A THERAPEUTIC STRATEGY AGAINST PERSISTENT CHLAMYDIA TRACHOMATIS INFECTION
Document Type
Presentation
Start Date
22-10-2010 9:15 AM
End Date
22-10-2010 9:30 AM
Description
Interferon gamma (IFND} induces indoleamine 2,3 dioxygenase (IDO1) expression in human epithelial cells, the permissive cell for the obligate intracellular bacteria Chlamydia trachomatis, which results in the catabolism of tryptophan via the kynurenine pathway. C. trachomatis is a tryptophan auxotroph and during tryptophan-limiting growth in vitro chlamydiae can transform into viable but non-cutivable organisms that persist within host cells. Here we have dissected the effects of an IDO1 inhibitor, levo-1-methyl-tryptophan (L-1 MT}, on IFN □ -induced C. trachomatis persistence. Treatment with 200 DM L-1 MT attenuated the IDO1 activity in Hela cells by decreasing tryptophan catabolism and kynurenine production. Morphological and gene expression data indicated that attenuation of IDO1 activity by L-1 MT blocked the induction C. trachomatis persistence by IFND. Surprisingly, however, L-1 MT treatment also limited the production of infectious elementary bodies, as indicated by an inefficient recovery of IFUs (infectious units) from L-1 MT and IFND-treated infected Hela cell lysates and culture supernatants. We also found that L-1 MT could re-activate C. trachomatis from established persistent growth but again did not result in productive multiplication. L-1 MT also improved the efficacy of doxycycline in clearing persistent C. trachomatis forms. These results indicate that L1 MT could be used to further examine the mechanisms and consequences of IFNl;J-mediated IDO1 induction on chlamydia! growth in relevant in vitro and in vivo animal models of C. trachomatis persistence. Persistent forms of the C. trachomatis have been associated with chronic chlamydia! diseases, including trachoma and pelvic inflammatory disease, and inhibitors of IDO1 such as L-1 MT may provide a novel means to target persistent forms, particularly when used in conjunction with conventional therapeutics.
Recommended Citation
Ibana, Joyce; Nagamatsu, T.; Zea, A.; Schust, D.; and Tate, D., "A THERAPEUTIC STRATEGY AGAINST PERSISTENT CHLAMYDIA TRACHOMATIS INFECTION" (2010). Dr. Joseph M. Moerschbaecher, III Graduate Research Day. 4.
https://digitalscholar.lsuhsc.edu/grad_rs/2010/presentation1/4
A THERAPEUTIC STRATEGY AGAINST PERSISTENT CHLAMYDIA TRACHOMATIS INFECTION
Interferon gamma (IFND} induces indoleamine 2,3 dioxygenase (IDO1) expression in human epithelial cells, the permissive cell for the obligate intracellular bacteria Chlamydia trachomatis, which results in the catabolism of tryptophan via the kynurenine pathway. C. trachomatis is a tryptophan auxotroph and during tryptophan-limiting growth in vitro chlamydiae can transform into viable but non-cutivable organisms that persist within host cells. Here we have dissected the effects of an IDO1 inhibitor, levo-1-methyl-tryptophan (L-1 MT}, on IFN □ -induced C. trachomatis persistence. Treatment with 200 DM L-1 MT attenuated the IDO1 activity in Hela cells by decreasing tryptophan catabolism and kynurenine production. Morphological and gene expression data indicated that attenuation of IDO1 activity by L-1 MT blocked the induction C. trachomatis persistence by IFND. Surprisingly, however, L-1 MT treatment also limited the production of infectious elementary bodies, as indicated by an inefficient recovery of IFUs (infectious units) from L-1 MT and IFND-treated infected Hela cell lysates and culture supernatants. We also found that L-1 MT could re-activate C. trachomatis from established persistent growth but again did not result in productive multiplication. L-1 MT also improved the efficacy of doxycycline in clearing persistent C. trachomatis forms. These results indicate that L1 MT could be used to further examine the mechanisms and consequences of IFNl;J-mediated IDO1 induction on chlamydia! growth in relevant in vitro and in vivo animal models of C. trachomatis persistence. Persistent forms of the C. trachomatis have been associated with chronic chlamydia! diseases, including trachoma and pelvic inflammatory disease, and inhibitors of IDO1 such as L-1 MT may provide a novel means to target persistent forms, particularly when used in conjunction with conventional therapeutics.