ESX-1 dependent impairment of autophagic flux by Mycobacterium tuberculosis in human dendritic cells

Alessandra Romagnoli, Marilena P. Etna, Elena Giacomini, Manuela Pardini, Maria Elena Remoli, Marco Corazzari, Laura Falasca, Delia Goletti, Valérie Gafa, Roxane Simeone, Giovanni Delogu, Mauro Piacentini, Roland Brosch, Gian Maria Fimia, Eliana M. Coccia

Research output: Contribution to journalArticlepeer-review

Abstract

Emerging evidence points to an important role of autophagy in the immune response mediated by dendritic cells (DC) against Mycobacterium tuberculosis (Mtb). Since current vaccination based on Bacillus Calmette-Guerin (BCG) is unable to stop the tuberculosis epidemic, a deeper comprehension of the alterations induced by Mtb in DC is essential for setting new vaccine strategies. Here, we compared the capacity of virulent (H37Rv) and avirulent (H37Ra) Mtb strains as well as BCG to modulate autophagy in human primary DC. We found that Mtb H37Rv impairs autophagy at the step of autophagosome-lysosome fusion. In contrast, neither Mtb H37Ra nor BCG strains were able to hamper autophagosome maturation. Both these attenuated strains have a functional inhibition of the 6kD early secreted antigenic target ESAT-6, an effector protein of the ESAT-6 Secretion System-1(ESX-1)/type VII secretion system. Notably, the ability to inhibit autophagy was fully restored in recombinant BCG and Mtb H37Ra strains in which ESAT-6 secretion was re-established by genetic complementation using either the ESX-1 region from Mtb (BCG::ESX-1) or the PhoP gene (Mtb H37Ra::PhoP), a regulator of ESAT-6 secretion. Importantly, the autophagic block induced by Mtb was overcome by rapamycin treatment leading to an increased interleukin-12 expression and, in turn, to an enhanced capacity to expand a Th1-oriented response. Collectively, our study demonstrated that Mtb alters the autophagic machinery through the ESX-1 system, and thereby opens new exciting perspectives to better understand the relationship between Mtb virulence and its ability to escape the DC-mediated immune response.

Original languageEnglish
Pages (from-to)1357-1370
Number of pages14
JournalAutophagy
Volume8
Issue number9
DOIs
Publication statusPublished - Sep 2012

Keywords

  • Autophagy
  • BCG
  • Dendritic cells
  • ESX1/type VII secretion system
  • Mycobacterium tuberculosis
  • Rd1 region
  • Vaccine

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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