Deciphering the role of VapBC toxin-antitoxin systems in Mycobacterium tuberculosis stress adaptation

Mycobacterium tuberculosis (Mtb) harbors a high number of Toxin-Antitoxin (TA) systems, wherein half of them belong to virulence associated proteins B and C (VapBC) family that has a characteristic PilT N-terminus domain and ribonuclease activity. Functional insights into Mtb VapBC TA modules unraveled their role in adaptation to various host-mediated stressors, including oxidative/nitrosative, chemical and nutrient starvation as well as multidrug tolerance and establishment of persistence. To understand the intricacies of Mtb's pathogenesis, absolute cellular targets of 19 VapC(s) were determined. Some exhibit a shared ribonuclease activity, whereas others harbor tRNAse and 23S rRNA cleavage activity. The detailed functional characterization of VapBC4, VapBC12 and VapBC22, including in vivo deletion mutant studies revealed their role in Mtb's virulence/persistence. For example, the VapC22 mutant was attenuated for Mtb's growth in mice and elicited a decreased T_H1 response, whereas mice infected with VapC12 mutant displayed a substantially higher bacillary load and pro-inflammatory response than the wild type, showing a hyper-virulent phenotype. Further experimental studies are needed to decode the functional role of VapBC systems and unravel their cellular targets. Taken together, Mtb VapBC TA systems seem to be promising drug targets owing to their key role in enduring stressors, antibiotic resistance and persistence.