Mycobacterium tuberculosis response to cholesterol is integrated with environmental pH and potassium levels via a lipid utilization regulator.

How bacterial response to environmental cues and nutritional sources may be integrated in enabling host colonization is poorly understood. Exploiting a reporter-based screen, we discovered that overexpression of Mycobacterium tuberculosis (Mtb) lipid utilization regulators altered Mtb acidic pH response dampening by low environmental potassium (K + ). Transcriptional analyses unveiled amplification of Mtb response to acidic pH in the presence of cholesterol, a major carbon source for Mtb during infection, and vice versa. Strikingly, deletion of the putative lipid regulator mce3R resulted in loss of augmentation of (i) cholesterol response at acidic pH, and (ii) low [K + ] response by cholesterol, with minimal effect on Mtb response to each signal individually. Finally, the Δ mce3R mutant was attenuated for colonization in a murine model that recapitulates lesions with lipid-rich foamy macrophages. These findings reveal critical coordination between bacterial response to environmental and nutritional cues, and establish Mce3R as a crucial integrator of this process.