Colibactin Contributes to the Hypervirulence of pks+ K1 CC23 Klebsiella pneumoniae in Mouse Meningitis Infections

Frontiers in Cellular and Infection Microbiology

Huang, Yi-Jhen¹  Hsiao, Pei-Yi²  Lin, Ching-Ting³  Chen, Ying-Tsong⁴  Lu, Min-Chi⁵  Liang, Chih-Lung⁶  Cheng, Ching-Chang⁷  Wang, Yao-Chen⁷  Chiang, Ming-Ko⁸  Lai, Yi-Chyi⁹ 

[1] Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan;Department of Life Science, National Chung Cheng University, Chia-Yi County, Taiwan;Department of Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan;Department of Microbiology and Immunology, School of Medicine, China Medical University, Taichung, Taiwan;Division of Infectious Diseases, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan;Graduate Institute of Chinese Medicine, School of Chinese Medicine, China Medical University, Taichung, Taiwan;Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung, Taiwan;Institute of Molecular and Genomic Medicine, National Health Research Institutes, Miaoli County, Taiwan;Laboratory Animal Service Center, China Medical University, Taichung, Taiwan

关键词: Klebsiella pneumoniae;    K1;    CC23;    Colibactin;    Meningitis;   

DOI  :  10.3389/fcimb.2017.00103

学科分类：生物科学（综合）

来源: Frontiers

【 摘 要 】

Klebsiella pneumoniae is the most common pathogen of community-acquired meningitis in Taiwan. However, the lack of a physiologically relevant meningitis model for K. pneumoniae has impeded research into its pathogenesis mechanism. Based on phylogenetic analyses of a core genome MLST scheme, the hypervirulent K1 K. pneumoniae strains, which are etiologically implicated in adult meningitis, mostly belong to a single clonal complex, CC23. Some K1 CC23 K. pneumoniae strains carry a gene cluster responsible for colibactin production. Colibactin is a small genotoxic molecule biosynthesized by an NRPS-PKS complex, which is encoded by genes located on the pks island. Compared to other hypervirulent K. pneumoniae which primarily infect the liver, the colibactin-producing (pks+) K1 CC23 strains had significant tropism towards the brain of BALB/c mice. We aimed in this study to develop a physiologically relevant meningitis model with the use of pks+ K1 CC23 K. pneumoniae. Acute meningitis was successfully induced in adult BALB/c male mice through orogastric, intranasal, and intravenous inoculation of pks+ K1 CC23 K. pneumoniae. Besides the typical symptoms of bacterial meningitis, severe DNA damages and caspase 3-independent cell death were elicited by the colibactin-producing K1 CC23 K. pneumoniae strain. The deletion of clbA, which abolished the production of colibactin, substantially hindered K. pneumoniae hypervirulence in the key pathogenic steps towards the development of meningitis. Our findings collectively demonstrated that colibactin was necessary but not sufficient for the meningeal tropism of pks+ K1 CC23 K. pneumoniae, and the mouse model established in this study can be applied to identify other virulence factors participating in the development of this life-threatening disease.

【 授权许可】

CC BY