title: Inhibition of indoleamine 2,3-dioxygenase activity by levo-1-methyl tryptophan blocks gamma interferon-induced Chlamydia trachomatis persistence in human epithelial cells.
abstract: Gamma interferon (IFN-γ) induces expression of the tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO1) in human epithelial cells, the permissive cells for the obligate intracellular bacterium Chlamydia trachomatis. IDO1 depletes tryptophan by catabolizing it to kynurenine with consequences for C. trachomatis, which is a tryptophan auxotroph. In vitro studies reveal that tryptophan depletion can result in the formation of persistent (viable but noncultivable) chlamydial forms. Here, we tested the effects of the IDO1 inhibitor, levo-1-methyl-tryptophan (L-1MT), on IFN-γ-induced C. trachomatis persistence. We found that addition of 0.2 mM L-1MT to IFN-γ-exposed infected HeLa cell cultures restricted IDO1 activity at the mid-stage (20 h postinfection [hpi]) of the chlamydial developmental cycle. This delayed tryptophan depletion until the late stage (38 hpi) of the cycle. Parallel morphological and gene expression studies indicated a consequence of the delay was a block in the induction of C. trachomatis persistence by IFN-γ. Furthermore, L-1MT addition allowed C. trachomatis to undergo secondary differentiation, albeit with limited productive multiplication of the bacterium. IFN-γ-induced persistent infections in epithelial cells have been previously reported to be more resistant to doxycycline than normal productive infections in vitro. Pertinent to this observation, we found that L-1MT significantly improved the efficacy of doxycycline in clearing persistent C. trachomatis forms. It has been postulated that persistent forms of C. trachomatis may contribute to chronic chlamydial disease. Our findings suggest that IDO1 inhibitors such as L-1MT might provide a novel means to investigate, and potentially target, persistent chlamydial forms, particularly in conjunction with conventional therapeutics.
authors.affiliation: Department of Microbiology, Immunology and Parasitiology, Medical Education Building, Louisiana State University Health Sciences Center, 1901 Perdido St., New Orleans, LA 70112, USA.
authors.forename: Joyce A
authors.initials: JA
authors.lastname: Ibana
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Belland
authors.forename: Arnold H
authors.initials: AH
authors.lastname: Zea
authors.forename: Danny J
authors.initials: DJ
authors.lastname: Schust
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagamatsu
authors.forename: Yasser M
authors.initials: YM
authors.lastname: AbdelRahman
authors.forename: David J
authors.initials: DJ
authors.lastname: Tate
authors.forename: Wandy L
authors.initials: WL
authors.lastname: Beatty
authors.forename: Ashok A
authors.initials: AA
authors.lastname: Aiyar
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Quayle
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology; D002692:Chlamydia trachomatis / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004318:Doxycycline / Q000494:pharmacology; D004847:Epithelial Cells / Q000382:microbiology*; D006367:HeLa Cells; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007371:Interferon-gamma / Q000494:pharmacology*; D007737:Kynurenine / Q000032:analysis; D013997:Time Factors; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000032:analysis / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D007737:Kynurenine; C028129:tryptophan methyl ester; D007371:Interferon-gamma; D014364:Tryptophan; D004318:Doxycycline