Cell Intrinsic Factors Modulate the Effects of IFNγ on the Development ofChlamydia trachomatis.
Chlamydia trachomatisis an obligate intracellular bacterial pathogen that cannot synthesize several amino acids, including tryptophan. Rather,C. trachomatisacquires these essential metabolites from its human host cell. Chlamydial dependence on host-provided tryptophan underlies a major host defense mechanism against the bacterium; namely, the induction of the host tryptophan-catabolizing enzyme, indoleamine 2,3- dioxygenase (IDO1) by interferon gamma (IFNγ), which leads to eradication ofC. trachomatisby tryptophan starvation. For this reason, IFNγ is proposed to be the major host protective cytokine against genitalC. trachomatisinfections. The protective effect of IFNγ againstC. trachomatiscan be recapitulatedin vitrousing epithelial cell-lines such as the cervical carcinoma derived cell-line Hela, the Hela subclone HEp-2, and the cervical carcinoma derived cell-line ME180. Addition of IFNγ to these cells infected withC. trachomatisresults in a strong bactericidal or bacteriostatic effect dependent on the concentration of IFNγ administered. Unlike Hela, HEp-2, and ME180, there are other human epithelial, or epithelial-like cell-lines where administration of IFNγ does not affect chlamydial replication, although they express the IFNγ receptor (IFNGR). In this report, we have characterized the mechanisms that underlie this dichotomy using the cell-lines C33A and 293. Akin to Hela, C33A is derived from a human cervical carcinoma, while 293 cells were produced by transfection of adenovirus type 5 DNA into embryonic kidney cells. We demonstrate that although IFNGR is expressed at high levels in C33A cells, its ligation by IFNγ does not result in STAT1 phosphorylation, an essential step for activation of the IDO1 promoter. Our results indicate that although the IFNγ-dependent signaling cascade is intact in 293 cells; the IDO1 promoter is not activated in these cells because it is epigenetically silenced, most likely by DNA methylation. Because polymorphisms in IFNγ, IFNGR, and the IDO1 promoter are known to affect other human infections or diseased states, our results indicate that the effect of allelic differences in these genes and the pathways they activate should be evaluated for their effect onC. trachomatispathology.
Department of Microbiology, Immunology & Parasitology, LSU Health Sciences Center, New Orleans, LA, USA.
Shardulendra
S
Sherchand
Institute of Biology, University of the Philippines, Diliman, Quezon City, Philippines, USA.
Joyce A
JA
Ibana
Department of Microbiology, Immunology & Parasitology, LSU Health Sciences Center, New Orleans, LA, USA.
Alison J
AJ
Quayle
Department of Microbiology, Immunology & Parasitology, LSU Health Sciences Center, New Orleans, LA, USA.
Ashok
A
Aiyar
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