PhoP: A Missing Piece in the Intricate Puzzle of Mycobacterium tuberculosis Virulence

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.

Phosphorylation of PhoP Protein Plays Direct Regulatory Role in Lipid Biosynthesis of Mycobacterium tuberculosis

“…Growing evidence indicates that PhoP regulates biosynthesis of sulfolipids (SL), diacyltrehaloses (DATs), and polyacyltrehaloses (PATs), and the absence of these complex lipid molecules in the phoP mutant is a major reason for the attenuated growth of the bacilli in a mouse model (5,6,8,9). More recent studies suggest that PhoP, in addition to complex lipid biosynthesis, impacts numerous aspects of M. tuberculosis physiology, including early and enduring hypoxic responses (10), regulation of ESAT-6 secretion, specific T-cell recognition during virulence regulation of the bacilli (10 -12), and pH sensing during intracellular adaptation (13). However, biochemical evidence showing the role of PhoP in transcription activation has been lacking.…”

MTBVAC from discovery to clinical trials in tuberculosis-endemic countries

“…The gene phoP encodes the transcription factor of the two-component virulence system PhoPR and the gene fadD26 is one of the 13 genes responsible for biosynthesis and export of phthiocerol dimycocerosates (PDIM), the main virulence-associated cell-wall lipids of M. tuberculosis [54][55][56]. PhoP has been shown to regulate more than 2% of M. tuberculosis genome, most of which implicated in virulence [57,58], and this regulation could be mediated through other transcription factors, for example, Whib6 of the ESX-1 system [43] or via noncoding RNAs (ncRNAs), such as the recently described mcr7 and its role in activating the TAT secretion system in MTBVAC leading to over secretion of major antigens such as the Ag85 complex [59]. Other relevant virulence genes regulated by PhoP include lipid metabolism genes (e.g.…”

Mycobacterium tuberculosis Transcriptome In Vivo Studies – A Key to Understand the Pathogen Adaptation Mechanism

“…In addition, M. tuberculosis has 12 two-component regulatory systems (Tucker et al, 2007). Two of them, phoPR (Gonzalo-Asensio et al, 2008) and dosRS (devRS) (Park et al, 2003), were studied more thoroughly than others. It was shown that functional activity of the phoPR system supports the M. tuberculosis virulence by regulating the metabolism of complex lipids and the work of the ESX secretion systems (Gonzalo-Asensio et al, 2008).…”

“…Two of them, phoPR (Gonzalo-Asensio et al, 2008) and dosRS (devRS) (Park et al, 2003), were studied more thoroughly than others. It was shown that functional activity of the phoPR system supports the M. tuberculosis virulence by regulating the metabolism of complex lipids and the work of the ESX secretion systems (Gonzalo-Asensio et al, 2008). The positive transcription regulator phoP was observed to induce genes under its control in a low-acid (pH 6.4) environment of mouse macrophage phagosomes (Rohde et al, 2007).…”