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

Kelly A Prendergast; Gayathri Nagalingam; Nicholas P West; James A Triccas

doi:10.3390/vaccines12010050

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

Vaccines (Basel). 2024 Jan 2;12(1):50. doi: 10.3390/vaccines12010050.

Authors

Kelly A Prendergast^{1

2}, Gayathri Nagalingam^{1

2}, Nicholas P West³, James A Triccas^{1

2}

Affiliations

¹ Sydney Infectious Diseases Institute (Sydney ID), Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2006, Australia.
² School of Medical Sciences, The University of Sydney, Camperdown, NSW 2006, Australia.
³ Australian Infectious Disease Research Centre, School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia.

Abstract

New control measures are urgently required to control tuberculosis (TB), as the current vaccine, Bacille Calmette-Guérin (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^ΔpdtaS) 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^loKLRG1⁺) was similar between wild-type M. tuberculosis and Mtb^ΔpdtaS and greater than that elicited by BCG. Heightened immunity induced by Mtb^ΔpdtaS compared to BCG was also observed by analysis of antigen-specific IFN-γ-secreting T cell responses induced by vaccination. Mtb^ΔpdtaS 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.

Keywords: PdtaS; immune response; tuberculosis; vaccine; virulence.

Grants and funding

APP1051246/National Health and Medical Research Council