title: Targeting host syntaxin-5 preferentially blocks Leishmania parasitophorous vacuole development in infected cells and limits experimental Leishmania infections.
abstract: Our previous observations established a role for syntaxin-5 in the development of Leishmania parasitophorous vacuoles (LPVs). In this study, we took advantage of the recent identification of Retro-2, a small organic molecule that can cause the redistribution of syntaxin-5; we show herein that Retro-2 blocks LPV development within 2 hours of adding it to cells infected with Leishmania amazonensis. In infected cells incubated for 48 hours with Retro-2, LPV development was significantly limited; furthermore, infected cells harbored four to five times fewer parasites than infected cells incubated in vehicle alone. In vivo studies revealed that Retro-2 curbed experimental L. amazonensis infections in a dose-dependent manner. Retro-2 did not have any appreciable effect on the host cell physiological characteristics; furthermore, it had no apparent toxicity in experimental animals. An unexpected, but welcome, finding was that Retro-2 inhibited the replication of Leishmania parasites in axenic cultures. This study is significant because it identifies an endoplasmic reticulum/Golgi SNARE as a potential target for the control of Leishmania infections; moreover, it suggests that small organic molecules can be identified that can selectively disrupt the vesicle fusion machinery that promotes the development of pathogen-containing compartments without exerting toxic effects on the host.
authors.affiliation: Department of Microbiology and Cell Science, University of Florida, Gainesville, Florida 32611, USA.
authors.forename: Johnathan
authors.initials: J
authors.lastname: Canton
authors.forename: Peter E
authors.initials: PE
authors.lastname: Kima
mesh_terms: D000818:Animals; D061245:Axenic Culture; D001549:Benzamides / Q000494:pharmacology; D002460:Cell Line; D015850:Interleukin-6 / Q000378:metabolism; D007891:Leishmania / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D007896:Leishmaniasis / Q000469:parasitology* / Q000473:pathology*; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000378:metabolism / Q000469:parasitology*; D051379:Mice; D008807:Mice, Inbred BALB C; D021381:Protein Transport / Q000187:drug effects; D050765:Qa-SNARE Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050683:R-SNARE Proteins / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D014617:Vacuoles / Q000187:drug effects / Q000378:metabolism*
chemical_list: C549073:2-(((5-methyl-2-thienyl)methylene)amino)-N-phenylbenzamide; D001549:Benzamides; D015850:Interleukin-6; D050765:Qa-SNARE Proteins; D050683:R-SNARE Proteins; C432415:Sec22b protein, mouse; D013876:Thiophenes