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Published October 1, 2016 | Supplemental Material + Accepted Version
Journal Article Open

Escherichia coli K1 Modulates Peroxisome Proliferator–Activated Receptor γ and Glucose Transporter 1 at the Blood-Brain Barrier in Neonatal Meningitis


Escherichia coli K1 meningitis continues to be a major threat to neonatal health. Previous studies demonstrated that outer membrane protein A (OmpA) of E. coli K1 interacts with endothelial cell glycoprotein 96 (Ecgp96) in the blood-brain barrier to enter the central nervous system. Here we show that the interaction between OmpA and Ecgp96 downregulates peroxisome proliferator–activated receptor γ (PPAR-γ) and glucose transporter 1 (GLUT-1) levels in human brain microvascular endothelial cells, causing disruption of barrier integrity and inhibition of glucose uptake. The suppression of PPAR-γ and GLUT-1 by the bacteria in the brain microvessels of newborn mice causes extensive pathophysiology owing to interleukin 6 production. Pretreatment with partial or selective PPAR-γ agonists ameliorate the pathological outcomes of infection by suppressing interleukin 6 production in the brain. Thus, inhibition of PPAR-γ and GLUT-1 by E. coli K1 is a novel pathogenic mechanism in meningitis, and pharmacological upregulation of PPAR-γ and GLUT-1 levels may provide novel therapeutic avenues.

Additional Information

© 2016 The Author. Published by Oxford University Press for the Infectious Diseases Society of America. Received May 20, 2015; Accepted July 13, 2016; First published online: July 24, 2016. We thank G. Esteban Fernandez for assistance with confocal imaging. This work was supported by the National Institute of Allergy and Infectious Diseases (AI40567) and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NS73115 to N. V. P.). Potential conflicts of interest: All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Attached Files

Accepted Version - J_Infect_Dis.-2016-Krishnan-infdis-jiw306.pdf

Supplemental Material - jiw306supp.docx


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