請用此 Handle URI 來引用此文件: http://hdl.handle.net/11455/20303
標題: 研究克雷伯氏肺炎桿菌在糖尿病小鼠引起肝膿瘍感染的致病機轉
The study of pathogenic mechanisms of K.pneumoniae-caused liver abscess in diabetic mice model
作者: 林怡均
Lin, Yi-Chun
關鍵字: 克雷伯氏肺炎桿菌
Klebsiella pneumoniae
肝膿瘍
liver abscess
出版社: 生命科學系所
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摘要: 在近三十年來,克雷伯氏肺炎桿菌引起的社區性肝膿瘍感染廣泛的流行,尤其是在台灣。類似的肝膿瘍病例也在世界各地陸續的被報導。克雷伯氏肺炎桿菌引起的肝膿瘍尤其好發於糖尿病病人。一般認為,克雷伯氏肺炎桿菌的莢膜與其致病性有關。莢膜的多醣類成分所造成的黏性特質被認為是克雷伯氏肺炎桿菌重要的毒力因子,其能幫助細菌躲避宿主的免疫攻擊。然而,在臨床上卻也發現低黏性的克雷伯氏肺炎桿菌也有造成組織膿瘍的能力。本研究首先即在探討莢膜的黏性特質在克雷伯氏肺炎桿菌的致病機轉上所扮演的角色,實驗所使用的糖尿病小鼠和正常血糖的控制組小鼠都分別使用由口或從氣管插管餵食高或低黏性莢膜的細菌。實驗結果顯示:克雷伯氏肺炎桿菌莢膜的黏性特質對於高黏性的1112菌株的致病性是重要的。但是,低黏性的1084菌株在糖尿病小鼠卻比高黏性的1112菌株造成更嚴重的菌血症及感染。由此顯示,除了莢膜的黏性特質之外,低黏性的克雷伯氏肺炎桿菌存在著其他重要的毒力因子;並且,宿主的免疫缺損或許在低黏性菌株的感染上扮演了重要的角色。目前雖有許多研究描述眾多與克雷伯氏肺炎桿菌引起的肝膿瘍有關的毒力因子,可是對於此菌所引發的肝細胞損傷的相關機制仍不清楚。在本實驗室所建立的克雷伯氏肺炎桿菌引起的肝膿瘍動物模式中發現肝細胞的Interferon-γ(IFN-γ) 有明顯增加的情形。IFN-γ已知能引發肝細胞的凋亡或抑制細胞生長週期並進而影響肝臟再生,可見其在肝臟疾病上的重要性。因此,在後續的研究中,帶有冷光基因的克雷伯氏肺炎桿菌也同樣感染糖尿病和正常血糖的控制組小鼠以研究其與IFN-γ訊息傳遞路徑的相關性。更進一步,利用非侵入式活體分子影像系統監測細菌在小鼠體內感染分布的狀況。實驗結果顯示:克雷伯氏肺炎桿菌所引起的肝膿瘍感染能活化肝細胞的IFN-γ/signal transducers and activators of transcription (STAT)/IFN regulatory factor-1 (IRF-1)訊息傳遞路徑。而克雷伯氏肺炎桿菌在糖尿病小鼠所造成較嚴重的肝細胞損傷,可能與Interleukin-1β(IL-1β) 和Macrophage inflammatory protein-2(MIP-2)的延遲增加導致過量的嗜中性白血球蓄積造成更嚴重的發炎,以及內質網壓力上升造成肝細胞的凋亡增加有關。
The community-acquired Klebsiella pneumoniae-caused liver abscess (KLA) infection is widespread mainly in the past three decades, especially in Taiwan. The similar prevalence of KLA is also reported in other countries gradually. The infections are predominant tended to occur in diabetic patients. The capsular polysaccharide (CPS) of K. pneumoniae is generally considered to be an important pathogenicity factor. The resulted hypermucoviscosity (HV) is related to the virulent strains of K. pneumoniae, which may circumvent host defenses. However, the emergences of tissue-abscesses-associated HV-negative isolates are noted in clinical infection. To identify the role of mucoviscosity property in the pathogenesis of K. pneumoniae, the diabetic or normal glycemic mice were administered orally or intratracheally with HV-positive or -negative strain. The results exhibited that the HV phenotype was required for the virulence of the clinically isolated HV-positive strain 1112. But the superior ability of the HV-negative stain 1084 over 1112 to cause bacteremia in diabetic mice suggested that the virulence of HV-negative K. pneumoniae may related with other factors, and the host with worsen immune system may play an important role. Although several bacterial characteristics has been contributed with KLA, it is uncertain that the cellular mechanisms relative to the pathogenesis of K. pneumonia infection in the liver. In our KLA mouse model, increased production of interferon-γ (IFN-γ) was significantly evoked by K. pneumoniae infections in the liver. IFN-γ can induce hepatocyte apoptosis or inhibit cell cycle progression, thereby suppressing liver regeneration may act as an essential mediators during liver disease. Next, auto-bioluminescence expressing K. pneumoniae was orally inoculated into diabetic mice and age-match naïve control to study the role of IFN-γ signaling pathway in hepatic response. Moreover, the utilization of in vivo imaging system (IVIS) can real-time detect the bacterial distribution during infection. These results revealed that KLA infection was associated with IFN-γ/signal transducers and activators of transcription (STAT)/IFN regulatory factor-1 (IRF-1) signaling. Inflammatory damage induced in the diabetic mice was enhanced due to massive infiltrates of neutrophils recruited by overproduction of interleukin-1β(IL-1β) and macrophage inflammatory protein-2 (MIP-2), and that was worsened by endoplasmic reticulum stress (ER stress) related liver apoptosis.
URI: http://hdl.handle.net/11455/20303
其他識別: U0005-2008201308194900
文章連結: http://www.airitilibrary.com/Publication/alDetailedMesh1?DocID=U0005-2008201308194900
顯示於類別:生命科學系所

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