Mycobacterium tuberculosis PhoP integrates stress response to intracellular survival by maintenance of cAMP level

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