, WHO. World Health Organization, 2017.

A. Calmette, Preventive Vaccination Against Tuberculosis with BCG, Proc R Soc Med, vol.24, pp.1481-90, 1931.

S. H. Kaufmann, Fact and fiction in tuberculosis vaccine research: 10 years later, Lancet Infect Dis, vol.11, p.21798463, 2011.

H. M. Dockrell and S. G. Smith, What Have We Learnt about BCG Vaccination in the Last 20 Years? Front Immunol, vol.8, p.28955344, 2017.

A. M. Abdallah, G. A. Hill-cawthorne, T. D. Otto, F. Coll, J. A. Guerra-assunção et al., Genomic expression catalogue of a global collection of BCG vaccine strains show evidence for highly diverged metabolic and cell-wall adaptations, Sci Rep, vol.5, p.15443, 2015.

V. Tran, M. A. Behr, J. Liu, . Bcg, and . Vaccines, Molecular Genetics of Mycobacteria, Second Edition. American Society of Microbiology, p.26082111, 2014.

A. D. Van-der-woude, J. Luirink, and W. Bitter, Getting Across the Cell Envelope: Mycobacterial Protein Secretion. Current topics in microbiology and immunology, p.23239236, 2012.

E. F. Perkowski, K. E. Zulauf, D. Weerakoon, J. D. Hayden, T. R. Ioerger et al., The EXIT Strategy: an Approach for Identifying Bacterial Proteins Exported during Host Infection, MBio, vol.8, p.28442606, 2017.

M. I. Gröschel, F. Sayes, R. Simeone, L. Majlessi, and R. Brosch, ESX secretion systems: mycobacterial evolution to counter host immunity, Nat Rev Microbiol, vol.14, p.27665717, 2016.

G. G. Mahairas, P. J. Sabo, M. J. Hickey, D. C. Singh, and C. K. Stover, Molecular analysis of genetic differences between Mycobacterium bovis BCG and virulent M. bovis, J Bacteriol, vol.178, p.8631702, 1996.

A. S. Pym, P. Brodin, R. Brosch, M. Huerre, and C. St, Loss of RD1 contributed to the attenuation of the live tuberculosis vaccines Mycobacterium bovis BCG and Mycobacterium microti, Mol Microbiol, vol.46, p.12410828, 2002.

T. Hsu, S. M. Hingley-wilson, C. B. Chen, M. Dai, A. Z. Morin et al., The primary mechanism of attenuation of bacillus Calmette-Guerin is a loss of secreted lytic function required for invasion of lung interstitial tissue, Proc Natl Acad Sci U S A, vol.100, p.14557547, 2003.

N. Van-der-wel, D. Hava, D. Houben, D. Fluitsma, M. Van-zon et al., tuberculosis and M. leprae translocate from the phagolysosome to the cytosol in myeloid cells, Cell, vol.129, p.17604718, 2007.

D. Houben, C. Demangel, J. Van-ingen, J. Perez, L. Baldeón et al., ESX-1-mediated translocation to the cytosol controls virulence of mycobacteria, Cell Microbiol, vol.14, p.22524898, 2012.

R. Simeone, A. Bobard, J. Lippmann, W. Bitter, L. Majlessi et al., Phagosomal rupture by Mycobacterium tuberculosis results in toxicity and host cell death, PLoS Pathog, vol.8, p.22319448, 2012.
URL : https://hal.archives-ouvertes.fr/pasteur-01899479

R. Simeone, F. Sayes, O. Song, M. I. Gröschel, P. Brodin et al., Cytosolic Access of Mycobacterium tuberculosis: Critical Impact of Phagosomal Acidification Control and Demonstration of

, Occurrence In Vivo. PLoS Pathog, vol.11, p.25658322, 2015.

A. S. Pym, P. Brodin, L. Majlessi, R. Brosch, C. Demangel et al., Recombinant BCG exporting ESAT-6 confers enhanced protection against tuberculosis, Nat Med, vol.9, p.12692540, 2003.

M. I. Gröschel, F. Sayes, S. J. Shin, W. Frigui, A. Pawlik et al., Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection, Cell Rep, vol.18, p.28297677, 2017.

N. Aguilo, J. Gonzalo-asensio, S. Alvarez-arguedas, D. Marinova, A. B. Gomez et al., Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis, Nat Commun, vol.8, p.28706226, 2017.

A. M. Abdallah, T. Verboom, E. M. Weerdenburg, G. Van-pittius, N. C. Mahasha et al., PPE and PE_PGRS proteins of Mycobacterium marinum are transported via the type VII secretion system ESX-5, Mol Microbiol, vol.73, p.19602152, 2009.

L. S. Ates, R. Ummels, S. Commandeur, R. Van-der-weerd, M. Sparrius et al., Essential Role of the ESX-5 Secretion System in Outer Membrane Permeability of Pathogenic Mycobacteria, PLOS Genet, vol.11, p.25938982, 2015.

N. C. Gey-van-pittius, S. L. Sampson, H. Lee, Y. Kim, P. D. Van-helden et al., Evolution and expansion of the Mycobacterium tuberculosis PE and PPE multigene families and their association with the duplication of the ESAT-6 (esx) gene cluster regions, BMC Evol Biol, vol.6, p.17105670, 2006.

D. Luca, M. Bottai, D. Batoni, G. Orgeur, M. Aulicino et al., The ESX-5 associated eccBEccC locus is essential for Mycobacterium tuberculosis viability, PLoS One, vol.7, p.23284869, 2012.

S. T. Cole, R. Brosch, J. Parkhill, T. Garnier, C. Churcher et al., Deciphering the biology of Mycobacterium tuberculosis from the complete genome sequence, Nature, vol.393, p.9634230, 1998.

C. Deb, J. Daniel, T. D. Sirakova, B. Abomoelak, V. S. Dubey et al., A novel lipase belonging to the hormone-sensitive lipase family induced under starvation to utilize stored triacylglycerol in Mycobacterium tuberculosis, J Biol Chem, vol.281, p.16354661, 2006.

M. H. Daleke, A. Cascioferro, K. De-punder, R. Ummels, A. M. Abdallah et al., Conserved Pro-Glu (PE) and Pro-Pro-Glu (PPE) protein domains target LipY lipases of pathogenic mycobacteria to the cell surface via the ESX-5 pathway, J Biol Chem, vol.286, p.21471225, 2011.

L. S. Ates, A. D. Van-der-woude, J. Bestebroer, G. Van-stempvoort, R. Musters et al., The ESX-5 System of Pathogenic Mycobacteria Is Involved In Capsule Integrity and Virulence through Its Substrate PPE10, PLoS Pathog, vol.12, p.27280885, 2016.

S. L. Sampson, Mycobacterial PE/PPE proteins at the host-pathogen interface, Clin Dev Immunol, p.21318182, 2011.
DOI : 10.1155/2011/497203

URL : https://doi.org/10.1155/2011/497203

L. S. Ates, E. Houben, and W. Bitter, Type VII Secretion: A Highly Versatile Secretion System. Virulence Mechanisms of Bacterial Pathogens, Fifth Edition. American Society of Microbiology, pp.357-384, 2016.

N. K. Saini, A. Baena, T. W. Ng, M. M. Venkataswamy, S. C. Kennedy et al., Suppression of autophagy and antigen presentation by Mycobacterium tuberculosis PE_PGRS47, Nat Microbiol, vol.1, p.27562263, 2016.

M. J. Brennan and G. Delogu, The PE multigene family: a "molecular mantra" for mycobacteria, Trends Microbiol, vol.10, p.11973159, 2002.

L. S. Ates, A. Dippenaar, R. Ummels, S. R. Piersma, A. D. Van-der-woude et al., Mutations in ppe38 block PE_PGRS secretion and increase virulence of Mycobacterium tuberculosis, Nat Microbiol, vol.3, p.29335553, 2018.
URL : https://hal.archives-ouvertes.fr/pasteur-02046016

C. Mcevoy, P. D. Van-helden, R. M. Warren, G. Van-pittius, and N. C. , Evidence for a rapid rate of molecular evolution at the hypervariable and immunogenic Mycobacterium tuberculosis PPE38 gene region, BMC Evol Biol, vol.9, p.19769792, 2009.

C. Mcevoy, R. M. Warren, P. D. Van-helden, G. Van-pittius, and N. C. , Multiple, independent, identical IS6110 insertions in Mycobacterium tuberculosis PPE genes, Tuberculosis (Edinb), vol.89, p.19734099, 2009.

D. A. Smith, T. Parish, S. M. Smith, H. M. Dockrell, N. G. Stoker et al., Deletion of mycobacterial phospholipases C and haemolysin alters virulence and inhibits T cell recognition of Mycobacterium tuberculosis H37Rv, Fifth Int Conf Pathog Mycobact Infect Stock, p.11, 2002.

L. Chevalier, F. Cascioferro, A. Frigui, W. Pawlik, A. Boritsch et al., Revisiting the role of phospholipases C in virulence and the lifecycle of Mycobacterium tuberculosis, Sci Rep, vol.5, p.26603639, 2015.

P. Supply, M. Marceau, S. Mangenot, D. Roche, C. Rouanet et al., Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis, Nat Genet, vol.45, p.23291586, 2013.

E. C. Boritsch, W. Frigui, A. Cascioferro, W. Malaga, G. Etienne et al., pks5-recombination-mediated surface remodelling in Mycobacterium tuberculosis emergence, Nat Microbiol, vol.1, p.27571976, 2016.
DOI : 10.1038/nmicrobiol.2015.19

URL : https://hal.archives-ouvertes.fr/pasteur-01265519

E. C. Boritsch, V. Khanna, A. Pawlik, N. Honoré, V. H. Navas et al., Key experimental evidence of chromosomal DNA transfer among selected tuberculosis-causing mycobacteria, Proc Natl Acad Sci U S A, vol.113, p.27528665, 2016.

R. S. Lee, N. Radomski, J. Proulx, I. Levade, B. J. Shapiro et al., Population genomics of Mycobacterium tuberculosis in the Inuit, Proc Natl Acad Sci U S A, 2000.

R. Brosch, S. V. Gordon, M. Marmiesse, P. Brodin, C. Buchrieser et al., A new evolutionary scenario for the Mycobacterium tuberculosis complex, Proc Natl Acad Sci U S A, vol.99, p.11891304, 2002.

M. Coscolla, A. Lewin, S. Metzger, K. Maetz-rennsing, S. Calvignac-spencer et al., Novel Mycobacterium tuberculosis complex isolate from a wild chimpanzee, Emerg Infect Dis, vol.19, p.23735084, 2013.

L. Zhu, J. Zhong, X. Jia, G. Liu, Y. Kang et al., Precision methylome characterization of Mycobacterium tuberculosis complex (MTBC) using PacBio single-molecule real-time (SMRT) technology, Nucleic Acids Res, vol.44, pp.730-743, 2016.

S. Mostowy, J. Inwald, S. Gordon, C. Martin, R. Warren et al., Revisiting the evolution of Mycobacterium bovis, J Bacteriol, vol.187, p.16159772, 2005.

J. Van-ingen, Z. Rahim, A. Mulder, M. J. Boeree, R. Simeone et al., Characterization of Mycobacterium orygis as M. tuberculosis complex subspecies, Emerg Infect Dis, vol.18, p.22469053, 2012.

E. Houben, J. Bestebroer, R. Ummels, L. Wilson, S. R. Piersma et al., Composition of the type VII secretion system membrane complex, Mol Microbiol, vol.86, p.22925462, 2012.

F. Sayes, L. Sun, D. Luca, M. Simeone, R. Degaiffier et al., Strong immunogenicity and crossreactivity of Mycobacterium tuberculosis ESX-5 type VII secretion: encoded PE-PPE proteins predicts vaccine potential, Cell Host Microbe, vol.11, p.22520463, 2012.
URL : https://hal.archives-ouvertes.fr/pasteur-01104794

W. Frigui, D. Bottai, L. Majlessi, M. Monot, E. Josselin et al., Control of M. tuberculosis ESAT-6 secretion and specific T cell recognition by PhoP, PLoS Pathog, vol.4, p.18282096, 2008.
URL : https://hal.archives-ouvertes.fr/pasteur-01370872

L. Majlessi, P. Brodin, R. Brosch, M. Rojas, H. Khun et al., Influence of ESAT-6 secretion system 1 (RD1) of Mycobacterium tuberculosis on the interaction between mycobacteria and the host immune system, J Immunol, vol.174, p.15749894, 2005.

P. Brodin, L. Majlessi, L. Marsollier, M. I. De-jonge, D. Bottai et al., Dissection of ESAT-6 system 1 of Mycobacterium tuberculosis and impact on immunogenicity and virulence, Infect Immun, vol.74, p.16368961, 2006.

L. Meng, J. Tong, H. Wang, C. Tao, Q. Wang et al., PPE38 Protein of Mycobacterium tuberculosis Inhibits Macrophage MHC Class I Expression and Dampens CD8+ T Cell Responses, Front Cell Infect Microbiol, vol.7, p.28348981, 2017.

R. Prados-rosales, L. J. Carreno, B. Weinrick, A. Batista-gonzalez, J. Xu et al., The presence of a mycobacterial capsule is associated with differences in the protective efficacy of BCG vaccination against Mycobacterium tuberculosis in mice, J Infect Dis, vol.153, 2016.

L. Arlehamn, C. S. Gerasimova, A. Mele, F. Henderson, R. Swann et al., Memory T Cells in Latent Mycobacterium tuberculosis Infection Are Directed against Three Antigenic Islands and Largely Contained in a CXCR3+CCR6+ Th1 Subset, PLoS Pathog, vol.9, p.23358848, 2013.

S. Bertholet, G. C. Ireton, D. J. Ordway, H. P. Windish, S. O. Pine et al., A Defined Tuberculosis Vaccine Candidate Boosts BCG and Protects Against Multidrug-Resistant Mycobacterium tuberculosis, Sci Transl Med, vol.2, issue.53, p.20944089, 2010.

S. L. Baldwin, V. A. Reese, P. D. Huang, E. A. Beebe, B. K. Podell et al., Protection and long-lived immunity induced by the ID93/GLA-SE vaccine candidate against a clinical Mycobacterium tuberculosis isolate, Clin Vaccine Immunol, vol.23, issue.2, p.26656121, 2015.

M. J. Brennan, The enigmatic PE/PPE Multi-gene Family of Mycobacteria and TB Vaccination, Infect Immun, vol.85, p.28348055, 2017.

F. Sayes, A. Pawlik, W. Frigui, M. I. Gröschel, S. Crommelynck et al., CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection, PLOS Pathog, vol.12, p.27467705, 2016.

C. Mcevoy, R. Cloete, B. Müller, A. C. Schürch, P. D. Helden et al., Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints, PLoS One, vol.7, p.22496726, 2012.

R. Copin, M. Coscollá, S. N. Seiffert, G. Bothamley, J. Sutherland et al., Sequence diversity in the pe_pgrs genes of Mycobacterium tuberculosis is independent of human T cell recognition, MBio, vol.5, p.24425732, 2014.

S. Bertholet, G. C. Ireton, M. Kahn, J. Guderian, R. Mohamath et al., Identification of Human T Cell Antigens for the Development of Vaccines against Mycobacterium tuberculosis, J Immunol, vol.181, issue.11, p.19017986, 2008.

A. Kim, Y. Hur, S. Gu, and S. Cho, Protective vaccine efficacy of the complete form of PPE39 protein from Mycobacterium tuberculosis Beijing/K strain in mice, Clin Vaccine Immunol, vol.24, issue.11, p.28877927, 2017.

N. A. Kruh, J. Troudt, A. Izzo, J. Prenni, and K. M. Dobos, Portrait of a pathogen: the Mycobacterium tuberculosis proteome in vivo, PLoS One, vol.5, p.21085642, 2010.

A. Kapopoulou, J. M. Lew, and C. St, The MycoBrowser portal: a comprehensive and manually annotated resource for mycobacterial genomes, Tuberculosis (Edinb), vol.91, p.20980200, 2011.

S. Bardarov, J. Kriakov, C. Carriere, S. Yu, C. Vaamonde et al., Conditionally replicating mycobacteriophages: a system for transposon delivery to Mycobacterium tuberculosis, Proc Natl Acad Sci U S A, vol.94, p.9380742, 1997.

D. Bottai, D. Luca, M. Majlessi, L. Frigui, W. Simeone et al., Disruption of the ESX-5 system of Mycobacterium tuberculosis causes loss of PPE protein secretion, reduction of cell wall integrity and strong attenuation, Mol Microbiol, vol.83, p.22340629, 2012.

K. Beckham, L. Ciccarelli, C. M. Bunduc, H. Mertens, R. Ummels et al., Structure of the mycobacterial ESX-5 type VII secretion system membrane complex by single particle analysis, Nat Microbiol, vol.2, p.28394313, 2017.

L. Brandt, T. Oettinger, A. Holm, A. B. Andersen, and P. Andersen, Key epitopes on the ESAT-6 antigen recognized in mice during the recall of protective immunity to Mycobacterium tuberculosis, J Immunol, vol.157, p.8871652, 1996.

Y. Wu, J. S. Woodworth, D. S. Shin, S. Morris, and S. M. Behar, Vaccine-elicited 10-kilodalton culture filtrate protein-specific CD8+ T cells are sufficient to mediate protection against Mycobacterium tuberculosis infection, Infect Immun, vol.76, p.18332205, 2008.

M. Marrichi, L. Camacho, D. G. Russell, and M. P. Delisa, Genetic toggling of alkaline phosphatase folding reveals signal peptides for all major modes of transport across the inner membrane of bacteria, J Biol Chem, vol.283, p.18819916, 2008.

D. Souza, S. Rosseels, V. Romano, M. Tanghe, A. Denis et al., Mapping of murine Th1 helper T-Cell epitopes of mycolyl transferases Ag85A, Ag85B, and Ag85C from Mycobacterium tuberculosis, Infect Immun, vol.71, p.12496199, 2003.

F. Sayes, C. Blanc, L. S. Ates, N. Deboosere, M. Orgeur et al., Multiplexed Quantitation of Intraphagocyte Mycobacterium tuberculosis Secreted Protein Effectors, Cell Rep, vol.23, issue.4, p.29694886, 2018.
URL : https://hal.archives-ouvertes.fr/pasteur-02046037

M. Kato-maeda, J. T. Rhee, T. R. Gingeras, H. Salamon, J. Drenkow et al., Comparing genomes within the species Mycobacterium tuberculosis, Genome Res, vol.11, p.11282970, 2001.

D. Alland, T. S. Whittam, M. B. Murray, M. D. Cave, M. H. Hazbon et al., Modeling bacterial evolution with comparative-genome-based marker systems: application to Mycobacterium tuberculosis evolution and pathogenesis, J Bacteriol, vol.185, p.12754238, 2003.

P. Brodin, K. Eiglmeier, M. Marmiesse, A. Billault, T. Garnier et al., Bacterial Artificial Chromosome-Based Comparative Genomic Analysis Identifies Mycobacterium microti as a Natural ESAT6 Deletion Mutant, Infect Immun, vol.70, p.12228284, 2002.

S. Mostowy, D. Cousins, and M. A. Behr, Genomic interrogation of the dassie bacillus reveals it as a unique RD1 mutant within the Mycobacterium tuberculosis complex, J Bacteriol, vol.186, p.14679230, 2004.

A. Dippenaar, S. Parsons, S. L. Sampson, R. G. Van-der-merwe, J. A. Drewe et al., Whole genome sequence analysis of Mycobacterium suricattae, Tuberculosis (Edinb), vol.95, p.26542221, 2015.

M. Merker, C. Blin, S. Mona, N. Duforet-frebourg, S. Lecher et al., Evolutionary history and global spread of the Mycobacterium tuberculosis Beijing lineage, Nat Genet, vol.47, p.25599400, 2015.
URL : https://hal.archives-ouvertes.fr/pasteur-01153552

D. Brites and S. Gagneux, Co-evolution of Mycobacterium tuberculosis and Homo sapiens, Immunol Rev, vol.264, p.25703549, 2015.

K. Bansal, S. R. Elluru, Y. Narayana, R. Chaturvedi, S. A. Patil et al., PE_PGRS Antigens of Mycobacterium tuberculosis Induce Maturation and Activation of Human Dendritic Cells, J Immunol, vol.184, p.20176745, 2010.

W. Deng, Q. Long, J. Zeng, P. Li, Y. W. Chen et al., Mycobacterium tuberculosis PE_PGRS41 Enhances the Intracellular Survival of M. smegmatis within Macrophages Via Blocking Innate Immunity and Inhibition of Host Defense, Sci Rep, vol.7, p.28440335, 2017.

S. Chatrath, V. K. Gupta, A. Dixit, and L. C. Garg, PE_PGRS30 of Mycobacterium tuberculosis mediates suppression of proinflammatory immune response in macrophages through its PGRS and PE domains, Microbes Infect, vol.18, p.27129781, 2016.

A. Zumbo, I. Palucci, A. Cascioferro, M. Sali, M. Ventura et al., Functional dissection of protein domains involved in the immunomodulatory properties of PE_PGRS33 of Mycobacterium tuberculosis, Pathog Dis, vol.69, p.24106104, 2013.

L. Ramakrishnan, N. A. Federspiel, and S. Falkow, Granuloma-specific expression of Mycobacterium virulence proteins from the glycine-rich PE-PGRS family, Science, vol.288, p.10827956, 2000.

S. Fishbein, N. Wyk, R. M. Warren, and S. L. Sampson, Phylogeny to function: PE/PPE protein evolution and impact on Mycobacterium tuberculosis pathogenicity, Mol Microbiol, vol.96, p.25727695, 2015.

K. M. Malone and S. V. Gordon, Mycobacterium tuberculosis Complex Members Adapted to Wild and Domestic Animals, Adv Exp Med Biol, vol.1019, p.29116633, 2017.

G. Delogu and M. J. Brennan, Comparative immune response to PE and PE_PGRS antigens of Mycobacterium tuberculosis, Infect Immun, vol.69, p.11500435, 2001.

K. W. Koh, S. E. Soh, and G. T. Seah, Strong antibody responses to Mycobacterium tuberculosis PE-PGRS62 protein are associated with latent and active tuberculosis, Infect Immun, vol.77, p.19487480, 2009.

, Phase 1 ID93 + GLA-SE Vaccine Trial in Healthy Adult Volunteers-Full Text View-ClinicalTrials.gov [Internet, 2017.

, Phase 2a ID93 + GLA-SE Vaccine Trial in TB Patients After Treatment Completion-Full Text ViewClinicalTrials.gov, 2017.

A. Arbues, J. I. Aguilo, J. Gonzalo-asensio, D. Marinova, S. Uranga et al., Construction, characterization and preclinical evaluation of MTBVAC, the first live-attenuated M. tuberculosis-based vaccine to enter clinical trials, Vaccine, vol.31, p.23965219, 2013.

L. A. Keating, P. R. Wheeler, H. Mansoor, J. K. Inwald, J. Dale et al., The pyruvate requirement of some members of the Mycobacterium tuberculosis complex is due to an inactive pyruvate kinase: implications for in vivo growth, Mol Microbiol, vol.56, p.15773987, 2005.

F. Bange, F. M. Collins, and W. R. Jacobs, Survival of mice infected with Mycobacterium smegmatis containing large DNA fragments from Mycobacterium tuberculosis, Tuber Lung Dis, vol.79, p.10656115, 1999.

M. R. Alderson, T. Bement, C. H. Day, L. Zhu, D. Molesh et al., Expression cloning of an immunodominant family of Mycobacterium tuberculosis antigens using human CD4(+) T cells, J Exp Med, vol.191, p.10662800, 2000.

A. M. Abdallah, T. Verboom, F. Hannes, M. Safi, M. Strong et al., A specific secretion system mediates PPE41 transport in pathogenic mycobacteria, Mol Microbiol, vol.62, p.17076665, 2006.

M. Johnson, I. Zaretskaya, Y. Raytselis, Y. Merezhuk, S. Mcginnis et al., NCBI BLAST: a better web interface, Nucleic Acids Res, vol.36, pp.5-9, 2008.