title: ESX-1 dependent impairment of autophagic flux by Mycobacterium tuberculosis in human dendritic cells.
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.
authors.affiliation: Department of Epidemiology and Preclinical Research, National Institute for Infectious Diseases L. Spallanzani, Rome, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Romagnoli
authors.forename: Marilena P
authors.initials: MP
authors.lastname: Etna
authors.forename: Elena
authors.initials: E
authors.lastname: Giacomini
authors.forename: Manuela
authors.initials: M
authors.lastname: Pardini
authors.forename: Maria Elena
authors.initials: ME
authors.lastname: Remoli
authors.forename: Marco
authors.initials: M
authors.lastname: Corazzari
authors.forename: Laura
authors.initials: L
authors.lastname: Falasca
authors.forename: Delia
authors.initials: D
authors.lastname: Goletti
authors.forename: Valérie
authors.initials: V
authors.lastname: Gafa
authors.forename: Roxane
authors.initials: R
authors.lastname: Simeone
authors.forename: Giovanni
authors.initials: G
authors.lastname: Delogu
authors.forename: Mauro
authors.initials: M
authors.lastname: Piacentini
authors.forename: Roland
authors.initials: R
authors.lastname: Brosch
authors.forename: Gian Maria
authors.initials: GM
authors.lastname: Fimia
authors.forename: Eliana M
authors.initials: EM
authors.lastname: Coccia
mesh_terms: D001343:Autophagy / Q000187:drug effects; D058947:Bacterial Secretion Systems / Q000187:drug effects; D015415:Biomarkers / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000382:microbiology* / Q000473:pathology* / Q000648:ultrastructure; D006801:Humans; D009163:Mycobacterium bovis / Q000187:drug effects / Q000502:physiology; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000502:physiology* / Q000648:ultrastructure; D010588:Phagosomes / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D020123:Sirolimus / Q000494:pharmacology; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000473:pathology
chemical_list: D058947:Bacterial Secretion Systems; D015415:Biomarkers; D020123:Sirolimus