Authors: 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 and Eliana M. Coccia

Alessandra Romagnoli

Department of Epidemiology and Preclinical Research; National Institute for Infectious Diseases “L. Spallanzani”; Rome, Italy

Marilena P. Etna

Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy

Elena Giacomini

Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy

Manuela Pardini

Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy

Maria Elena Remoli

Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy

Marco Corazzari

Department of Epidemiology and Preclinical Research; National Institute for Infectious Diseases “L. Spallanzani”; Rome, Italy

Laura Falasca

Department of Epidemiology and Preclinical Research; National Institute for Infectious Diseases “L. Spallanzani”; Rome, Italy

Delia Goletti

Department of Epidemiology and Preclinical Research; National Institute for Infectious Diseases “L. Spallanzani”; Rome, Italy

Valérie Gafa

Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy

Roxane Simeone

Institut Pasteur; Unité de Pathogénomique Mycobactérienne Intégrée; Paris, France

Giovanni Delogu

Istituto di Microbiologia; Università Cattolica del Sacro Cuore; Rome, Italy

Mauro Piacentini

Department of Epidemiology and Preclinical Research; National Institute for Infectious Diseases “L. Spallanzani”; Rome, Italy; Department of Biology; University of Rome “Tor Vergata”; Rome, Italy

Roland Brosch

Institut Pasteur; Unité de Pathogénomique Mycobactérienne Intégrée; Paris, France

Gian Maria Fimia

Corresponding author: gianmaria.fimia@inmi.it
Department of Epidemiology and Preclinical Research; National Institute for Infectious Diseases “L. Spallanzani”; Rome, Italy

Eliana M. Coccia

Corresponding author: eliana.coccia@iss.it
Department of Infectious, Parasitic and Immune-mediated Diseases; Istituto Superiore di Sanità; Rome, Italy

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.

Received: January 7, 2012; Accepted: May 25, 2012; Published Online: August 13, 2012

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