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3. Marine sponge microbe provides insights into evolution and virulence of the tubercle bacillus.

Author

Pidot, Sacha J., Klatt, Stephan, Ates, Louis S., Frigui, Wafa, Sayes, Fadel, Majlessi, Laleh, Izumi, Hiroshi, Monk, Ian R., Porter, Jessica L., Bennett-Wood, Vicki, Seemann, Torsten, Otter, Ashley, Taiaroa, George, Cook, Gregory M., West, Nicholas, Tobias, Nicholas J., Fuerst, John A., Stutz, Michael D., Pellegrini, Marc, and McConville, Malcolm

Subjects
BCG vaccines, COMPARATIVE genomics, TUBERCULOSIS vaccines, DNA vaccines, COMMUNICABLE diseases, MYCOBACTERIUM tuberculosis, MYCOBACTERIUM bovis, MOUNTAIN soils
Abstract

Reconstructing the evolutionary origins of Mycobacterium tuberculosis, the causative agent of human tuberculosis, has helped identify bacterial factors that have led to the tubercle bacillus becoming such a formidable human pathogen. Here we report the discovery and detailed characterization of an exceedingly slow growing mycobacterium that is closely related to M. tuberculosis for which we have proposed the species name Mycobacterium spongiae sp. nov., (strain ID: FSD4b-SM). The bacterium was isolated from a marine sponge, taken from the waters of the Great Barrier Reef in Queensland, Australia. Comparative genomics revealed that, after the opportunistic human pathogen Mycobacterium decipiens, M. spongiae is the most closely related species to the M. tuberculosis complex reported to date, with 80% shared average nucleotide identity and extensive conservation of key M. tuberculosis virulence factors, including intact ESX secretion systems and associated effectors. Proteomic and lipidomic analyses showed that these conserved systems are functional in FSD4b-SM, but that it also produces cell wall lipids not previously reported in mycobacteria. We investigated the virulence potential of FSD4b-SM in mice and found that, while the bacteria persist in lungs for 56 days after intranasal infection, no overt pathology was detected. The similarities with M. tuberculosis, together with its lack of virulence, motivated us to investigate the potential of FSD4b-SM as a vaccine strain and as a genetic donor of the ESX-1 genetic locus to improve BCG immunogenicity. However, neither of these approaches resulted in superior protection against M. tuberculosis challenge compared to BCG vaccination alone. The discovery of M. spongiae adds to our understanding of the emergence of the M. tuberculosis complex and it will be another useful resource to refine our understanding of the factors that shaped the evolution and pathogenesis of M. tuberculosis. Author summary: Tuberculosis, caused by Mycobacterium tuberculosis, is still one of the world's deadliest infectious diseases. However, the origins and rise of M. tuberculosis as a successful pathogen are not well understood. Here, we report the isolation and characterisation of a marine sponge-derived mycobacterium (M. spongiae) from the Great Barrier Reef that has striking genotypic similarity to M. tuberculosis, with 80% average nucleotide identity. We further show by proteomic and lipidomic analyses that M. spongiae shares virulence factors and unique cell wall lipids with the tubercle bacillus. In spite of these conserved genotypic and phenotypic features, M. spongiae was not virulent in a mouse model of infection, leading us to investigate its potential as a vaccine strain or genetic donor for enhancing the current BCG vaccine for tuberculosis. Our findings contribute to understanding the evolutionary origins of M. tuberculosis and provide further insights into its pathogenesis. [ABSTRACT FROM AUTHOR]

Published
2024
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5. A marine sponge-associated mycobacterium closely related to Mycobacterium tuberculosis

Author

Pidot, Sacha J, primary, Klatt, Stephan, additional, Ates, Louis S, additional, Frigui, Wafa, additional, Sayes, Fadel, additional, Majlessi, Laleh, additional, Izumi, Hiroshi, additional, Monk, Ian R, additional, Porter, Jessica L, additional, Bennett-Wood, Vicki, additional, Seemann, Torsten, additional, Otter, Ashley, additional, Taiaroa, George, additional, Cook, Gregory M, additional, West, Nicholas, additional, Tobias, Nicholas J, additional, Fuerst, John A, additional, Stutz, Michael D, additional, Pelligrini, Marc, additional, McConville, Malcolm, additional, Brosch, Roland, additional, Stinear, Timothy P, additional, and Stinear, Timothy P., additional

Published
2024
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7. A host-directed oxadiazole compound potentiates antituberculosis treatment via zinc poisoning in human macrophages and in a mouse model of infection.

Author

Maure, Alexandra, Lawarée, Emeline, Fiorentino, Francesco, Pawlik, Alexandre, Gona, Saideep, Giraud-Gatineau, Alexandre, Eldridge, Matthew J. G., Danckaert, Anne, Hardy, David, Frigui, Wafa, Keck, Camille, Gutierrez, Claude, Neyrolles, Olivier, Aulner, Nathalie, Mai, Antonello, Hamon, Mélanie, Barreiro, Luis B., Brodin, Priscille, Brosch, Roland, and Rotili, Dante

Subjects
LABORATORY mice, ANIMAL disease models, MYCOBACTERIUM tuberculosis, POISONING, ZINC, TUBERCULOSIS in cattle
Abstract

Antituberculosis drugs, mostly developed over 60 years ago, combined with a poorly effective vaccine, have failed to eradicate tuberculosis. More worryingly, multiresistant strains of Mycobacterium tuberculosis (MTB) are constantly emerging. Innovative strategies are thus urgently needed to improve tuberculosis treatment. Recently, host-directed therapy has emerged as a promising strategy to be used in adjunct with existing or future antibiotics, by improving innate immunity or limiting immunopathology. Here, using high-content imaging, we identified novel 1,2,4-oxadiazole-based compounds, which allow human macrophages to control MTB replication. Genome-wide gene expression analysis revealed that these molecules induced zinc remobilization inside cells, resulting in bacterial zinc intoxication. More importantly, we also demonstrated that, upon treatment with these novel compounds, MTB became even more sensitive to antituberculosis drugs, in vitro and in vivo, in a mouse model of tuberculosis. Manipulation of heavy metal homeostasis holds thus great promise to be exploited to develop host-directed therapeutic interventions. Multidrug resistant strains of Mycobacterium tuberculosis are widespread and new treatment strategies are urgently needed. This study uses a high-throughput screen to identify an oxadiazole-based compound that induces intracellular zinc redistribution in host cells, synergizing with other anti-tuberculosis drugs to control Mycobacterium tuberculosis infection in human macrophages and a mouse model of infection. [ABSTRACT FROM AUTHOR]

Published
2024
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9. Natural mutations in the sensor kinase of the PhoPR two-component regulatory system modulate virulence of ancestor-like tuberculosis bacilli

Author

Malaga, Wladimir, primary, Payros, Delphine, additional, Meunier, Eva, additional, Frigui, Wafa, additional, Sayes, Fadel, additional, Pawlik, Alexandre, additional, Orgeur, Mickael, additional, Berrone, Céline, additional, Moreau, Flavie, additional, Mazères, Serge, additional, Gonzalo-Asensio, Jesus, additional, Rengel, David, additional, Martin, Carlos, additional, Astarie-Dequeker, Catherine, additional, Mourey, Lionel, additional, Brosch, Roland, additional, and Guilhot, Christophe, additional

Published
2023
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15. Genome Plasticity of BCG and Impact on Vaccine Efficacy

Author

Brosch, Roland, Gordon, Stephen V., Garnier, Thierry, Eiglmeier, Karin, Frigui, Wafa, Valenti, Philippe, Dos Santos, Sandrine, Duthoy, Stéphanie, Lacroix, Céline, Garcia-Pelayo, Carmen, Inwald, Jacqueline K., Golby, Paul, Garcia, Javier Nuñez, Hewinson, R. Glyn, Behr, Marcel A., Quail, Michael A., Churcher, Carol, Barrell, Bart G., Parkhill, Julian, and Cole, Stewart T.

Published
2007
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17. De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis

Author

Laval, Thomas, primary, Pedró-Cos, Laura, additional, Malaga, Wladimir, additional, Guenin-Macé, Laure, additional, Pawlik, Alexandre, additional, Mayau, Véronique, additional, Yahia-Cherbal, Hanane, additional, Delos, Océane, additional, Frigui, Wafa, additional, Bertrand-Michel, Justine, additional, Guilhot, Christophe, additional, and Demangel, Caroline, additional

Published
2021
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18. Author response: De novo synthesized polyunsaturated fatty acids operate as both host immunomodulators and nutrients for Mycobacterium tuberculosis

Author

Laval, Thomas, primary, Pedró-Cos, Laura, additional, Malaga, Wladimir, additional, Guenin-Macé, Laure, additional, Pawlik, Alexandre, additional, Mayau, Véronique, additional, Yahia-Cherbal, Hanane, additional, Delos, Océane, additional, Frigui, Wafa, additional, Bertrand-Michel, Justine, additional, Guilhot, Christophe, additional, and Demangel, Caroline, additional

Published
2021
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19. Pathogenomic analyses of Mycobacterium microti, an ESX-1-deleted member of the Mycobacterium tuberculosis complex causing disease in various hosts

Author

Orgeur, Mickael, Frigui, Wafa, Pawlik, Alexandre, Clark, Simon, Williams, Ann, Ates, Louis, Ma, Laurence, Bouchier, Christiane, Parkhill, Julian, Brodin, Priscille, Brosch, Roland, Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Public Health England [Salisbury] (PHE), University of Amsterdam [Amsterdam] (UvA), Pôle Biomics (C2RT), Centre de Ressources et de Recherche Technologique - Center for Technological Resources and Research (C2RT), Institut Pasteur [Paris] (IP)-Institut Pasteur [Paris] (IP), University of Cambridge [UK] (CAM), The Wellcome Trust Sanger Institute [Cambridge], 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 grants from the European Commission (TBVAC2020, grant 260872) and the Agence Nationale de la Recherche (grants ANR-16-CE35-0009 and ANR-10-LABX-62-IBEID). M. O. was supported by the Fondation pour la Recherche Médicale (SPF20160936136) and the Institut Pasteur (Pasteur-Roux-Cantarini postdoctoral fellowship program). The Biomics platform is supported by France Génomique (ANR-10-INBS-09–09) and IBISA., We thank the pathology team (Public Health England, Porton, Salisbury, UK) for the generation of histopathology data and images, the staff of the Biological Investigations Group (Public Health England, Porton, Salisbury, UK) for their assistance in conducting the guinea pig study, and the core Sequencing and Informatic groups (Sanger Institute, Hinxton, UK) for processing the Illumina whole-genome sequencing. We also thank Julien Guglielmini, Thomas Bigot and Varun Khanna (C3BI, HUB Bioinformatics and Biostatistics, Institut Pasteur, Paris, France) for their help in data analysis and phylogenetic reconstruction, as well as Laleh Majlessi, Fadel Sayes (Institut Pasteur, Paris, France) and Anzaan Dippenaar (Stellenbosch University, Cape Town, South Africa) for advice and fruitful discussions., ANR-16-CE35-0009,TBemerg,Naissance d'un tueur: facteurs génétiques et adaptations métaboliques impliquées dans l'émergence des bacilles tuberculeux épidémiques(2016), ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-INBS-0009,France-Génomique,Organisation et montée en puissance d'une Infrastructure Nationale de Génomique(2010), European Project: 260872,EC:FP7:HEALTH,FP7-HEALTH-2010-single-stage,MM4TB(2011), Parkhill, Julian [0000-0002-7069-5958], Apollo - University of Cambridge Repository, Christiane, Bouchier, Naissance d'un tueur: facteurs génétiques et adaptations métaboliques impliquées dans l'émergence des bacilles tuberculeux épidémiques - - TBemerg2016 - ANR-16-CE35-0009 - AAPG2016 - VALID, Integrative Biology of Emerging Infectious Diseases - - IBEID2010 - ANR-10-LABX-0062 - LABX - VALID, Organisation et montée en puissance d'une Infrastructure Nationale de Génomique - - France-Génomique2010 - ANR-10-INBS-0009 - INBS - VALID, More Medicines for Tuberculosis - MM4TB - - EC:FP7:HEALTH2011-02-01 - 2016-01-31 - 260872 - VALID, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-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, and Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)

Subjects
Antigens, Bacterial, Whole Genome Sequencing, Arvicolinae, ESX-1, [SDV]Life Sciences [q-bio], Guinea Pigs, High-Throughput Nucleotide Sequencing, Mice, SCID, Mycobacterium tuberculosis, [SDV] Life Sciences [q-bio], Disease Models, Animal, Mice, Bacterial Proteins, whole-genome sequencing, Bacterial Vaccines, Animals, Humans, Tuberculosis, mouse and guinea pig models, Mycobacterium microti, protective efficacy, Gene Deletion, Phylogeny, virulence evaluation
Abstract

International audience; Mycobacterium microti is an animal-adapted member of the Mycobacterium tuberculosis complex (MTBC), which was originally isolated from voles, but has more recently also been isolated from other selected mammalian hosts, including occasionally from humans. Here, we have generated and analysed the complete genome sequences of five representative vole and clinical M. microti isolates using PacBio- and Illumina-based technologies, and have tested their virulence and vaccine potential in SCID (severe combined immune deficient) mouse and/or guinea pig infection models. We show that the clinical isolates studied here cluster separately in the phylogenetic tree from vole isolates and other clades from publicly available M. microti genome sequences. These data also confirm that the vole and clinical M. microti isolates were all lacking the specific RD1 mic region, which in other tubercle bacilli encodes the ESX-1 type VII secretion system. Biochemical analysis further revealed marked phenotypic differences between isolates in type VII-mediated secretion of selected PE and PPE proteins, which in part were attributed to specific genetic polymorphisms. Infection experiments in the highly susceptible SCID mouse model showed that the clinical isolates were significantly more virulent than the tested vole isolates, but still much less virulent than the M. tuberculosis H37Rv control strain. The strong attenuation of the ATCC 35872 vole isolate in immunocompromised mice, even compared to the attenuated BCG (bacillus Calmette–Guérin) vaccine, and its historic use in human vaccine trials encouraged us to test this strain’s vaccine potential in a guinea pig model, where it demonstrated similar protective efficacy as a BCG control, making it a strong candidate for vaccination of immunocompromised individuals in whom BCG vaccination is contra-indicated. Overall, we provide new insights into the genomic and phenotypic variabilities and particularities of members of an understudied clade of the MTBC, which all share a recent common ancestor that is characterized by the deletion of the RD1 mic region.

Published
2021
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21. Common evolutionary origin for the unstable virulence plasmid pMUM found in geographically diverse strains of Mycobacterium ulcerans

Author

Stinear, Timothy P., Hong, Hui, Frigui, Wafa, Pryor, Melinda J., Brosch, Roland, Garnier, Thierry, Leadlay, Peter F., and Cole, Stewart T.

Subjects
Virulence (Microbiology) -- Natural history, Mycobacteria -- Genetic aspects, Mycobacteria -- Natural history, Mycobacterium -- Genetic aspects, Mycobacterium -- Natural history, Biological sciences
Abstract

The 174-kb virulence plasmid pMUM001 in Mycobacterium ulcerans epidemic strain Agy99 harbors three very large and homologous genes that encode giant polyketide synthases (PKS) responsible for the synthesis of the lipid toxin mycolactone. Deeper investigation of M. ulcerans Agy99 resulted in identification of two types of spontaneous deletion variants of pMUM001 within a population of cells that also contained the intact plasmid. These variants arose from recombination between two 8-kb sections of the same plasmid sequence, resulting in the loss of a 65-kb region bearing two of the three mycolactone PKS genes. Investigation of nine diverse M. ulcerans strains by using PCR and Southern hybridization for eight pMUM001 gene sequences confirmed the presence of pMUM001-like elements (collectively called pMUM) in all M. ulcerans strains. Physical mapping of these plasmids revealed that like M. ulcerans Agy99, three strains had undergone major deletions in their mycolactone PKS loci. Online liquid chromatography-sequential mass spectrometry analysis of lipid extracts confirmed that strains with PKS deletions were unable to produce mycolactone or any related cometabolites. Interstrain comparisons of the plasmid gene sequences revealed greater than 98% nucleotide identity, and the phylogeny inferred from these sequences closely mimicked the phylogeny from a previous multilocus sequence typing study in which chromosomally encoded loci were used, a result that is consistent with the hypothesis that M. ulcerans diverged from the closely related organism Mycobacterium marinum by acquiring pMUM. Out results suggest that pMUM is a defining characteristic of M. ulcerans but that in the absence of purifying selection, deletion of plasmid sequences and a corresponding loss of mycolactone production readily arise.

Published
2005

26. RD5-mediated lack of PE_PGRS and PPE-MPTR export in BCG vaccine strains results in strong reduction of antigenic repertoire but little impact on protection

Author

Ates, Louis S., primary, Sayes, Fadel, additional, Frigui, Wafa, additional, Ummels, Roy, additional, Damen, Merel P. M., additional, Bottai, Daria, additional, Behr, Marcel A., additional, van Heijst, Jeroen W. J., additional, Bitter, Wilbert, additional, Majlessi, Laleh, additional, and Brosch, Roland, additional

Published
2018
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27. Multiplexed Quantitation of Intraphagocyte Mycobacterium tuberculosis Secreted Protein Effectors

Author

Sayes, Fadel, primary, Blanc, Catherine, additional, Ates, Louis S., additional, Deboosere, Nathalie, additional, Orgeur, Mickael, additional, Le Chevalier, Fabien, additional, Gröschel, Matthias I., additional, Frigui, Wafa, additional, Song, Ok-Ryul, additional, Lo-Man, Richard, additional, Brossier, Florence, additional, Sougakoff, Wladimir, additional, Bottai, Daria, additional, Brodin, Priscille, additional, Charneau, Pierre, additional, Brosch, Roland, additional, and Majlessi, Laleh, additional

Published
2018
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28. ESAT-6 Secretion-Independent Impact of ESX-1 Genes espF and espG1 on Virulence of Mycobacterium tuberculosis

Author

Bottai, Daria, Majlessi, Laleh, Simeone, Roxane, Frigui, Wafa, Laurent, Christine, Lenormand, Pascal, Chen, Jeffrey, Rosenkrands, Ida, Huerre, Michel, Leclerc, Claude, Cole, Stewart T., Brosch, Roland, Bottai, Daria, Majlessi, Laleh, Simeone, Roxane, Frigui, Wafa, Laurent, Christine, Lenormand, Pascal, Chen, Jeffrey, Rosenkrands, Ida, Huerre, Michel, Leclerc, Claude, Cole, Stewart T., and Brosch, Roland

Abstract

Background. The pathogenesis of Mycobacterium tuberculosis largely depends on the secretion of the 6-kD early secreted antigenic target ESAT-6 (EsxA) and the 10-kD culture filtrate protein CFP-10 (EsxB) via the ESX-1/typeVII secretion system. Although gene products from the core RD1 region have been shown to be deeply implicated in this process, less is known about proteins encoded further upstream in the 5′ region of the ESX-1 cluster, such as the ESX-1 secretion-associated proteins (Esps) EspF or EspG1. Methods. To elucidate the role of EspF/G1, whose orthologs in Mycobacterium marinum and Mycobacterium smegmatis are reportedly involved in EsxA/B secretion, we constructed 3 M. tuberculosis knockout strains deleted for espF, espG1 or the segment corresponding to the combined RD1bcg-RD1mic region of bacille Calmette-Guérin (BCG) and Mycobacterium microti, which also contains espF and espG1. Results. Analysis of these strains revealed that, unlike observations with the model organisms M. smegmatis or M. marinum, disruption of espF and espG1 in M. tuberculosis did not impact the secretion and T cell recognition of EsxA/B but still caused severe attenuation. Conclusions. The separation of the 2 ESX-1-connected phenotypes (ie, EsxA/B secretion and virulence) indicates that EsxA/B secretion is not the only readout for a functional ESX-1 system and suggests that other processes involving EspF/G1 also play important roles in ESX-1-mediated pathogenicity

Published
2017

29. PknG senses amino acid availability to control metabolism and virulence of Mycobacterium tuberculosis

Author

Rieck, Barbara, primary, Degiacomi, Giulia, additional, Zimmermann, Michael, additional, Cascioferro, Alessandro, additional, Boldrin, Francesca, additional, Lazar-Adler, Natalie R., additional, Bottrill, Andrew R., additional, le Chevalier, Fabien, additional, Frigui, Wafa, additional, Bellinzoni, Marco, additional, Lisa, María-Natalia, additional, Alzari, Pedro M., additional, Nguyen, Liem, additional, Brosch, Roland, additional, Sauer, Uwe, additional, Manganelli, Riccardo, additional, and O’Hare, Helen M., additional

Published
2017
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30. Recombinant BCG Expressing ESX-1 of Mycobacterium marinum Combines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection

Author

Gröschel, Matthias I., primary, Sayes, Fadel, additional, Shin, Sung Jae, additional, Frigui, Wafa, additional, Pawlik, Alexandre, additional, Orgeur, Mickael, additional, Canetti, Robin, additional, Honoré, Nadine, additional, Simeone, Roxane, additional, van der Werf, Tjip S., additional, Bitter, Wilbert, additional, Cho, Sang-Nae, additional, Majlessi, Laleh, additional, and Brosch, Roland, additional

Published
2017
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31. Reductive evolution and niche adaptation inferred from the genome of Mycobacterium ulcerans, the causative agent of Buruli ulcer

Author

Stinear, Timothy P., Seemann, Torsten, Frigui, Wafa; Reysset, Gilles, Garnier, Thierry, Meurice, Guillaume, Simon, David, Pidot, Sacha, Bouchier, Christiane, Tichit, Magali, Porter, Jessica L., Ryan, Janine, Ma, Laurence, Johnson, Paul D.R., Jenkin, Grant A., Davies, John K., Small, Pamela L.C., and Jones, Louis M.

Subjects
Mycobacteria -- Genetic aspects, Mycobacteria -- Physiological aspects, Mycobacterium -- Genetic aspects, Mycobacterium -- Physiological aspects, Nucleotide sequence -- Research, Health
Abstract

A complete 5.8-Mb genome sequence of Mycobacterium ulcerans, which causes Buruli ulcer in humans, is described, showing that it comprises two circular replicons, a chromosome of 5632 kb and a virulence plasmid of 174 kb. The data indicate that M. ulcerans has evolved via lateral gene transfer and reductive evolution from the generalist, more rapid-growing environmental species M. marinum to become a niche-adapted specialist.

Published
2007

32. CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection

Author

Sayes, Fadel, primary, Pawlik, Alexandre, additional, Frigui, Wafa, additional, Gröschel, Matthias I., additional, Crommelynck, Samuel, additional, Fayolle, Catherine, additional, Cia, Felipe, additional, Bancroft, Gregory J., additional, Bottai, Daria, additional, Leclerc, Claude, additional, Brosch, Roland, additional, and Majlessi, Laleh, additional

Published
2016
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33. pks5-recombination-mediated surface remodelling in Mycobacterium tuberculosis emergence

Author

Boritsch, Eva C., primary, Frigui, Wafa, additional, Cascioferro, Alessandro, additional, Malaga, Wladimir, additional, Etienne, Gilles, additional, Laval, Françoise, additional, Pawlik, Alexandre, additional, Le Chevalier, Fabien, additional, Orgeur, Mickael, additional, Ma, Laurence, additional, Bouchier, Christiane, additional, Stinear, Timothy P., additional, Supply, Philip, additional, Majlessi, Laleh, additional, Daffé, Mamadou, additional, Guilhot, Christophe, additional, and Brosch, Roland, additional

Published
2016
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34. Genome analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of the etiologic agent of tuberculosis

Author

Supply, Philip, Marceau, Michael, Mangenot, Sophie, Roche, David, Rouanet, Carine, Khanna, Varun, Majlessi, Laleh, Criscuolo, Alexis, Tap, Julien, Pawlik, Alexandre, Fiette, Laurence, Orgeur, Mickael, Fabre, Michel, Parmentier, Cécile, Frigui, Wafa, Simeone, Roxane, Boritsch, Eva C., Debrie, Anne-Sophie, Willery, Eve, Walker, Danielle, Quail, Michael A., Ma, Laurence, Bouchier, Christiane, Salvignol, Grégory, Sayes, Fadel, Cascioferro, Alessandro, Seemann, Torsten, Barbe, Valérie, Locht, Camille, Gutierrez, Maria-Cristina, Leclerc, Claude, Bentley, Stephen, Stinear, Timothy P., Brisse, Sylvain, Médigue, Claudine, Parkhill, Julian, Cruveiller, Stéphane, and Brosch, Roland

Subjects
Mice, Inbred BALB C, Base Sequence, Virulence, Inverted Repeat Sequences, Molecular Sequence Data, Adaptation, Biological, Genetic Variation, Genomics, Mycobacterium tuberculosis, Sequence Analysis, DNA, Polymorphism, Single Nucleotide, Article, Evolution, Molecular, Mice, Species Specificity, Animals, Cluster Analysis, Lung, Genome, Bacterial, Phylogeny, Spleen
Abstract

Global spread and limited genetic variation are hallmarks of M. tuberculosis, the agent of human tuberculosis. In contrast, Mycobacterium canettii and related tubercle bacilli that also cause human tuberculosis and exhibit unusual smooth colony morphology are restricted to East Africa. Here, we sequenced and analyzed the whole genomes of five representative strains of smooth tubercle bacilli (STB) using Sanger (4-5× coverage), 454/Roche (13-18× coverage) and/or Illumina DNA sequencing (45-105× coverage). We show that STB isolates are highly recombinogenic and evolutionarily early branching, with larger genome sizes, higher rates of genetic variation, fewer molecular scars and distinct CRISPR-Cas systems relative to M. tuberculosis. Despite the differences, all tuberculosis-causing mycobacteria share a highly conserved core genome. Mouse infection experiments showed that STB strains are less persistent and virulent than M. tuberculosis. We conclude that M. tuberculosis emerged from an ancestral STB-like pool of mycobacteria by gain of persistence and virulence mechanisms, and we provide insights into the molecular events involved.

Published
2013

35. The changes in mycolic acid structures caused byhadCmutation have a dramatic effect on the virulence ofMycobacterium tuberculosis

Author

Slama, Nawel, primary, Jamet, Stevie, additional, Frigui, Wafa, additional, Pawlik, Alexandre, additional, Bottai, Daria, additional, Laval, Françoise, additional, Constant, Patricia, additional, Lemassu, Anne, additional, Cam, Kaymeuang, additional, Daffé, Mamadou, additional, Brosch, Roland, additional, Eynard, Nathalie, additional, and Quémard, Annaïk, additional

Published
2015
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41. Validation of the reshaped shared epitope HLA-DRB1 classification in rheumatoid arthritis

Author

Michou, Laëtitia, Croiseau, Pascal, Petit-Teixeira, Elisabeth, Tezenas Du Montcel, Sophie, Lemaire, Isabelle, Pierlot, Céline, Osorio, José, Frigui, Wafa, Lasbleiz, Sandra, Quillet, Patrick, Bardin, Thomas, Prum, Bernard, Clerget-Darpoux, Françoise, Cornélis, François, The European Consortium On Rheumatoid Arthritis Families, Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel), Université d'Évry-Val-d'Essonne (UEVE), Génétique épidémiologique et structures des populations humaines (Inserm U535), Epidémiologie, sciences sociales, santé publique (IFR 69), Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Paris 1 Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de Biostatistique, Santé Publique et Information Médicale [CHU Pitié-Salpêtrière] (BIOSPIM ), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire de Biologie, Centre Hospitalier Sud Francilien, CH Evry-Corbeil-CH Evry-Corbeil, Unité de Génétique Clinique Adulte, Hôpital Lariboisière-Fernand-Widal [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Laboratoire Statistique et Génome (SG), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), Consultation de Génétique Adulte, This work was supported by Association Française des Polyarthritiques, Société Française de Rhumatologie, Association Rhumatisme et Travail, Association Polyarctique, Groupe Taitbout, Académie de Médecine, Association de Recherche sur la Polyarthrite, Genopole, Conseil Régional Ile de France, Fondation pour la Recherche Médicale, Université Evry-Val d'Essonne and unrestricted institutional support from Wyeth, Schering-Plough, Pfizer and Amgen., Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Vaillant, Christine, Laboratoire de recherche européen pour la polyarthrite rhumatoïde (GenHotel - EA 3886), Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Panthéon-Sorbonne (UP1)-Université Paris-Sud - Paris 11 (UP11)-École des hautes études en sciences sociales (EHESS)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM), Service de biostatistiques et information médicale [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], and Hôpital Lariboisière

Subjects
[SDV.MHEP.RSOA] Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.MHEP.RSOA]Life Sciences [q-bio]/Human health and pathology/Rhumatology and musculoskeletal system, [SDV.BBM.GTP]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN], [SDV.BBM.GTP] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Genomics [q-bio.GN]
Abstract

Recently, we proposed a classification of HLA-DRB1 alleles that reshapes the shared epitope hypothesis in rheumatoid arthritis (RA); according to this model, RA is associated with the RAA shared epitope sequence (72-74 positions) and the association is modulated by the amino acids at positions 70 and 71, resulting in six genotypes with different RA risks. This was the first model to take into account the association between the HLA-DRB1 gene and RA, and linkage data for that gene. In the present study we tested this classification for validity in an independent sample. A new sample of the same size and population (100 RA French Caucasian families) was genotyped for the HLA-DRB1 gene. The alleles were grouped as proposed in the new classification: S1 alleles for the sequences A-RAA or E-RAA; S2 for Q or D-K-RAA; S3D for D-R-RAA; S3P for Q or R-R-RAA; and X alleles for no RAA sequence. Transmission of the alleles was investigated. Genotype odds ratio (OR) calculations were performed through conditional logistic regression, and we tested the homogeneity of these ORs with those of the 100 first trio families (one case and both parents) previously reported. As previously observed, the S2 and S3P alleles were significantly over-transmitted and the S1, S3D and X alleles were under-transmitted. The latter were grouped as L alleles, resulting in the same three-allele classification. The risk hierarchy of the six derived genotypes was the same: (by decreasing OR and with L/L being the reference genotype) S2/S3P, S2/S2, S3P/S3P, S2/L and S3P/L. The homogeneity test between the ORs of the initial and the replication samples revealed no significant differences. The new classification was therefore considered validated, and both samples were pooled to provide improved estimates of RA risk genotypes from the highest (S2/S3P [OR 22.2, 95% confidence interval 9.9-49.7]) to the lowest (S3P/L [OR 4.4, 95% confidence interval 2.3-8.4]).

Published
2006
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44. Na1.67Mn2.17(MoO4)3

Author

Bouzidi, Chahira, primary, Zid, Mohamed Faouzi, additional, Driss, Ahmed, additional, and Frigui, Wafa, additional

Published
2014
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45. Multiplexed Quantitation of Intraphagocyte Mycobacterium tuberculosisSecreted Protein Effectors

Author

Sayes, Fadel, Blanc, Catherine, Ates, Louis S., Deboosere, Nathalie, Orgeur, Mickael, Le Chevalier, Fabien, Gröschel, Matthias I., Frigui, Wafa, Song, Ok-Ryul, Lo-Man, Richard, Brossier, Florence, Sougakoff, Wladimir, Bottai, Daria, Brodin, Priscille, Charneau, Pierre, Brosch, Roland, and Majlessi, Laleh

Abstract

The pathogenic potential of Mycobacterium tuberculosislargely depends on ESX secretion systems exporting members of the multigenic Esx, Esp, and PE/PPE protein families. To study the secretion and regulation patterns of these proteins while circumventing immune cross-reactions due to their extensive sequence homologies, we developed an approach that relies on the recognition of their MHC class II epitopes by highly discriminative T cell receptors (TCRs) of a panel of T cell hybridomas. The latter were engineered so that each expresses a unique fluorescent reporter linked to specific antigen recognition. The resulting polychromatic and multiplexed imaging assay enabled us to measure the secretion of mycobacterial effectors inside infected host cells. We applied this novel technology to a large panel of mutants, clinical isolates, and host-cell types to explore the host-mycobacteria interplay and its impact on the intracellular bacterial secretome, which also revealed the unexpected capacity of phagocytes from lung granuloma to present mycobacterial antigens via MHC class II.

Published
2018
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47. Genomic analysis of smooth tubercle bacilli provides insights into ancestry and pathoadaptation of Mycobacterium tuberculosis

Author

Supply, Philip, primary, Marceau, Michael, additional, Mangenot, Sophie, additional, Roche, David, additional, Rouanet, Carine, additional, Khanna, Varun, additional, Majlessi, Laleh, additional, Criscuolo, Alexis, additional, Tap, Julien, additional, Pawlik, Alexandre, additional, Fiette, Laurence, additional, Orgeur, Mickael, additional, Fabre, Michel, additional, Parmentier, Cécile, additional, Frigui, Wafa, additional, Simeone, Roxane, additional, Boritsch, Eva C, additional, Debrie, Anne-Sophie, additional, Willery, Eve, additional, Walker, Danielle, additional, Quail, Michael A, additional, Ma, Laurence, additional, Bouchier, Christiane, additional, Salvignol, Grégory, additional, Sayes, Fadel, additional, Cascioferro, Alessandro, additional, Seemann, Torsten, additional, Barbe, Valérie, additional, Locht, Camille, additional, Gutierrez, Maria-Cristina, additional, Leclerc, Claude, additional, Bentley, Stephen D, additional, Stinear, Timothy P, additional, Brisse, Sylvain, additional, Médigue, Claudine, additional, Parkhill, Julian, additional, Cruveiller, Stéphane, additional, and Brosch, Roland, additional

Published
2013
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48. CD4+ T Cells Recognizing PE/PPE Antigens Directly or via Cross Reactivity Are Protective against Pulmonary Mycobacterium tuberculosis Infection.

Author

Sayes, Fadel, Pawlik, Alexandre, Frigui, Wafa, Gröschel, Matthias I., Crommelynck, Samuel, Fayolle, Catherine, Cia, Felipe, Bancroft, Gregory J., Bottai, Daria, Leclerc, Claude, Brosch, Roland, and Majlessi, Laleh

Subjects
T-cell receptor genes, ANTIGENS, LUNG infections, HOST-parasite relationships, MYCOBACTERIUM tuberculosis, VACCINATION, THERAPEUTICS
Abstract

Mycobacterium tuberculosis (Mtb), possesses at least three type VII secretion systems, ESX-1, -3 and -5 that are actively involved in pathogenesis and host-pathogen interaction. We recently showed that an attenuated Mtb vaccine candidate (Mtb Δppe25-pe19), which lacks the characteristic ESX-5-associated pe/ppe genes, but harbors all other components of the ESX-5 system, induces CD4+ T-cell immune responses against non-esx-5-associated PE/PPE protein homologs. These T cells strongly cross-recognize the missing esx-5-associated PE/PPE proteins. Here, we characterized the fine composition of the functional cross-reactive Th1 effector subsets specific to the shared PE/PPE epitopes in mice immunized with the Mtb Δppe25-pe19 vaccine candidate. We provide evidence that the Mtb Δppe25-pe19 strain, despite its significant attenuation, is comparable to the WT Mtb strain with regard to: (i) its antigenic repertoire related to the different ESX systems, (ii) the induced Th1 effector subset composition, (iii) the differentiation status of the Th1 cells induced, and (iv) its particular features at stimulating the innate immune response. Indeed, we found significant contribution of PE/PPE-specific Th1 effector cells in the protective immunity against pulmonary Mtb infection. These results offer detailed insights into the immune mechanisms underlying the remarkable protective efficacy of the live attenuated Mtb Δppe25-pe19 vaccine candidate, as well as the specific potential of PE/PPE proteins as protective immunogens. [ABSTRACT FROM AUTHOR]

Published
2016
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50. Recombinant BCG Expressing ESX-1 of Mycobacterium marinumCombines Low Virulence with Cytosolic Immune Signaling and Improved TB Protection

Author

Gröschel, Matthias I., Sayes, Fadel, Shin, Sung Jae, Frigui, Wafa, Pawlik, Alexandre, Orgeur, Mickael, Canetti, Robin, Honoré, Nadine, Simeone, Roxane, van der Werf, Tjip S., Bitter, Wilbert, Cho, Sang-Nae, Majlessi, Laleh, and Brosch, Roland

Abstract

Recent insights into the mechanisms by which Mycobacterium tuberculosis, the etiologic agent of human tuberculosis, is recognized by cytosolic nucleotide sensors have opened new avenues for rational vaccine design. The only licensed anti-tuberculosis vaccine, Mycobacterium bovisBCG, provides limited protection. A feature of BCG is the partial deletion of the ESX-1 type VII secretion system, which governs phagosomal rupture and cytosolic pattern recognition, key intracellular phenotypes linked to increased immune signaling. Here, by heterologously expressing the esx-1region of Mycobacterium marinumin BCG, we engineered a low-virulence, ESX-1-proficient, recombinant BCG (BCG::ESX-1Mmar) that induces the cGas/STING/TBK1/IRF-3/type I interferon axis and enhances AIM2 and NLRP3 inflammasome activity, resulting in both higher proportions of CD8+T cell effectors against mycobacterial antigens shared with BCG and polyfunctional CD4+Th1 cells specific to ESX-1 antigens. Importantly, independent mouse vaccination models show that BCG::ESX-1Mmarconfers superior protection relative to parental BCG against challenges with highly virulent M. tuberculosis.

Published
2017
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