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

Krishnan, Subramanian and Chang, Alexander C. and Stoltz, Brian M. and Prasadarao, Nemani V. (2016) Escherichia coli K1 Modulates Peroxisome Proliferator–Activated Receptor γ and Glucose Transporter 1 at the Blood-Brain Barrier in Neonatal Meningitis. Journal of Infectious Diseases, 214 (7). pp. 1092-1104. ISSN 0022-1899. PMCID PMC5021232. http://resolver.caltech.edu/CaltechAUTHORS:20170106-160004918

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Abstract

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1093/infdis/jiw306DOIArticle
http://jid.oxfordjournals.org/content/214/7/1092PublisherArticle
http://jid.oxfordjournals.org/content/214/7/1092/suppl/DC1PublisherSupplementary Data
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5021232PubMed CentralArticle
ORCID:
AuthorORCID
Krishnan, Subramanian0000-0001-5780-7452
Chang, Alexander C.0000-0001-7096-7151
Stoltz, Brian M.0000-0001-9837-1528
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.
Funders:
Funding AgencyGrant Number
NIHAI40567
NIHNS73115
National Institute of Allergy and Infectious DiseasesUNSPECIFIED
National Institute of Child Health and Human Development (NICHD)UNSPECIFIED
Subject Keywords:Escherichia coli K1; meningitis, blood-brain barrier; PPAR-γ; GLUT-1; glucose uptake
PubMed Central ID:PMC5021232
Record Number:CaltechAUTHORS:20170106-160004918
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20170106-160004918
Official Citation:Subramanian Krishnan, Alexander C. Chang, Brian M. Stoltz, and Nemani V. Prasadarao Escherichia coli K1 Modulates Peroxisome Proliferator–Activated Receptor γ and Glucose Transporter 1 at the Blood-Brain Barrier in Neonatal Meningitis J Infect Dis. (2016) 214 (7): 1092-1104 first published online July 24, 2016 doi:10.1093/infdis/jiw306
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:73319
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:07 Jan 2017 00:18
Last Modified:04 Apr 2019 18:18

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