(639d) An Integrated Experimental and Computational Study Reveals New Insights on Nutritional Stress Response and Persistence Mechanism of Chlamydia Trachomatis

Infection caused by the obligate intracellular bacterium Chlamydia trachomatis is the leading cause of sexually transmitted disease worldwide. It undergoes a biphasic developmental cycle involving interconversion between the elementary body and the reticulate body. An interesting feature of C. trachomatis is, when it is starved of nutrients, it deviates from its normal development and enters persistence. It is unclear if persistence is an adaptive response to stress or an indicator of its absence. To distinguish between these possibilities, experimental transcriptomics data were generated for untreated and nutrient-starved C. trachomatis. Processing these data through a machine-learning algorithm identified core and stress-specific components of C. trachomatis transcriptome leading to the discovery of the global transcriptomic response. We reconstructed condition-specific genome-scale metabolic models to project the global transcriptomic response to C. trachomatis metabolism. Thermodynamics driving force and enzyme cost analysis on these models indicated that lacking stringent action against nutrient stress is the likely reason for the persistence. Furthermore, the above-mentioned analyses pinpointed two reactions in glycolysis that enabled C. trachomatis to enter the persistence. Based on biomass growth rate in different stress conditions and thermodynamic analysis, persistence has an element of priming for a metabolic burst once the nutrient stress is withdrawn. Similar analyses also found a metabolic reaction, phosphoglyceromutase, that prevents C. trachomatis from leaving persistence. Overall, this experimental and computational study, for the first time, explained C. trachomatis persistence from a thermodynamics driving force and enzymatic cost perspective and will provide a better understanding of the persistence of C. trachomatis.