Mycobacterium tuberculosis Deficient in PdtaS Cytosolic Histidine Kinase Displays Attenuated Growth and Affords Protective Efficacy against Aerosol M. tuberculosis Infection in Mice

New control measures are urgently required to control tuberculosis (TB), as the current vaccine, Bacille Calmette-Gu & eacute;rin (BCG), has had a limited impact on disease spread. The identification of virulence mechanisms of Mycobacterium tuberculosis is an important strategy in vaccine design, as it permits the development of strains attenuated for growth that may have vaccine potential. In this report, we determined the role of the PdtaS response regulator in M. tuberculosis virulence and defined the vaccine potential of a pdtaS-deficient strain. Deletion of pdtaS (Mtb(Delta pdtaS)) resulted in reduced persistence of M. tuberculosis within mouse organs, which was equivalent to the persistence of the BCG vaccine in the lung and liver of infected mice. However, the generation of effector CD4(+) and CD8(+) T cells (CD44(+)CD62L(lo)KLRG1(+)) was similar between wild-type M. tuberculosis and Mtb(Delta pdtaS) and greater than that elicited by BCG. Heightened immunity induced by Mtb(Delta pdtaS) compared to BCG was also observed by analysis of antigen-specific IFN-gamma-secreting T cell responses induced by vaccination. Mtb(Delta pdtaS) displayed improved protection against aerosol M. tuberculosis compared to BCG, which was most apparent in the lung at 20 weeks post-infection. These results suggest that the deletion of the PdtaS response regulator warrants further appraisal as a tool to combat TB in humans.