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 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.

Interactions between microbiota and cervical epithelial, immune, and mucus barrier

“…HPV/CT co-infected women had a higher microbial diversity, Aerococcus christensenii was associated with C. trachomatis infection. addition to tryptophan depletion, a recent study found that IFN-g also can down regulate c-Myc, the key regulator of host cell metabolism, resulting in the reduction of TCA cycle intermediates and nucleotides to prevent chlamydial replication and promoting persistence (Rajeeve et al, 2020;Vollmuth et al, 2022). Constitutive expression of c-Myc can rescue CT from persistence induced by IFN-g. Dong et al (Dong et al, 2022) proved that the abundance of Prevotella correlates with the expression of cervical TLR4, NF-kB, C-myc, and hTERT genes.…”

Aberrant Bodies: An Alternative Metabolic Homeostasis Allowing Survivability?

“…Most recent studies suggest that IFNγ-induced persistence in Chlamydiae is not induced by the activity of IDO, but rather by host cell transcription factor c-Myc [ 39 ]. c-Myc is a major polyvalent regulator of cell growth and proliferation and is essential for successful C. trachomatis infection.…”

“…Upon IFNγ stress, c-Myc levels are depleted concomitantly with TCA cycle intermediary products, leading to chlamydial persistence. Persistence could be rescued with over-expression of c-Myc or by adding TCA intermediates despite the ongoing stress, in cell cultures as well as in organoids derived from human fallopian tubes [ 39 ].…”

“…The inactivation of GSK3β prevents c-Myc phosphorylation at threonine 58, which initiates a cascade resulting in its degradation by the proteasome complex [ 65 ]. Overall, it seems that IDO allows not only the depletion of an essential tryptophan pool, but that its role also extends to the decrease in a broad range of host metabolism products taken up by the Chlamydiae through the indirect degradation of c-Myc [ 39 ].…”

“…Following host cell immune response by interferon gamma (IFNγ), the cytoplasmic tryptophan pool is depleted by the indolamine 2,3-dioxygenase enzyme (IDO) [ 59 ]. The absence of tryptophan then activates glycogen synthase kinase-3 beta (GSK3β), an enzyme that initiates host cell c-Myc degradation [ 39 ]. The consequence of this is a decreased production of glutaminases and glutamine transporters necessary for the TCA cycle to function.…”