臺灣博碩士論文加值系統

創傷弧菌為伺機性感染人類的病原體，透過傷口感染或食用汙染海鮮後引起胃腸道相關症狀，感染者可能造成嚴重皮膚損傷及敗血症，而引起敗血症的個案死亡率極高。臨床上病患感染後之臨床表現差異極大，是否因病原菌本身的毒力差異或是感染個案本身因子的影響值得探討。因此，瞭解菌株所攜帶的毒力因子及病人臨床預後因子對於此感染者的即時治療很重要。在本研究中，共收集了49株創傷弧菌臨床菌株及其相關人類臨床資料進行分析。為比較創傷弧菌的毒力，使用sek-1突變先天免疫缺陷秀麗隱桿線蟲作為活體(in-vivo)感染的試驗對象，各菌株透過PCR方法檢測創傷弧菌的重要毒力基因(包括vvhA、vcgC、16S rRNA type B、CPS1、PRXII、nanA、toxR及manllA)，並且收集病例的臨床資料包括年齡、性別、發燒、肝病（肝炎或肝硬化）、糖尿病或脾腫大等臨床因子做為預後評估。在本研究中，發現所有的分離株皆攜帶vvhA、 vcgC、nanA、16S rRNA type B及manIIA基因。菌株中僅一株未帶有toxR基因，而所有菌株皆未帶有PRXII基因。73.5%菌株中被偵測出帶有CPS1基因，進一步經線蟲模式評估結果顯示帶有CPS1基因毒力有顯著毒力作用。所有菌株皆具vvpE基因，且在攜帶特異vvpE基因型的創傷弧菌分離株對秀麗隱桿線蟲生存具有顯著影響。進一步依人類感染後生存和死亡組別比較其感染菌株在線蟲感染模式結果，顯示統計學上顯著差異。在預後因子的評估中，肝病（肝炎或肝硬化）、糖尿病和脾腫大是與創傷弧菌感染後是否存活之顯著相關因子。進一步依個案年齡、性別、肝病(肝炎或肝硬化)、糖尿病及脾腫大因子，以邏輯式回歸分析後建構個案臨床指標，指標值大於-0.40者對死亡之預測具有83%敏感度及86%特異度。本研究具體的結論為台灣臨床創傷弧菌具有相似的毒力特徵，因此對於感染病人的存活預後結果，台灣人類臨床因素相較於菌株毒力本身的毒力作用更為重要。

Vibrio vulnificus is an opportunistic human pathogen, which causes wound infections or gastrointestinal-related symptoms, but may potentially result in septicaemia with high case-fatality rate. Therefore, it is of major importance to know if the bacteria carrying certain virulence factors could be more pathogenic to humans and what the prognostic factors are in human clinical cases. In this study, a total of 49 V. vulnificus isolates and their relevant human clinical records were collected for analysis. To compare virulence of V. vulnificus, Caenorhabditis elegans sek-1 mutant was applied as an in-vivo model. Important virulence genes of V. vulnificus were detected by PCR. Human factors regarding age, sex, fever, underlying conditions such as liver diseases (hepatitis or cirrhosis), diabetes and/or splenomegaly, as well as survival condition after the infection were collected for studying prognosis. In our study, it was found that all the isolates carry virulence genes of vvhA, vcgC, nanA, 16S rRNA type B and manIIA. Only one isolate was PCR negative for toxR and none of the isolates carried PRXII gene. 73.5% of the isolates carried CPS1 gene, and it was found significant effect on C. elegans survival while comparing the CPS1-positive isolates to the CPS1-negative ones. V. vulnificus isolates carrying a specific genotype of vvpE, were significantly influence C. elegans survival. There is significant difference of C. elegans survival after V. vulnificus challenge between the human survival and death groups. For prognosis evaluation, liver disease (hepatitis or cirrhosis), diabetes and splenomegaly were significant factors associated with human survival after the infection. Using conditions of age, sex, liver disease, diabetes and splenomegaly to construct the clinical index (CLI) by logistic regression analysis, it showed that the individual with CLI greater than -0.40 was with sensitivity of 83% and specificity of 86% to determine death. The overall results suggest that clinical V. vulnificus isolates in Taiwan are generally with similar virulence profiles, but human clinical factors are more important than V. vulnificus virulence factors to determine human survival.

目次
第一章 文獻探討 1
第一節 創傷弧菌的介紹 1
第二節 創傷弧菌預後因子 2
第三節 創傷弧菌的毒力因子 3
一、 細胞毒素/溶血素基因(cytolyxin / hemolysin gene; vvhA gene) 3
二、 金屬蛋白酶 (metalloprotease; VvpE)基因 4
三、 毒力相關基因(virulence-correlated gene; vcg gene) 4
四、 莢膜多醣體(capsular polysaccharide; CPS)相關基因 4
五、 nanA基因 5
六、 toxR 基因 5
七、 16S rRNA 基因 5
八、 manll A 基因 5
第四節 以秀麗隱桿線蟲為實驗動物模式進行病原毒力評估 6
第五節 秀麗隱桿線蟲先天性免疫 7
第六節 研究目的 8
第二章 材料與方法 9
第一節 樣本來源 9
第二節 菌株來源及培養 9
一、 細菌培養 9
二、 菌株保存 11
三、 菌株DNA萃取 11
四、 毒力基因之聚合酶連鎖反應(Polymerase chain reaction; PCR)檢測 12
第三節 秀麗隱桿線蟲存活曲線測定 14
一、 秀麗隱桿線蟲線蟲感染 14
二、 秀麗隱桿線蟲感染V. vulnificus存活率評估 14
第四節 線蟲培養基及溶液配置 15
一、 NG agar 15
二、 ENG agar 15
三、 M9 buffer 16
第五節 統計分析 16
一、 線蟲存活分析 16
二、 預後因子評估分析 16
第三章 結果 18
第一節 V. vulnificus各毒力基因檢測結果 18
第二節 V. vulnificus vvpE基因序列比對與演化樹狀圖建構 18
第三節 秀麗隱桿線蟲全程感染V. vulnificus之毒力測試結果評估 19
一、 以全程V. vulnificus感染秀麗隱桿線蟲毒力測試結果比較V. vulnificus臨床感染者於存活與死亡組別之差異 19
二、 CPS1毒力基因於感染秀麗隱桿線蟲後之毒力測試比較 19
三、 不同vvpE genogroup之V. vulnificus以全程感染秀麗隱桿線蟲之方式比較存活差異 19
第四節 秀麗隱桿線蟲單次感染V. vulnificus之毒力測試評估 20
一、 以單次V. vulnificus感染秀麗隱桿線蟲毒力測試結果比較V. vulnificus臨床感染者於存活與死亡組別之差異 20
二、 CPS1毒力基因於感染秀麗隱桿線蟲後之毒力測試比較 20
三、 不同vvpE genogroup之V. vulnificus以單次感染秀麗隱桿線蟲之方式比較存活差異 21
第五節 V. vulnificus感染個案之預後因子分析 21
一、 預後因子單變項分析 21
二、 臨床預後因子多變項邏輯式回歸分析 21
三、 臨床預後因子ROC曲線分析 22
第四章 討 論 23
結論 28
參考文獻 29

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