Chlamydia trachomatis and Chlamydia muridarum response to environmental stressors reveals a transcriptional regulatory pathway linking virulence gene expression with persistence

Chlamydia trachomatis is the most common sexually transmitted bacterial infection globally. It is an obligate intracellular pathogen with a biphasic developmental cycle. The outer membrane complex proteins OmcA and OmcB, produced from a single transcript, are only expressed in the infectious elementary body (EB), serving as markers of reticulate body (RB) to EB conversion. Chlamydial development entering persistence has been associated with failure to generate new EBs. Assaying expression of an omcA::gfp reporter by real time imaging, we observed reduced expression in C. trachomatis infected HeLa cells treated with interferon gamma (IFN- γ). Similar results were obtained with other stressors previously determined to influence expression of OmcB and correlated with down-regulation of pgp3 transcription, a key virulence effector. We also examined the effect of 2-deoxyglucose (2DG), penicillin, iron limitation, and hyperosmolality on C. muridarum expressing omcA::gfp growing in L929 mouse fibroblasts. We detected expression of the fluorescent reporter, regardless of stressor, indicating that omcAB transcription by C. muridarum was unresponsive to environmental signals. However, immunofluorescent staining revealed that 2DG-trated C. muridarum still reduced expression of OmcB coincident with transition to a ‘persistent’ inclusion phenotype while expression and secretion of Pgp3 was sustained. These results indicate that post-translational pathways leading to persistence are active in C. muridarum, but the transcriptional pathway that coordinates down-regulation of virulence-associated genes in response to stress in C. trachomatis is absent or inactive in the mouse virulent strain. Future studies will confirm these findings by examining glycogen production under the stress conditions previously identified. These findings may explain the contrasting disease severity and speed of pathogen clearance observed between humans and mice infected with this pathogen.