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

• Published in: Frontiers in cellular and infection microbiology Vol. 7; p. 103
• Main Authors: Lu, Min-Chi, Chen, Ying-Tsong, Chiang, Ming-Ko, Wang, Yao-Chen, Hsiao, Pei-Yi, Huang, Yi-Jhen, Lin, Ching-Ting, Cheng, Ching-Chang, Liang, Chih-Lung, Lai, Yi-Chyi
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 31.03.2017
• Subjects: Animals; Antigens, Bacterial - analysis; Brain - pathology; Cell Death; Disease Models, Animal; Humans; Klebsiella pneumoniae - classification; Klebsiella pneumoniae - isolation & purification; Klebsiella pneumoniae - pathogenicity; Male; Meningitis, Bacterial - microbiology; Meningitis, Bacterial - pathology; Mice, Inbred BALB C; Microbiology; Peptides - metabolism; Polyketides - metabolism; Polysaccharides, Bacterial - analysis; Taiwan; Virulence Factors - metabolism; K1; CC23; Klebsiella pneumoniae; colibactin; meningitis
• ISSN: 2235-2988; 2235-2988
• DOI: 10.3389/fcimb.2017.00103

is the most common pathogen of community-acquired meningitis in Taiwan. However, the lack of a physiologically relevant meningitis model for has impeded research into its pathogenesis mechanism. Based on the core genome MLST analyses, the hypervirulent K1 strains, which are etiologically implicated in adult meningitis, mostly belong to a single clonal complex, CC23. Some K1 CC23 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 island. Compared to other hypervirulent which primarily infect the liver, the colibactin-producing ( ) K1 CC23 strains had significant tropism toward the brain of BALB/c mice. We aimed in this study to develop a physiologically relevant meningitis model with the use of K1 CC23 . Acute meningitis was successfully induced in adult BALB/c male mice through orogastric, intranasal, and intravenous inoculation of K1 CC23 . Besides the typical symptoms of bacterial meningitis, severe DNA damages, and caspase 3-independent cell death were elicited by the colibactin-producing K1 CC23 strain. The deletion of , which abolished the production of colibactin, substantially hindered hypervirulence in the key pathogenic steps toward the development of meningitis. Our findings collectively demonstrated that colibactin was necessary but not sufficient for the meningeal tropism of K1 CC23 , 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.