German Cancer Research Center (DKFZ), Heidelberg, Germany
Yongxia Guo
Department of Microbiology, Biocenter, University of Wuerzburg, Wuerzburg, Germany; College of Veterinary Medicine, China Agricultural University, Beijing, China
Pargev Hovhannisyan
Department of Microbiology, Biocenter, University of Wuerzburg, Wuerzburg, Germany
Sudha Janaki-Raman
Memorial Sloan Kettering Cancer Center, New York, United States
Naziia Kurmasheva
Department of Microbiology, Biocenter, University of Wuerzburg, Wuerzburg, Germany
Werner Schmitz
Department of Biochemistry and Molecular Biology, University of Wuerzburg, Würzburg, Germany
Almut Schulze
German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Biochemistry and Molecular Biology, University of Wuerzburg, Würzburg, Germany
Kathrin Stelzner
Department of Microbiology, Biocenter, University of Wuerzburg, Wuerzburg, Germany
Karthika Rajeeve
Department of Microbiology, Biocenter, University of Wuerzburg, Wuerzburg, Germany; Pathogen Biology, Rajiv Gandhi Centre for Biotechnology (RGCB), Thiruvananthapuram, India
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.
