Mycobacterium tuberculosis (Mtb), the leading cause of infectious disease death worldwide, remains a global health threat. The success of Mtb as a pathogen can be attributed to its ability to sense and adapt to the host environment. Understanding the mechanisms of Mtb adaptation to the host environment has the potential to inform the development of novel and effective tuberculosis treatments. An important aspect of Mtb adaptation is its ability to regulate growth rate, as slow growing and growth arrested Mtb has been shown to exhibit increased phenotypic tolerance to killing by the immune system or antibiotics. In response to the important host cue of acidic pH, I have observed that Mtb exhibits carbon source specific growth arrest. While the majority of carbon sources were unable to promote growth at acidic pH in minimal medium, carbon sources associated with the anaplerotic node and with the host relevant nutrient cholesterol were permissive for Mtb growth. Transcriptional profiling of Mtb at acidic pH demonstrated that Mtb induces genes involved in anaplerotic metabolism, lipid synthesis, and redox homeostasis. Furthermore, deletion of the two-component regulatory system phoPR that is induced at acidic pH led to enhanced growth at acidic pH, suggesting that slow growth is an aspect of Mtb adaptation to acidic pH. By performing growth curves and metabolic profiling of wild type Mtb as well as mutants lacking specific enzymes of the anaplerotic node, I have also sought to characterize the mechanisms of metabolic remodeling that occur at acidic pH and their role in growth regulation. Finally, through the isolation of mutants with enhanced growth at acidic pH, I have demonstrated that growth arrest at acidic pH is a regulated process in Mtb necessary for phenotypic tolerance.
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