c-Myc plays a key role in IFN-γ induced persistence of Chlamydia trachomatis

Summary Chlamydia trachomatis (Ctr) can persist over long periods of time 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 Chlamydia . Here we show that IFN-γ depletes c-Myc, the key regulator of host cell metabolism, in a STAT1-dependent manner. Expression of c-Myc rescued Chlamydia from IFN-γ-induced persistence in cultured cell lines, but also in human fallopian tube organoids. L-tryptophan concentrations control c-Myc levels via the PI3K-GSK3ß axis. Unbiased metabolic analysis revealed that Chlamydia 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 Chlamydia from IFN-γ-induced persistence. Thus, our results challenge the longstanding hypothesis of L-tryptophan depletion through IDO as the major mechanism of IFN-γ-induced metabolic immune defence and significantly extends the understanding of the role IFN-γ as a broad modulator of host cell metabolism.