Control of M. tuberculosis ESAT-6 secretion and specific T cell recognition by PhoP.

Wafa Frigui (1, 2) , Daria Bottai (3, 2) , Laleh Majlessi (1) , Marc Monot (2) , Emmanuelle Josselin (4) , Priscille Brodin (2) , Thierry Garnier (2) , Brigitte Gicquel (5) , Carlos Martin (6, 7) , Claude Leclerc (4) , Stewart T Cole (8, 2) , Roland Brosch (1, 2)

1 Pathogénomique mycobactérienne intégrée
2 Génétique Moléculaire Bactérienne
3 Dipartimento di Patologia Sperimentale
4 Régulation Immunitaire et Vaccinologie
5 Génétique mycobactérienne - Mycobacterial genetics
6 CIBERES - Centro de Investigación Biomédica en Red Enfermedades Respiratorias
7 Grupo de Genetica de Micobacterias
8 Global Health Institute - Institut d'Infectiologie [Lausanne]

Analysis of mycobacterial strains that have lost their ability to cause disease is a powerful approach to identify yet unknown virulence determinants and pathways involved in tuberculosis pathogenesis. Two of the most widely used attenuated strains in the history of tuberculosis research are Mycobacterium bovis BCG (BCG) and Mycobacterium tuberculosis H37Ra (H37Ra), which both lost their virulence during in vitro serial passage. Whereas the attenuation of BCG is due mainly to loss of the ESAT-6 secretion system, ESX-1, the reason why H37Ra is attenuated remained unknown. However, here we show that a point mutation (S219L) in the predicted DNA binding region of the regulator PhoP is involved in the attenuation of H37Ra via a mechanism that impacts on the secretion of the major T cell antigen ESAT-6. Only H37Ra "knock-ins" that carried an integrated cosmid with the wild-type phoP gene from M. tuberculosis H37Rv showed changes in colony morphology, increased virulence, ESAT-6 secretion, and induction of specific T cell responses, whereas other H37Ra constructs did not. This finding established a link between the PhoP regulator and ESAT-6 secretion that opens exciting new perspectives for elucidating virulence regulation in M. tuberculosis.

Domaines: Biologie moléculaire

Wafa Frigui, Daria Bottai, Laleh Majlessi, Marc Monot, Emmanuelle Josselin, et al.. Control of M. tuberculosis ESAT-6 secretion and specific T cell recognition by PhoP.. PLoS Pathogens, 2008, 4 (2), pp.e33. ⟨10.1371/journal.ppat.0040033⟩. ⟨pasteur-01370872⟩