c-Myc plays a key role in IFN-γ-induced persistence of Chlamydia trachomatis.
Elife
; 112022 09 26.
Article
in En
| MEDLINE
| ID: mdl-36155135
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-GSK3ß 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Chlamydia trachomatis
/
Proto-Oncogene Proteins c-myc
/
Interferon-gamma
Limits:
Female
/
Humans
Language:
En
Journal:
Elife
Year:
2022
Document type:
Article
Affiliation country:
Alemania