TY - JOUR TI - c-Myc plays a key role in IFN-γ-induced persistence of Chlamydia trachomatis AU - Vollmuth, Nadine AU - Schlicker, Lisa AU - Guo, Yongxia AU - Hovhannisyan, Pargev AU - Janaki-Raman, Sudha AU - Kurmasheva, Naziia AU - Schmitz, Werner AU - Schulze, Almut AU - Stelzner, Kathrin AU - Rajeeve, Karthika AU - Rudel, Thomas A2 - Helaine, Sophie A2 - Soldati-Favre, Dominique VL - 11 PY - 2022 DA - 2022/09/26 SP - e76721 C1 - eLife 2022;11:e76721 DO - 10.7554/eLife.76721 UR - https://doi.org/10.7554/eLife.76721 AB - 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 biosynthesis. 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. KW - Chlamydia trachomatis KW - persistence KW - c-Myc KW - interferon-gamma JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -