Iron limitation-induced modulation of transcription in Chlamydia trachomatis

Chlamydia trachomatis (C. trachomatis) is an obligate intracellular bacterial pathogen responsible for trachoma and sexually transmitted infections. Like other Chlamydiota members, such as Waddlia chondrophila, C. trachomatis undergoes a biphasic developmental cycle alternating between infectious elementary bodies (EBs) and replicative reticulate bodies (RBs). Under stressful conditions, RBs differentiate into non-dividing aberrant bodies (ABs), a reversible state associated with persistence. Here, we investigate how early iron deprivation affects transcriptional regulation in C. trachomatis. We performed RNA sequencing to compare transcriptional profiles between EBs and RBs and between RBs and ABs induced by iron chelation with 2,2′-bipyridyl at 8 hpi. In EBs, 29% of genes were downregulated and 30% upregulated compared to RBs, revealing extensive transcriptional remodeling. At 24 hpi, ABs displayed downregulation of two-component system (TCS) genes (atoS, atoC, and chxR), while genes encoding inclusion membrane proteins (Incs) and the trpRBA operon were upregulated. These findings show how C. trachomatis adapts transcriptionally to iron deprivation, revealing stress- and time-dependent changes in metabolism, stress responses, and host–pathogen interactions. Persistence alters the developmental cycle while maintaining inclusion integrity and modulating host interactions, contributing to chronic infection. Uncovering the mechanisms driving persistence may offer crucial insights into chlamydial pathogenesis.