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Earlier we demonstrated that the adenylyl cyclase (AC) encoded by the  MSMEG_4279  gene plays a key role in the resuscitation and growth of dormant  Mycobacterium smegmatis  and that overexpression of this gene leads to an increase in intracellular cAMP concentration and prevents the transition of  M. smegmatis  from active growth to dormancy in an extended stationary phase accompanied by medium acidification. We surmised that the homologous  Rv2212  gene of  M. tuberculosis  ( Mtb ), the main cAMP producer, plays similar physiological roles by supporting, under these conditions, the active state and reactivation of dormant bacteria. To test this hypothesis, we established  Mtb  strain overexpressing  Rv2212  and compared its  in vitro  and  in vivo  growth characteristics with a control strain.  In vitro , the AC-overexpressing pMind Rv2212  strain demonstrated faster growth in a liquid medium, prolonged capacity to form CFUs and a significant delay or even prevention of transition toward dormancy. AC-overexpressing cells exhibited easier recovery from dormancy.  In vivo , AC-overexpressing bacteria demonstrated significantly higher growth rates (virulence) in the lungs and spleens of infected mice compared to the control strain, and, unlike the latter, killed mice in the TB-resistant strain before month 8 of infection. Even in the absence of selecting hygromycin B, all pMind Rv2212  CFUs retained the  Rv2212  insert during  in vivo  growth, strongly suggesting that AC overexpression is beneficial for bacteria. Taken together, our results indicate that cAMP supports the maintenance of  Mtb  cells vitality under unfavorable conditions  in vitro  and their virulence  in vivo .

frontiers in cellular and infection microbiology

Overexpression of Adenylyl Cyclase Encoded by the Mycobacterium tuberculosis Rv2212 Gene Confers Improved Fitness, Accelerated Recovery from Dormancy and Enhanced Virulence in Mice