Abstract
Inactivation of the transcriptional regulator PhoP results in Mycobacterium tuberculosis attenuation. Preclinical testing has shown that attenuated M. tuberculosis phoP mutants hold promise as safe and effective live vaccine candidates. We focused this study to decipher the virulence networks regulated by PhoP. A combined transcriptomic and proteomic analysis revealed that PhoP controls a variety of functions including: hypoxia response through DosR crosstalking, respiratory metabolism, secretion of the major T-cell antigen ESAT-6, stress response, synthesis of pathogenic lipids and the M. tuberculosis persistence through transcriptional regulation of the enzyme isocitrate lyase. We also demonstrate that the M. tuberculosis phoP mutant SO2 exhibits an antigenic capacity similar to that of the BCG vaccine. Finally, we provide evidence that the SO2 mutant persists better in mouse organs than BCG. Altogether, these findings indicate that PhoP orchestrates a variety of functions implicated in M. tuberculosis virulence and persistence, making phoP mutants promising vaccine candidates.
Highlights
The lifecycle of intracellular pathogens requires adaptation to the environment prevailing in the host tissues either to interact with cells or to survive within them
Genes positively regulated by PhoP include those required for hypoxia adaptation, genes involved in aerobic/anaerobic respiration, genes within the Region of Difference 1 (RD1), genes encoding stress proteins and genes involved in lipid metabolism
Analysis from two sets of 2D electrophoresis gels revealed that ICL, EspB - an antigenic protein encoded in the extended RD1 region - and stress proteins such as Hsp65 (GroEL2) and alpha crystallin (HspX or Acr) are differentially expressed between both strains
Summary
The lifecycle of intracellular pathogens requires adaptation to the environment prevailing in the host tissues either to interact with cells or to survive within them. This is important for M. tuberculosis which is transmitted by aerosol route with the lung being the primary organ affected. Macrophages are activated by interferon-c (IFN-c) and, are able to control the intracellular growth of M. tuberculosis by triggering a hostile environment that includes acidification of the phagosome, lysosome maturation and production of NO and reactive oxygen/nitrogen intermediates. Surviving bacteria are believed to enter a state of persistence [2] which can be lifelong This persistent lifestyle is probably a key reason for the success of M. tuberculosis as intracellular pathogen. Onethird of the human population is latently infected with the bacilli, which represent an important niche
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