Document Detail


Inhibition of indoleamine 2,3-dioxygenase activity by levo-1-methyl tryptophan blocks gamma interferon-induced Chlamydia trachomatis persistence in human epithelial cells.
MedLine Citation:
PMID:  21911470     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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:
Joyce A Ibana; Robert J Belland; Arnold H Zea; Danny J Schust; Takeshi Nagamatsu; Yasser M AbdelRahman; David J Tate; Wandy L Beatty; Ashok A Aiyar; Alison J Quayle
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2011-09-12
Journal Detail:
Title:  Infection and immunity     Volume:  79     ISSN:  1098-5522     ISO Abbreviation:  Infect. Immun.     Publication Date:  2011 Nov 
Date Detail:
Created Date:  2011-10-14     Completed Date:  2011-12-08     Revised Date:  2014-09-14    
Medline Journal Info:
Nlm Unique ID:  0246127     Medline TA:  Infect Immun     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4425-37     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Anti-Bacterial Agents / pharmacology
Chlamydia trachomatis / drug effects*,  physiology
Dose-Response Relationship, Drug
Doxycycline / pharmacology
Epithelial Cells / microbiology*
HeLa Cells
Humans
Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*,  metabolism
Interferon-gamma / pharmacology*
Kynurenine / analysis
Time Factors
Tryptophan / analogs & derivatives*,  analysis,  pharmacology
Grant Support
ID/Acronym/Agency:
AI055172/AI/NIAID NIH HHS; AI095859/AI/NIAID NIH HHS; CA 112564/CA/NCI NIH HHS; R21 AI095859/AI/NIAID NIH HHS; R21 AI095859-01/AI/NIAID NIH HHS; U19AI061972/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Anti-Bacterial Agents; 0/Indoleamine-Pyrrole 2,3,-Dioxygenase; 343-65-7/Kynurenine; 7303-49-3/tryptophan methyl ester; 82115-62-6/Interferon-gamma; 8DUH1N11BX/Tryptophan; N12000U13O/Doxycycline
Comments/Corrections

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