Colibactin in avian pathogenic Escherichia coli contributes to the development of meningitis in a mouse model

Abstract

Colibactin is synthesized by a 54-kb genomic island, leads to toxicity in eukaryotic cells, and plays a vital role in many diseases, including neonatal sepsis and meningitis. Avian pathogenic Escherichia coli (APEC) is speculated to be an armory of extraintestinal pathogenic Escherichia coli and can be a potential zoonotic bacterium that threatens human and animal health. In this study, the APEC XM meningitis mouse model was successfully established to investigate the effect of colibactin in in vivo infection. The clbH -deletion mutant strain induced lower γ-H2AX expression, no megalocytosis, and no cell cycle arrest in bEnd.3 cells, which showed that the deletion of clbH decreased the production of colibactin in the APEC XM strain. The deletion of clbH did not affect the APEC XM strain’s ability of adhering to and invading bEnd.3 cells. In vitro , the non-colibactin-producing strain displayed significantly lower serum resistance and it also induced a lower level of cytokine mRNA and few disruptions of tight junction proteins in infected bEnd.3 cells. Meningitis did not occur in APEC Δ clbH -infected mice in vivo , who showed fewer clinical symptoms and fewer lesions on radiological and histopathological analyses. Compared with the APEX XM strain, APEC Δ clbH induced lower bacterial colonization in tissues, lower mRNA expression of cytokines in brain tissues, and slight destruction of the brain blood barrier. These results indicate that clbH is a necessary component for the synthesis of genotoxic colibactin, and colibactin is related to the development of meningitis induced by APEC XM.

Phosphopantetheinyl transferase ClbA contributes to the virulence of avian pathogenic Escherichia coli in meningitis infection of mice

“…coli [ 6 ]. Previous studies showed that the deletion of clbG or clbH abolished the production of colibactin and then affected the development of meningitis in mice induced by APEC [ 30 , 31 ]. This study demonstrated that the deficiency of clbA significantly attenuated APEC virulence in systemic infections and the process of meningitis development including bacteremia, penetration of the BBB and induction of pro-inflammatory factor expression.…”

“…Due to a pleiotropic phenotype of clbA mutant related to colibactin and siderophores, this reduction of BBB disruption could be caused by a direct or indirect combined effects of colibactin and siderophores. The previous study showed that colibactin contributed to serum resistance ability of APEC [ 30 ]. Deletion of colibactin-encoded genes such as clbH , clbG decreased the bacterial load in the blood of APEC infected mice [ 30 , 31 ].…”

“…The previous study showed that colibactin contributed to serum resistance ability of APEC [ 30 ]. Deletion of colibactin-encoded genes such as clbH , clbG decreased the bacterial load in the blood of APEC infected mice [ 30 , 31 ]. ClbA deletion also showed the similar phenotype in our study.…”

Oxygen concentration modulates colibactin production

“…Epithelial cells exhibit DNA damage, cell cycle arrest, senescence and death upon exposure to pks + bacteria (11). Colibactin induces apoptotic cell death in lymphocytes and promotes virulence of pks+ E. coli during sepsis and meningitis (12–14). Colibactin is also produced in the gut by commensal pks + E. coli and inflicts DNA damage in intestinal epithelial cells (15–17).…”

“…Epithelial cells exhibit DNA damage, cell cycle arrest, senescence and death upon exposure to pks+ bacteria (11). Colibactin induces apoptotic cell death in lymphocytes and promotes virulence of pks+ E. coli during sepsis and meningitis (12)(13)(14).…”