c-Myc plays a key role in IFN-gamma-induced persistence of Chlamydia trachomatis
ELIFE(2022)
摘要
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-gamma) released by immune cells as a mechanism of immune defence. IFN-gamma activates the catabolic depletion of L-tryptophan (Trp) via indoleamine-2,3-dioxygenase (IDO), resulting in persistent Ctr. Here, we show that IFN-gamma 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-gamma-induced persistence in cell lines and human fallopian tube organoids. Trp concentrations control c-Myc levels most likely via the PI3K-GSK3 beta 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-gamma-induced persistence. Thus, our results challenge the longstanding hypothesis of Trp depletion through IDO as the major mechanism of IFN-gamma-induced metabolic immune defence and significantly extends the understanding of the role of IFN-gamma as a broad modulator of host cell metabolism.
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关键词
Chlamydia trachomatis,persistence,c-Myc,interferon-gamma,Other
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