<i>Mycobacterium tuberculosis</i> PhoP integrates stress response to intracellular survival by regulating cAMP level.

Abstract

Survival of <i>Mycobacterium tuberculosis</i> within the host macrophages requires the bacterial virulence regulator PhoP, but the underlying reason remains unknown. 3',5'-Cyclic adenosine monophosphate (cAMP) is one of the most widely used second messengers, which impacts a wide range of cellular responses in microbial pathogens including <i>M. tuberculosis</i>. Herein, we hypothesized that intra-bacterial cAMP level could be controlled by PhoP since this major regulator plays a key role in bacterial responses against numerous stress conditions. A transcriptomic analysis reveals that PhoP functions as a repressor of cAMP-specific phosphodiesterase (PDE) Rv0805, which hydrolyzes cAMP. In keeping with these results, we find specific recruitment of the regulator within the promoter region of <i>rv0805</i> PDE, and absence of <i>phoP</i> or ectopic expression of <i>rv0805</i> independently accounts for elevated PDE synthesis, leading to the depletion of intra-bacterial cAMP level. Thus, genetic manipulation to inactivate PhoP-<i>rv0805</i>-cAMP pathway decreases cAMP level, stress tolerance, and intracellular survival of the bacillus.