Cytosolic Access of Mycobacterium tuberculosis: Critical Impact of Phagosomal Acidification Control and Demonstration of Occurrence In Vivo

Autor: Fadel Sayes, Ok-Ryul Song, Laleh Majlessi, Matthias I. Gröschel, Roxane Simeone, Priscille Brodin, Roland Brosch
Přispěvatelé: Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris] (IP), Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204 (CIIL), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Centre National de la Recherche Scientifique (CNRS), This work was supported by the European Community’s Framework Programme 7 grants NEWTBVAC 241745, MM4TB 260872 and INTRACELLTB 260901, the Institut Pasteur (PTR441), the Agence Nationale de Recherche, the Feder (12001407 (D-AL) Equipex Imaginex BioMed), the Region Nord Pas de Calais and the Fondation pour la Recherche Médicale FRM noDEQ20130326471 (to RB). MIG is a recipient of a Jan Kornelis de Cock Stichting scholarship., European Project: 241745,EC:FP7:HEALTH,FP7-HEALTH-2009-single-stage,NEWTBVAC(2010), European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011), European Project: 260901,EC:FP7:ERC,ERC-2010-StG_20091118,INTRACELLTB(2010), SAYES, FADEL, Discovery and preclinical development of new generation tuberculosis vaccines - NEWTBVAC - - EC:FP7:HEALTH2010-01-01 - 2014-02-28 - 241745 - VALID, More Medicines for Tuberculosis - MM4TB - - EC:FP7:HEALTH2011-02-01 - 2016-01-31 - 260872 - VALID, A Chemical Genomics Approach of Intracellular Mycobacterium tuberculosis Towards Defining Specific Host Pathogen Interactions - INTRACELLTB - - EC:FP7:ERC2010-12-01 - 2015-11-30 - 260901 - VALID, Institut Pasteur [Paris], Centre National de la Recherche Scientifique (CNRS)-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille)-Université de Lille-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)
Jazyk: angličtina
Rok vydání: 2015
Předmět:
MESH: Hydrogen-Ion Concentration
MESH: Mycobacterium tuberculosis
Phagocyte
MESH: Mice
Mutant Strains
[SDV]Life Sciences [q-bio]
chemistry.chemical_compound
Mice
Phagosomes
MESH: Animals
MESH: Tuberculosis
Biology (General)
MESH: Bacterial Secretion Systems
Bacterial Secretion Systems
Cation Transport Proteins
Phagosome
biology
Bafilomycin
Hydrogen-Ion Concentration
3. Good health
Transport protein
[SDV] Life Sciences [q-bio]
MESH: Leukocyte Common Antigens
medicine.anatomical_structure
Research Article
MESH: Cell Line
Tumor
QH301-705.5
Phagosome acidification
Immunology
Spleen
Microbiology
Mycobacterium tuberculosis
MESH: Cation Transport Proteins
MESH: Phagosomes
Virology
Cell Line
Tumor
Genetics
medicine
Animals
Humans
Tuberculosis
Secretion
MESH: Mice
Molecular Biology
MESH: Humans
Macrophages
MESH: Macrophages
RC581-607
biology.organism_classification
Mice
Mutant Strains
chemistry
Leukocyte Common Antigens
Parasitology
Immunologic diseases. Allergy
Zdroj: PLoS Pathogens
PLoS Pathogens, 2015, 11 (2), pp.e1004650. ⟨10.1371/journal.ppat.1004650⟩
PLoS Pathogens, Vol 11, Iss 2, p e1004650 (2015)
PLoS Pathogens, Public Library of Science, 2015, 11 (2), pp.e1004650. ⟨10.1371/journal.ppat.1004650⟩
ISSN: 1553-7374
1553-7366
Popis: Mycobacterium tuberculosis (Mtb) uses efficient strategies to evade the eradication by professional phagocytes, involving—as recently confirmed—escape from phagosomal confinement. While Mtb determinants, such as the ESX-1 type VII secretion system, that contribute to this phenomenon are known, the host cell factors governing this important biological process are yet unexplored. Using a newly developed flow-cytometric approach for Mtb, we show that macrophages expressing the phagosomal bivalent cation transporter Nramp-1, are much less susceptible to phagosomal rupture. Together with results from the use of the phagosome acidification inhibitor bafilomycin, we demonstrate that restriction of phagosomal acidification is a prerequisite for mycobacterial phagosomal rupture and cytosolic contact. Using different in vivo approaches including an enrichment and screen for tracking rare infected phagocytes carrying the CD45.1 hematopoietic allelic marker, we here provide first and unique evidence of M. tuberculosis-mediated phagosomal rupture in mouse spleen and lungs and in numerous phagocyte types. Our results, linking the ability of restriction of phagosome acidification to cytosolic access, provide an important conceptual advance for our knowledge on host processes targeted by Mtb evasion strategies.
Author Summary The intracellular fate of the agent of the human tuberculosis agent in phagocytes is a question of great biological relevance. Among the mycobacterial survival strategies, the escape of Mycobacterium tuberculosis from phagosomes has been subject of scientific debate for a long time. However, technically improved methods recently reinforced the occurrence of this phenomenon. Here, we focused on the host factors involved in phagosomal rupture and provide first and singular evidence of M. tuberculosis-mediated phagosomal rupture in vivo in mouse lungs and inside the granuloma. We show that partial blockage of phagosomal acidification, induced by mycobacteria, is a prerequisite for efficient vacuolar breakage by M. tuberculosis and link maturation arrest, cytosolic contact and the corresponding immune responses. From our results we conclude that vacuolar breakage induced by M. tuberculosis is not an ex vivo artifact of cell cultures, but an important process that occurs inside infected phagocytes within organs during several days that strongly determines the outcome of infection with this key pathogen.
Databáze: OpenAIRE
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