Escherichia coli K1 invasion increases human brain microvascular endothelial cell monolayer permeability by disassembling vascular-endothelial cadherins at tight junctions.
We investigated the permeability changes that occur in the human brain microvascular endothelial cell (HBMEC) monolayer, an in vitro model of the blood-brain barrier, during Escherichia coli K1 infection. An increase in permeability of HBMECs and a decrease in transendothelial electrical resistance were observed. These permeability changes occurred only when HBMECs were infected with E. coli expressing outer membrane protein A (OmpA) and preceded the traversal of bacteria across the monolayer. Activated protein kinase C (PKC)-alpha interacts with vascular-endothelial cadherins (VECs) at the tight junctions of HBMECs, resulting in the dissociation of beta-catenins from VECs and leading to the increased permeability of the HBMEC monolayer. Overexpression of a dominant negative form of PKC-alpha in HBMECs blocked the E. coli-induced increase in permeability of HBMECs. Anti-OmpA and anti-OmpA receptor antibodies exerted inhibition of E. coli-induced permeability of HBMEC monolayers. This inhibition was the result of the absence of PKC-alpha activation in HBMECs treated with the antibodies.
Division of Infectious Diseases, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
Sunil K
SK
Sukumaran
Nemani V
NV
Prasadarao
D001425:Bacterial Outer Membrane Proteins / Q000502:physiology; D001812:Blood-Brain Barrier / Q000382:microbiology* / Q000473:pathology; D015153:Blotting, Western; D001921:Brain / Q000098:blood supply*; D001927:Brain Diseases / Q000382:microbiology* / Q000473:pathology*; D015820:Cadherins / Q000502:physiology; D002199:Capillary Permeability; D017097:Electric Impedance; D004730:Endothelium, Vascular / Q000382:microbiology* / Q000473:pathology; D004926:Escherichia coli / Q000502:physiology; D004927:Escherichia coli Infections / Q000473:pathology*; D006801:Humans; D008856:Microscopy, Fluorescence; D011233:Precipitin Tests; D011493:Protein Kinase C / Q000502:physiology; D051571:Protein Kinase C-alpha; D019108:Tight Junctions / Q000382:microbiology
D001425:Bacterial Outer Membrane Proteins; D015820:Cadherins; C078167:OMPA outer membrane proteins; C496628:PRKCA protein, human; D011493:Protein Kinase C; D051571:Protein Kinase C-alpha