African trypanosome interactions with an in vitro model of the human blood-brain barrier.
The neurological manifestations of sleeping sickness in man are attributed to the penetration of the blood-brain barrier (BBB) and invasion of the central nervous system by Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense. However, how African trypanosomes cross the BBB remains an unresolved issue. We have examined the traversal of African trypanosomes across the human BBB using an in vitro BBB model system constructed of human brain microvascular endothelial cells (BMECs) grown on Costar Transwell inserts. Human-infective T. b. gambiense strain IL 1852 was found to cross human BMECs far more readily than the animal-infective Trypanosoma brucei brucei strains 427 and TREU 927. Tsetse fly-infective procyclic trypomastigotes did not cross the human BMECs either alone or when coincubated with bloodstreamform T. b. gambiense. After overnight incubation, the integrity of the human BMEC monolayer measured by transendothelial electrical resistance was maintained on the inserts relative to the controls when the endothelial cells were incubated with T. b. brucei. However, decreases in electrical resistance were observed when the BMEC-coated inserts were incubated with T. b. gambiense. Light and electron microscopy studies revealed that T. b. gambiense initially bind at or near intercellular junctions before crossing the BBB paracellularly. This is the first demonstration of paracellular traversal of African trypanosomes across the BBB. Further studies are required to determine the mechanism of BBB traversal by these parasites at the cellular and molecular level.
Grab
Dennis J
DJ
Department of Pediatrics, The Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA. dgrab@jhmi.edu
Nikolskaia
Olga
O
Kim
Yuri V
YV
Lonsdale-Eccles
John D
JD
Ito
Susumu
S
Hara
Tatsuru
T
Fukuma
Toshihide
T
Nyarko
Elvis
E
Kim
Kee Jun
KJ
Stins
Monique F
MF
Delannoy
Michael J
MJ
Rodgers
Jean
J
Kim
Kwang Sik
KS
D000818:Animals; D001812:Blood-Brain Barrier / Q000166:cytology / Q000469:parasitology* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017097:Electric Impedance; D042783:Endothelial Cells / Q000469:parasitology* / Q000648:ultrastructure; D006801:Humans; D066298:In Vitro Techniques; D008855:Microscopy, Electron, Scanning; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D014162:Transfection; D014346:Trypanosoma brucei brucei / Q000502:physiology*; D014347:Trypanosoma brucei gambiense / Q000502:physiology*
D002118:Calcium