ClbG in Avian Pathogenic Escherichia coli Contributes to Meningitis Development in a Mouse Model.

Xia Meng,Haoran Zhong,Heng Wang,Jiaxiang Zhang,Qingqing Gao,Guoqiang Zhu,Luying Cui,Jun Li,Peili Wang,Pengpeng Xia,Junsheng Dong,Yanfei Chen,Jianji Li

doi:10.3390/toxins13080546

Abstract

Colibactin is a complex secondary metabolite that leads to genotoxicity that interferes with the eukaryotic cell cycle. It plays an important role in many diseases, including neonatal mouse sepsis and meningitis. Avian pathogenic Escherichia coli (APEC) is responsible for several diseases in the poultry industry and may threaten human health due to its potential zoonosis. In this study, we confirmed that clbG was necessary for the APEC XM strain to produce colibactin. The deletion of clbG on APEC XM contributed to lowered γH2AX expression, no megalocytosis, and no cell cycle arrest in vitro. None of the 4-week Institute of Cancer Research mice infected with the APEC XM ΔclbG contracted meningitis or displayed weakened clinical symptoms. Fewer histopathological lesions were observed in the APEC XM ΔclbG group. The bacterial colonization of tissues and the relative expression of cytokines (IL-1β, IL-6, and TNF-α) in the brains decreased significantly in the APEC XM ΔclbG group compared to those in the APEC XM group. The tight junction proteins (claudin-5, occludin, and ZO-1) were not significantly destroyed in APEC XM ΔclbG group in vivo and in vitro. In conclusion, clbG is necessary for the synthesis of the genotoxin colibactin and affects the development of APEC meningitis in mice.

Highlights

In 2006, colibactin was identified in a neonatal meningitis E. coli (NMEC) strain (IHE3034) by Nougayrède and colleagues [1]
Colibactin is a natural and genotoxic chemical compound, which is synthesized by a hybrid non-ribosomal peptide synthetase-polyketide synthase (NRPS-PKS) assembly line encoded by the pks genomic island
The results indicated that clbG was a necessary component for the synthesis of genotoxic colibactin and impact the development of meningitis in mouse

Summary

Introduction

In 2006, colibactin was identified in a neonatal meningitis E. coli (NMEC) strain (IHE3034) by Nougayrède and colleagues [1]. Colibactin is a natural and genotoxic chemical compound, which is synthesized by a hybrid non-ribosomal peptide synthetase-polyketide synthase (NRPS-PKS) assembly line encoded by the pks genomic island. E. coli, Citrobacter koseri, Klebsiella pneumoniae, and Klebsiella aerogenes harbor this pks genomic island [2]. The pks island contains 19 genes (clbA to clbS), including phosphopantetheinyl transferase (clbA), the nonribosomal peptide synthetases (clbN and clbB), freestanding acyltransferase (clbG), prodrug transporter (clbM), and colibactin-maturing peptidase (clbP). Colibactin has been proven to be related to mammalian cell DNA double-strand breaks (DSBs), chromosome aberrations, and cell cycle arrest in the G2/M phase [1,3]. Our previous work found expression of many genes in pks island changed when avian pathogenic E. coli (APEC)

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