c-Myc plays a key role in IFN-γ-induced persistence of Chlamydia trachomatis Journal Article
| Authors: | Vollmuth, N.; Schlicker, L.; Guo, Y.; Hovhannisyan, P.; Janaki-Raman, S.; Kurmasheva, N.; Schmitz, W.; Schulze, A.; Stelzner, K.; Rajeeve, K.; Rudel, T. |
| Article Title: | c-Myc plays a key role in IFN-γ-induced persistence of Chlamydia trachomatis |
| Abstract: | Chlamydia trachomatis (Ctr) can persist over extended times within their host cell and thereby establish chronic infections. One of the major inducers of chlamydial persistence is interferon-gamma (IFN-γ) released by immune cells as a mechanism of immune defence. IFN-γ activates the catabolic depletion of L-tryptophan (Trp) via indoleamine-2,3-dioxygenase (IDO), resulting in persistent Ctr. Here, we show that IFN-γ induces the downregulation of c-Myc, the key regulator of host cell metabolism, in a STAT1-dependent manner. Expression of c-Myc rescued Ctr from IFN-γ-induced persistence in cell lines and human fallopian tube organoids. Trp concentrations control c-Myc levels most likely via the PI3K-GSK3β axis. Unbiased metabolic analysis revealed that Ctr infection reprograms the host cell tricarboxylic acid (TCA) cycle to support pyrimidine biosyn-thesis. Addition of TCA cycle intermediates or pyrimidine/purine nucleosides to infected cells rescued Ctr from IFN-γ-induced persistence. Thus, our results challenge the longstanding hypothesis of Trp depletion through IDO as the major mechanism of IFN-γ-induced metabolic immune defence and significantly extends the understanding of the role of IFN-γ as a broad modulator of host cell metabolism. © 2022, eLife Sciences Publications Ltd. All rights reserved. |
| Keywords: | genetics; metabolism; pyrimidines; phosphatidylinositol 3 kinase; physiology; gamma interferon; glycogen synthase kinase 3beta; interferon-gamma; indoleamine 2,3 dioxygenase; indoleamine-pyrrole 2,3,-dioxygenase; pyrimidine derivative; tryptophan; glycogen synthase kinase 3 beta; phosphatidylinositol 3-kinases; chlamydia trachomatis; purine nucleosides; purine nucleoside; tricarboxylic acid; humans; human; female; tricarboxylic acids |
| Journal Title: | eLife |
| Volume: | 11 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2022-09-26 |
| Start Page: | e76721 |
| Language: | English |
| DOI: | 10.7554/eLife.76721 |
| PUBMED: | 36155135 |
| PROVIDER: | scopus |
| PMCID: | PMC9512400 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 November 2022 -- Source: Scopus |
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