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GrgA controls Chlamydia trachomatis growth and development by regulating expression of transcription factors Euo and HrcA

The obligate intracellular bacterium Chlamydia trachomatis is an important human pathogen whose biphasic developmental cycle consists of an infectious elementary body and a replicative reticulate body. Whereas σ66, the primary sigma factor, is necessary for transcription of most chlamydial genes throughout the developmental cycle, σ28 is required for expression of some late genes. We previously showed that the Chlamydia-specific transcription factor GrgA physically interacts with both of these sigma factors and activates transcription from σ66- and σ28-dependent promoters in vitro. Here, we investigate the organismal functions of GrgA. We show that GrgA overexpression decreased RB proliferation via time-dependent transcriptomic changes. Significantly, σ66-dependent genes that code for two important transcription repressors are among the direct targets of GrgA. One of these repressors is Euo, which prevents the expression of late genes during early phases. The other is HrcA, which regulates gene expression in response to heat shock. The direct regulon of GrgA also includes a σ28-dependent gene that codes for the putative virulence factor PmpI. Conditional overexpression of Euo and HrcA also inhibited chlamydial growth and affected GrgA expression. Transcriptomic studies suggest that GrgA, Euo, and HrcA have distinct but overlapping indirect regulons. Furthermore, overexpression of either GrgA leads to decreased expression of numerous tRNAs. These findings indicate that a GrgA-mediated transcriptional regulatory network controls C. trachomatis growth and development. IMPORTANCE Chlamydia trachomatis is the most prevalent sexually transmitted bacterial pathogen worldwide and is a leading cause of preventable blindness in under-developed areas as well as developed countries. Previous studies showed that the novel transcription factor GrgA activated chlamydial gene transcription in vitro, but did not addressed the organismal function of GrgA. Here, we demonstrate growth inhibition in C. trachomatis engineered to conditionally overexpress GrgA. GrgA overexpression immediately increases the expression of two other critical transcription factors (Euo and HrcA) and a candidate virulence factor (PmpI), among several other genes. We also reveal chlamydial growth reduction and transcriptomic changes including decreased GrgA mRNA levels in response to either Euo or HrcA overexpression. Thus, the transcription network controlled by GrgA likely plays a crucial role in chlamydial growth and pathogenesis.