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.
Sukumaran
Sunil K
SK
Division of Infectious Diseases, Children's Hospital Los Angeles and Keck School of Medicine, University of Southern California, Los Angeles, California 90027, USA.
Prasadarao
Nemani V
NV
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