Mycobacterium tuberculosis exploits the formation of new blood vessels for its dissemination.
The mechanisms by which the airborne pathogen Mycobacterium tuberculosis spreads within the lung and leaves its primary niche to colonize other organs, thus inducing extrapulmonary forms of tuberculosis (TB) in humans, remains poorly understood. Herein, we used a transcriptomic approach to investigate the host cell gene expression profile in M. tuberculosis-infected human macrophages (ΜΦ). We identified 33 genes, encoding proteins involved in angiogenesis, for which the expression was significantly modified during infection, and we show that the potent angiogenic factor VEGF is secreted by M. tuberculosis-infected ΜΦ, in an RD1-dependent manner. In vivo these factors promote the formation of blood vessels in murine models of the disease. Inhibiting angiogenesis, via VEGF inactivation, abolished mycobacterial spread from the infection site. In accordance with our in vitro and in vivo results, we show that the level of VEGF in TB patients is elevated and that endothelial progenitor cells are mobilized from the bone marrow. These results strongly strengthen the most recent data suggesting that mycobacteria take advantage of the formation of new blood vessels to disseminate.
Institut Pasteur, Unité de Génétique Mycobactérienne, Paris, France.|Univ. Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, rue du Dr. Roux, F-75015 Paris, France.
Helena
H
Polena
Institut Pasteur, Unité de Génétique Mycobactérienne, Paris, France.
Frédéric
F
Boudou
Institut Pasteur, Unité de Génétique Mycobactérienne, Paris, France.
Sylvain
S
Tilleul
Institut Pasteur, Unité de Génétique Mycobactérienne, Paris, France.|Univ. Paris Diderot, Sorbonne Paris Cité, Cellule Pasteur, rue du Dr. Roux, F-75015 Paris, France.
Nicolas
N
Dubois-Colas
Institut Pasteur, Unité de Génétique Mycobactérienne, Paris, France.
Cécile
C
Lecointe
Institut Pasteur, Unité de Génétique Mycobactérienne, Paris, France.|Institut Pasteur de Madagascar, Unité des Mycobactéries, Antananarivo, Madagascar.
Niaina
N
Rakotosamimanana
University of Milano-Bicocca, Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
Mattia
M
Pelizzola
Institut Pasteur de Madagascar, Unité d'Epidémiologie, Antananarivo, Madagascar.
Soa Fy
SF
Andriamandimby
Institut Pasteur de Madagascar, Unité d'Epidémiologie, Antananarivo, Madagascar.
Vaomalala
V
Raharimanga
Institut Pasteur, Unité de Génétique Mycobactérienne, Paris, France.
Patricia
P
Charles
INSERM U1173, UFR Sciences de la Santé Simone Veil, Université Versailles-Saint-Quentin, 78180 Saint-Quentin en Yvelines, France.|Service de Microbiologie, Hôpital Raymond Poincaré, Assistance Publique Hôpitaux de Paris, 92380 Garches, France.
Jean-Louis
JL
Herrmann
University of Milano-Bicocca, Department of Biotechnology and Bioscience, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy.
Paola
P
Ricciardi-Castagnoli
Institut Pasteur de Madagascar, Unité des Mycobactéries, Antananarivo, Madagascar.
Voahangy
V
Rasolofo
Institut Pasteur, Unité de Génétique Mycobactérienne, Paris, France.
Brigitte
B
Gicquel
Institut Pasteur, Unité de Génétique Mycobactérienne, Paris, France.
Ludovic
L
Tailleux
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D054884:Host-Pathogen Interactions; D006801:Humans; D008168:Lung / Q000098:blood supply* / Q000382:microbiology / Q000473:pathology; D016513:Mice, SCID; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000382:microbiology*; D059467:Transcriptome; D014397:Tuberculosis, Pulmonary / Q000382:microbiology / Q000503:physiopathology*; D015854:Up-Regulation
D042501:Angiogenic Proteins