝組織石臘切片圖……………81
圖十、正常鼠及糖尿鼠灌食感染 K. pneumoniae 後肝組織冷凍切片圖………82
圖十一、K. pneumoniae 感染正常鼠及糖尿鼠後肝功能指數的變化……………83
圖十二、比較正常鼠及糖尿鼠肝臟組織細胞凋亡的情形………………………84
圖十三、比較正常鼠及糖尿鼠肝臟組織 MAP Kinase 的訊息傳遞……………85
圖十四、比較正常鼠及糖尿鼠肝臟組織內質網壓力的程度……………………86
圖十五、比較正常鼠及糖尿鼠肝臟組織細胞自噬的情形………………………87
圖十六、以顯微鏡觀察克雷白氏肺炎桿菌感染人類肝癌細胞 (Hep G2)………88
圖十七、以顯微鏡觀察 K. pneumoniae 感染 BALB/c 肝細胞株 (BNL)……90
圖十八、以 K. pneumoniae 誘發人類肝癌細胞 (Hep G2) 凋亡的情形………89
圖十九、以 K. pneumoniae 誘發 BALB/c 肝細胞株 (BNL) 凋亡的情形…91
圖二十、實驗假說…………………………………………………………………92
附圖一、pGFPuv-TC map……………………………………………………………93
附圖二、以脈衝式電泳分析臨床克雷白氏肺炎桿菌的基因型…………………94
附圖三、不同克雷白氏肺炎桿菌菌種及大腸桿菌(E. coli-DH-5a)生長曲線圖…95

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