title: Chlamydia trachomatis growth depends on eukaryotic cholesterol esterification and is affected by Acyl-CoA:cholesterol acyltransferase inhibition.
abstract: Chlamydia trachomatis is auxotrophic for a variety of essential metabolites. Inhibitors that interrupt host cell catabolism may inhibit chlamydial growth and reveal Chlamydia metabolite requirements. We used the known indoleamine-2,3-dioxygenase (IDO)-inhibitor 4-phenyl imidazole (4-PI) to reverse Interferon (IFN)-γ-induced chlamydial growth inhibition. However, at elevated inhibitor concentrations chlamydial growth was arrested even in the absence of IFN-γ. Since 4-PI is known to interfere with cholesterol metabolism, the effect of cholesterol add-back was tested. Chlamydia growth was restored in the presence of cholesterol in serum-containing, but not serum-free medium suggesting that cholesterol and other serum components are required for growth recovery. When serum factors were tested, either cholesteryl linoleate or the combination of cholesterol and linoleic acid restored chlamydial growth. However, growth was not restored when either cholesterol or linoleic acid were added alone, suggesting that the production of cholesteryl esters from cholesterol and fatty acids was affected by 4-PI treatment. In eukaryotic cells, the enzyme Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes the production of cholesteryl esters. When HeLa cells were treated with the ACAT-specific inhibitor 4-hydroxycinnamicacid amide C. trachomatis growth was interrupted, but was restored by the addition of cholesteryl linoleate, suggesting that ACAT activity is necessary for intracellular Chlamydia growth.
authors.affiliation: Department of Microbiology, Immunology & Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA jpeter37@uthsc.edu.
authors.forename: Jan
authors.initials: J
authors.lastname: Peters
authors.affiliation: Department of Microbiology, Immunology & Biochemistry, University of Tennessee Health Science Center, Memphis, TN 38163, USA Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN 38163, USA.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Byrne
mesh_terms: D002692:Chlamydia trachomatis / Q000254:growth & development* / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D002788:Cholesterol Esters / Q000378:metabolism; D002934:Cinnamates / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000378:metabolism; D004847:Epithelial Cells / Q000201:enzymology / Q000378:metabolism / Q000382:microbiology; D004951:Esterification; D006367:HeLa Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002788:Cholesterol Esters; D002934:Cinnamates; D004791:Enzyme Inhibitors; C021976:cholesteryl linoleate; D002784:Cholesterol; D002785:Sterol O-Acyltransferase
keywords: cholesteryl esters; sterol o-acyltransferase