Back to Search
Start Over
Blood-brain barrier traversal by African trypanosomes requires calcium signaling induced by parasite cysteine protease.
- Source :
-
The Journal of clinical investigation [J Clin Invest] 2006 Oct; Vol. 116 (10), pp. 2739-47. Date of Electronic Publication: 2006 Sep 21. - Publication Year :
- 2006
-
Abstract
- In this study we investigated why bloodstream forms of Trypanosoma brucei gambiense cross human brain microvascular endothelial cells (BMECs), a human blood-brain barrier (BBB) model system, at much greater efficiency than do T. b. brucei. After noting that T. b. gambiense displayed higher levels of cathepsin L-like cysteine proteases, we investigated whether these enzymes contribute to parasite crossing. First, we found that T. b. gambiense crossing of human BMECs was abrogated by N-methylpiperazine-urea-Phe-homopheylalanine-vinylsulfone-benzene (K11777), an irreversible inhibitor of cathepsin L-like cysteine proteases. Affinity labeling and immunochemical studies characterized brucipain as the K11777-sensitive cysteine protease expressed at higher levels by T. b. gambiense. K11777-treated T. b. gambiense failed to elicit calcium fluxes in BMECs, suggesting that generation of activation signals for the BBB is critically dependant on brucipain activity. Strikingly, crossing of T. b. brucei across the BBB was enhanced upon incubation with brucipain-rich supernatants derived from T. b. gambiense. The effects of the conditioned medium, which correlated with ability to evoke calcium fluxes, were canceled by K11777, but not by the cathepsin B inhibitor CA074. Collectively, these in vitro studies implicate brucipain as a critical driver of T. b. gambiense transendothelial migration of the human BBB.
- Subjects :
- Animals
Blood-Brain Barrier cytology
Blood-Brain Barrier metabolism
Blood-Brain Barrier parasitology
Calcium metabolism
Calcium Signaling drug effects
Cathepsins antagonists & inhibitors
Cathepsins metabolism
Cell Communication drug effects
Cell Communication physiology
Cell Movement drug effects
Cells, Cultured
Culture Media, Conditioned pharmacology
Cysteine Proteinase Inhibitors pharmacology
Dipeptides pharmacology
Egtazic Acid analogs & derivatives
Egtazic Acid pharmacology
Endothelial Cells cytology
Endothelial Cells metabolism
Endothelial Cells parasitology
Estrenes pharmacokinetics
Humans
Leucine analogs & derivatives
Leucine pharmacology
Naphthalenes pharmacology
Phenylalanine analogs & derivatives
Piperazines
Protozoan Proteins metabolism
Pyrrolidinones pharmacokinetics
Tosyl Compounds
Trypanosoma metabolism
Trypanosoma brucei brucei enzymology
Trypanosoma brucei brucei metabolism
Trypanosoma brucei gambiense enzymology
Trypanosoma brucei gambiense metabolism
Trypanosoma brucei rhodesiense enzymology
Trypanosoma brucei rhodesiense metabolism
Vinyl Compounds pharmacology
Calcium Signaling physiology
Cell Movement physiology
Cysteine Endopeptidases metabolism
Trypanosoma enzymology
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9738
- Volume :
- 116
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- The Journal of clinical investigation
- Publication Type :
- Academic Journal
- Accession number :
- 16998589
- Full Text :
- https://doi.org/10.1172/JCI27798