Cytotoxic Necrotizing Factor 1 Contributes to Escherichia coli Meningitis

Ming-Hsien Wang,Kwang Kim

doi:10.3390/toxins5112270

Ming-Hsien Wang, Kwang Kim

Open Access

https://doi.org/10.3390/toxins5112270

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Abstract

E. coli is the most common Gram-negative bacteria causing neonatal meningitis, and E. coli meningitis continues to be an important cause of mortality and morbidity throughout the world. Recent reports of E. coli meningitis caused by antimicrobial resistant strains are a particular concern. These findings indicate that a novel strategy is needed to identify new targets for prevention and therapy of E. coli meningitis. Cytotoxic necrotizing factor 1 (CNF1) is a bacterial virulence factor associated principally with E. coli strains causing urinary tract infection and meningitis. We have shown that CNF1 contributes to E. coli invasion of the blood-brain barrier and penetration into the brain, the essential step in the development of E. coli meningitis, and identified the host receptor for CNF1, 37-kDa laminin receptor precursor (37LRP). CNF1, however, is a cytoplasmic protein and its contribution to E. coli invasion of the blood-brain barrier requires its secretion from the bacterial cytoplasm. No signal peptide is found in the CNF1 sequence. CNF1 secretion is, therefore, a strategy utilized by meningitis-causing E. coli to invade the blood-brain barrier. Elucidation of the mechanisms involved in CNF1 secretion, as shown in this report with the involvement of Fdx and YgfZ provides the novel information on potential targets for prevention and therapy of E. coli meningitis by virtue of targeting the secretion of CNF1.

Highlights

Neonatal Gram-negative bacillary meningitis continues to be an important cause of mortality and morbidity throughout the world
Cytotoxic necrotizing factor 1 (CNF1) secretion in prevention of E. coli meningitis. These findings suggest that modulation of bacterial secretion systems (CNF1 secretion) is likely to represent a novel approach for investigating the pathogenesis and prevention of E. coli meningitis
Coli penetration of the blood-brain barrier [42]. These findings demonstrate that pharmacological inhibition of the human brain mircovascular endothelial cells (HBMEC) receptors that interact with E. coli factors and host cell signaling molecules contributing to E. coli invasion of HBMEC might be a novel strategy for prevention of E. coli meningitis

Summary

Introduction

Neonatal Gram-negative bacillary meningitis continues to be an important cause of mortality and morbidity throughout the world. Several lines of evidence from human cases of E. coli meningitis and animal models of experimental hematogenous E. coli meningitis indicate that E. coli invasion into the brain follows a high level of bacteremia and cerebral capillaries are the portal of entry into the brain [16,17,18], but how meningitis-causing E. coli strains invade the blood-brain barrier and penetrate into the brain remains incompletely understood. It remains speculative to suggest whether CNF1-producing E. coli infection and/or its interaction with 37LRP/67LR may be a risk factor for cancer development such as colon cancer

Identification of the Host Receptor for CNF1

Secretion of CNF1 across the Bacterial Inner and Outer Membrane

Identification of Tn5 Mutants Defective in CNF1 Secretion

Findings

Conclusion