Inhibition of tRNA Synthetases Induces Persistence in Chlamydia

• Published in: Infection and immunity Vol. 88; no. 4
• Main Authors: Hatch, Nathan D, Ouellette, Scot P
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 23-03-2020
• Subjects: Molecular Pathogenesis; leucine; amino acid starvation; IFN-γ; Chlamydia; amino acid limitation; codon-dependent transcription; tRNA synthetase inhibitors; persistence; tRNA synthetases; tryptophan
• ISSN: 0019-9567; 1098-5522
• DOI: 10.1128/IAI.00943-19

is the leading cause of bacterial sexually transmitted infections, and
causes community-acquired respiratory infections.
, the host immune system will release gamma interferon (IFN-γ) to combat infection. IFN-γ activates human cells to produce the tryptophan (Trp)-catabolizing enzyme indoleamine 2,3-dioxygenase (IDO). Consequently, there is a reduction in cytosolic Trp in IFN-γ-activated host cells. In evolving to obligate intracellular dependence,
has significantly reduced its genome size and content, as it relies on the host cell for various nutrients. Importantly,
and
are Trp auxotrophs and are starved for this essential nutrient when the human host cell is exposed to IFN-γ. To survive this, chlamydiae enter an alternative developmental state referred to as persistence. Chlamydial persistence is characterized by a halt in the division cycle, aberrant morphology, and, in the case of IFN-γ-induced persistence, Trp codon-dependent changes in transcription. We hypothesize that these changes in transcription are dependent on the particular amino acid starvation state. To investigate the chlamydial response mechanisms acting when other amino acids become limiting, we tested the efficacy of prokaryote-specific tRNA synthetase inhibitors, indolmycin and AN3365, to mimic starvation of Trp and leucine, respectively. We show that these drugs block chlamydial growth and induce changes in morphology and transcription consistent with persistence. Importantly, growth inhibition was reversed when the compounds were removed from the medium. With these data, we find that indolmycin and AN3365 are valid tools that can be used to mimic the persistent state independently of IFN-γ.