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

Abstract Survival of M. tuberculosis within the host macrophages requires the virulence regulator PhoP, but the underlying mechanism remains unknown. Because growing evidence connects PhoP with varying stress response, we hypothesized that the level of 3ʹ,5ʹ cAMP, one of the most widely used second messengers, was regulated by the phoP locus, linking numerous stress response with cAMP production. A transcriptomic analysis discovers that PhoP functions as a repressor of cAMP-specific phosphodiesterase (PDE) Rv0805, which hydrolytically degrades cAMP. The most fundamental insight is derived from the PhoP-dependent regulation of rv0805 expression by specific recruitment of the regulator within the promoter region of the PDE. Consistent with these results, absence of PhoP or ectopic expression of rv0805 independently accounts for elevated PDE synthesis and depletion of intra-mycobacterial cAMP level. Thus, genetic manipulation to inactivate PhoP-rv0805-cAMP pathway leads to disruption of cAMP homeostasis, decreased stress tolerance and reduced survival of the bacilli.