Host cell amplification of nutritional stress contributes to persistence in Chlamydia trachomatis

Abstract

Persistence, a viable, but non-replicating state has been implicated in diseases caused by Chlamydia trachomatis. Multiple nutritional stressors produce a superficially similar “persistent” state, yet no systematic comparison has been made to determine their likeness. We employed host-pathogen dual RNA-sequencing under both iron- and tryptophan-starved conditions to gain insight into chlamydial persistence and identify contributions by the host cell. Analysis of the transcriptome of iron- or tryptophan-starved Chlamydia revealed a common “core” component and a stress-specific “accessory” subset. Despite the overall transcriptomic differences of host cells starved for either iron or tryptophan, both stressors induced persistence. A common metabolic consequence of the stressors was a reduction in intracellular GTP levels. Mizoribine inhibition of IMDPH1, which catalyzes the rate-limiting step in de novo guanine nucleotide synthesis reproduced to a similar extent GTP depletion, and inhibited chlamydial growth as expected for a pathogen that is auxotrophic for GTP. Thus, the reduction of guanine nucleotide synthesis manifests amplification of either iron or tryptophan starvation contributing to persistence. These findings illustrate that a nutritionally stressed host cell remains effective in arresting growth of Chlamydia by targeting metabolic pathways required by the pathogen.