Host cholesterol modulates the generation and enrichment of persister population during Mycobacterium tuberculosis infection.

We previously reported that the utilization of host cholesterol is essential for mycobacterial persistence. In this study, we demonstrated that cholesterol-induced activation of a ribonuclease toxin (VapC12) inhibits translation by targeting proT tRNA in Mtb. The resulting cholesterol-specific growth modulation increases the frequency of the generation of persisters in a heterogeneous Mtb population. A vapC12-null mutant strain (ΔvapC12) failed to persist and demonstrated a hypervirulent phenotype in a guinea pig model of Mtb infection. This is the first study to identify a novel strategy through which cholesterol-specific activation of a toxin–antitoxin (TA) module in Mtb enhances persister formation during infection. In addition to identifying the mechanism, the study provides opportunity for targeting persisters, a new paradigm facilitating tuberculosis drug development.