在台灣克雷白氏肺炎桿菌是造成隱源性化膿性肝膿瘍的主要致病菌。近期的流行病學研究指出，隱源性化膿性肝 膿瘍與肝癌以及大腸直腸癌發生率的增加有顯著的相關性。在一部分的大腸桿菌的基因體中被發現帶有一個 polyketide synthases (pks) 的致病島群。這個 54-kb 的pks 致病島群負責製造一個命名為colibactin 的 peptide-polyketide hybrid 基因毒素的主要合成酵素。Colibactin 具有誘導哺乳動物細胞產生DNA 損害以及 基因體不穩定的能力。我們在最近的研究當中發現，在中台灣收集的克雷白氏肺炎桿菌臨床分離株中有超過 25%的菌株帶有這個pks 致病島群，而當中大部分pks+ 的菌株屬於莢膜K1 血清型。因此，我們計畫在本研究中 探討帶有pks 致病島群的克雷白氏肺炎桿菌是否具有癌誘發的潛質。這個致病島群在克雷白氏肺炎桿菌在大腸直 腸癌癌化發生的不同階段中扮演的腳色將運用細胞以及小鼠模式進行深入探討。我們將分析細胞受到不同感染乘 數的野生型pks+克雷白氏肺炎桿菌以及同源的基因剔除突變菌株的感染時，DNA損害以及基因體不穩定的程度。 在小鼠模式中，我們將比較分析對照組與實驗組的小鼠其大腸直腸組織中腫瘤的發生率以及癌變的程度是否有因 為pks+克雷白氏肺炎桿菌的感染或是長期定殖而顯著提升。此外，我們亦將針對Wnt 訊號傳遞路徑當中的成員在 pks+克雷白氏肺炎桿菌誘導大腸直腸癌的過程中扮演的角色進行探討。本計畫的完成將幫助我們更進一步了解克 雷白氏肺炎桿菌的感染與癌症之間的關聯性。
Klebsiella pneumoniae is the primary pathogen of cryptogenic pyogenic liver abscess (PLA) in Taiwan. Recent epidemiological studies demonstrate that cryptogenic PLA is significantly correlated with increased risk of liver cancer and colorectal cancer (CRC) in Taiwan. Some Escherichia coli strains were identified to carry a polyketide synthases (pks) pathogenicity island. The 54-kb pks island encodes multi-enzymatic machinery for synthesizing a peptidepolyketide hybrid genotoxin named Colibactin and that is capable of inducing DNA damage and genomic instability of mammalian cells. We have recently discovered that more than 25% of K. pneumoniae isolates in central Taiwan harbor this pks island, and most of pks+ K. pneumoniae strains belong to K1 serotype. In this project, we will determine whether the pks island endows K. pneumoniae with a cancer-inducing potential. The role of pks+ K.island endows K. pneumoniae with a cancer-inducing potential. The role of pks+ K. pneumoniae in the initiation, promotion and progression of CRC will be investigated in a number of cell and murine models. DNA damage and genomic instability of cells will be assessed upon low- and high-dose infection with pks+ K. pneumoniae and its isogenic mutants. The cancer-inducing potential of pks+ K. pneumoniae will be evaluated by comparing the adenoma pathology, the incidence of colorectal tumors, and multiplicity among the control and experimental groups of mice to determine whether pks+ K. pneumoniae enhances the occurrence and development of CRC. The roles of components of Wnt signaling pathway in the pks+ K. pneumoniae-related CRC development will be investigated. The completion of this project is expected to provide new insights into our understanding of the yet uncertain link between K. pneumoniae infections, such as pyogenic liver abscess and cancer.
