Figure 6.

Schematic representation of the PhoPR-related phenotypes in M. tuberculosis (left side) and MTBVAC (right side) in the context of the macrophage environment

Until the publication of this manuscript, three virulence networks were documented to be regulated by PhoPR in M. tuberculosis: the synthesis of di- and poli-acyltrehaloses (DAT and PAT, respectively) and sulfolipid (SL), the latter lipid being involved in the inhibition of innate immunity and the production of cough; the secretion of ESAT-6, which mediates phagosomal rupture and the consequent cytosolic escape; and the downregulation of TatC, known to be an essential constituent of the twin arginine translocation (TAT), which results in restrained antigen secretion. These phenotypes are inactivated in MTBVAC because of a phoP-inactivating mutation and result in a lack of PhoPR-regulated lipids, the absence of ESAT-6 secretion, and increased secretion of TAT substrates. We demonstrate here that, in addition to the aforementioned phenotypes, c-di-AMP synthesis and secretion are negatively regulated by PhoPR in M. tuberculosis. Accordingly, the high c-di-AMP levels in the MTBVAC vaccine result in enhanced innate immune responses.