糖尿病是克雷白氏肺炎桿菌感染的危險因子。在台灣 45-75% 的克雷白氏肺炎桿菌 肝膿瘍患者具有糖尿病。絕大多數克雷白氏肺炎桿菌肝膿瘍相關的敗血性轉移病灶(腦 膜炎與眼內炎)尤其會發生在糖尿病患者身上。雖然臨床上具有顯著的相關性，對於為 何克雷白氏肺炎桿菌在糖尿病者體內引起轉移性病灶的原因目前仍不清楚。因此我們將 在本計畫中針對克雷白氏肺炎桿菌與糖尿病宿主交互作用的分子機制，尤其是肝臟與腦 部的感染機制，進行探討。運用全基因體學的研究方法，我們將搜尋在克雷白氏肺炎桿 菌引起糖尿病鼠在肝臟、腦部、與眼睛產生轉移性病灶的過程中所參與的宿主與細菌因 子。這些因子在感染過程中所扮演的角色將運用遺傳，生化與細胞生物的方法學進行功 能上的定性，並且也進行細胞微生物感染的訊息傳導研究。本計畫的完成將幫助我們找 到與克雷白氏肺炎桿菌感染相關的糖尿病因子以及細菌的致病因子，而這些因子將有機 會可以當作藥物標的分子以提供未來新型抗菌藥物的篩選以及幫助糖尿病患者建立有 效的感染性疾病防禦機制。 Diabetes mellitus (DM) is an important risk factor for Klebsiella pneumoniae infections. In Taiwan, DM underlies 45-75% of patients with K. pneumoniae-caused liver abscess (KLA). Most of the KLA-related septic metastatic lesions, meningitis and endophthalmitis, occur particularly in DM individuals. Although the clinical correlation is significant, it is unclear why K. pneumoniae establishes metastatic lesions particularly in DM individuals. We aim in this project to elucidate the molecular mechanism underlying the host-pathogen interaction between K. pneumoniae and DM mice. By means of mechanistic approaches, K. pneumoniae virulence factors and the DM host factors, including signaling pathways, that are required for K. pneumoniae-caused liver abscess and CNS infection in DM mice will be identified. The roles of the identified host and pathogen factors in the development of CNS infection will be functionally characterized in cell lines and in the DM mice by using a series of genetic, biochemical, and cell biology approaches. Through the completion of this project, the DM host factors may suit as potential targets for drug therapy and that will contribute to the development of prevention strategy and new therapy for a better prognosis and control of K. pneumoniae infections in diabetic patients. Besides, the DM-associated K. pneumoniae factors may serve as an ideal chemical scaffold for discovery of novel antimicrobial drugs.
