208 results on '"Neyrolles O"'
Search Results
2. MenT1 toxin (rv0078a) from Mycobacterium tuberculosis H37Rv
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Xu, X., primary, Usher, B., additional, Gutierrez, C., additional, Barriot, R., additional, Arrowsmith, T.J., additional, Han, X., additional, Redder, P., additional, Neyrolles, O., additional, Blower, T.R., additional, and Genevaux, P., additional
- Published
- 2023
- Full Text
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3. MenAT1 toxin-antitoxin complex (rv0078a-rv0078b) from Mycobacterium tuberculosis H37Rv
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Xu, X., primary, Usher, B., additional, Gutierrez, C., additional, Barriot, R., additional, Arrowsmith, T.J., additional, Han, X., additional, Redder, P., additional, Neyrolles, O., additional, Blower, T.R., additional, and Genevaux, P., additional
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- 2023
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4. MRC1 deficiency rewires bone marrow and circulating immune profile in diet-induced obesity
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Nour, J., primary, Moregola, A., additional, Svecla, M., additional, Da Dalt, L., additional, Bellini, R., additional, Neyrolles, O., additional, Fadini, G.P., additional, Rombouts, Y., additional, Albiero, M., additional, Bonacina, F., additional, and Norata, G., additional
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- 2023
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5. Dendritic cell immunoreceptor 2 (DCIR2) deficiency impacts immune cells distribution and atherosclerosis in LDLR-/- mice
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Bellini, R., primary, Moregola, A., additional, Nour, J., additional, Rombouts, Y., additional, Neyrolles, O., additional, Uboldi, P., additional, Bonacina, F., additional, and Norata, G., additional
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- 2023
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6. Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model
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Péricat, D., primary, Leon-Icaza, S. A., additional, Sánchez-Rico, M., additional, Mühle, C., additional, Zoicas, I., additional, Schumacher, F., additional, Planès, R., additional, Mazars, R., additional, Gros, G., additional, Carpinteiro, A., additional, Becker, K. A., additional, Izopet, J., additional, Strub-Wourgaft, N., additional, Sjö, P., additional, Neyrolles, O., additional, Kleuser, B., additional, Limosin, F., additional, Gulbins, E., additional, Kornhuber, J., additional, Meunier, E., additional, Hoertel, N., additional, and Cougoule, C., additional
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- 2023
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7. Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells
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Reversade, Bruno, Planes, R.; Pinilla, M.; Santoni, K.; Hessel, A.; Passemar, C.; Lay, K.; Paillette, P.; Valadao, A.C.; Robinson, K.S.; Bastard, P.; Lam, N.; Fadrique, R.; Rossi, I.; Pericat, D.; Bagayoko, S.; Leon-Icaza, S.A.; Rombouts, Y.; Perouzel, E.; Tiraby, M.; COVID Human Genetic Effort; Zhang, Q.; Cicuta, P.; Jouanguy, E.; Neyrolles, O.; Bryant, C.E.; Floto, A.R.; Goujon, C.; Lei, F.Z.; Martin-Blondel, G.; Silva, S.; Casanova, J.L.; Cougoule, C.; Marcoux, J.; Ravet, E.; Meunier, E., School of Medicine, Reversade, Bruno, Planes, R.; Pinilla, M.; Santoni, K.; Hessel, A.; Passemar, C.; Lay, K.; Paillette, P.; Valadao, A.C.; Robinson, K.S.; Bastard, P.; Lam, N.; Fadrique, R.; Rossi, I.; Pericat, D.; Bagayoko, S.; Leon-Icaza, S.A.; Rombouts, Y.; Perouzel, E.; Tiraby, M.; COVID Human Genetic Effort; Zhang, Q.; Cicuta, P.; Jouanguy, E.; Neyrolles, O.; Bryant, C.E.; Floto, A.R.; Goujon, C.; Lei, F.Z.; Martin-Blondel, G.; Silva, S.; Casanova, J.L.; Cougoule, C.; Marcoux, J.; Ravet, E.; Meunier, E., and School of Medicine
- Abstract
Inflammation observed in SARS-CoV-2-infected patients suggests that inflammasomes, proinflammatory intracellular complexes, regulate various steps of infection. Lung epithelial cells express inflammasome-forming sensors and constitute the primary entry door of SARS-CoV-2. Here, we describe that the NLRP1 in-flammasome detects SARS-CoV-2 infection in human lung epithelial cells. Specifically, human NLRP1 is cleaved at the Q333 site by multiple coronavirus 3CL proteases, which triggers inflammasome assembly and cell death and limits the production of infectious viral particles. Analysis of NLRP1-associated pathways unveils that 3CL proteases also inactivate the pyroptosis executioner Gasdermin D (GSDMD). Subsequently, caspase-3 and GSDME promote alternative cell pyroptosis. Finally, analysis of pyroptosis markers in plasma from COVID-19 patients with characterized severe pneumonia due to autoantibodies against, or inborn errors of, type I interferons (IFNs) highlights GSDME/caspase-3 as potential markers of disease severity. Overall, our findings identify NLRP1 as a sensor of SARS-CoV-2 infection in lung epithelia., Fondation pour la Recherche Med-icale (F.R.M.); European Union (EU); Horizon 2020; ERC StG (INFLAME); ERC StG (ANTIViR); French Ministry of Health; Goupe-ment Interregional de Recherche Clinique et d’Innovation Sud-Ouest Outre-Mer (PHRCI 2020 IMMUNOMARK-COV); LABEX; CIFRE PhD Fellowship; Investissement d'Avenir and foundation Bettencourt; InvivoGen; Mali Ministry of Education; Vaincre La Mucoviscidose (VLM); InvivoGen
- Published
- 2022
8. Rôle des cellules dendritiques humaines dans la tuberculose : protecteur ou non protecteur ?
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Herrmann, J.L., Tailleux, L., Nigou, J., Giquel, B., Puzo, G., Lagrange, P.H., and Neyrolles, O.
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- 2006
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9. Overview of leukocyte 3D migration: necessary role of podosomes for mesenchymal 3D migration: 155
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Cougoule, C., Van-Goethem, E., Le-Cabec, V., Lafouresse, F., Dupré, L., Lugo-Villarino, G., Neyrolles, O., Mehraj, V., Mège, J. L., Behar, A., and Maridonneau-Parini, I.
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- 2012
10. Mycobacterial P1-type ATPases mediate resistance to zinc poisoning in human macrophages: 106
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Botella, H., Peyron, P., Levillain, F., Poincloux, R., Poquet, Y., Brandli, I., Charrière, G. M., Maridonneau-Parini, I., de Chastellier, C., and Neyrolles, O.
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- 2012
11. TBVAC2020: Advancing Tuberculosis Vaccines from Discovery to Clinical Development
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Kaufmann, SHE, Dockrell, H.M., Drager, N., Ho, M.M., McShane, H., Neyrolles, O., Ottenhoff, THM, Patel, B., Roordink, D., Spertini, F., Stenger, S., Thole, J., Verreck, FAW, Williams, A., TBVAC2020 Consortium, Britton, W., Triccas, J., Counoupas, C., Grooten, J., Demoitie, M.A., Romano, M., Mascart, F., Andersen, P., Aagaard, C., Christensen, D., Ruhwald, M., Lindenstrom, T., Neyrolles, O., Charneau, P., Guilhot, C., Peixoto, A., Gilleron, M., Locht, C., Brosch, R., Inchauspe, G., Long, SLT, Kaufmann, S., Weiner, J., Maertzdorf, J., Neuwenhuizen, N., Bastian, M., Stenger, S., Caccamo, N., Goletti, D., Nisini, R., Shin, S.J., Lee, H., Sigal, A., Scriba, T., Walzl, G., Loxton, A., Wilkinson, R., Cardona, P.J., Vilaplana, C., Martin, C., Marinova, D., Aguilo, N., Spertini, F., Aebersold, R., Caron, E., Pinschewer, D., De Libero, G., Siegrist, C.A., Collin, N., Barnier-Quer, C., Sander, P., Verreck, F., Ottenhoff, T., Joosten, S., van Meijgaarden, K., Coppola, M., Geluk, A., Drager, N., Roordink, D., Thole, J., Perrie, Y., Baird, M., Levin, M., Dockrell, H., Smith, S., Fletcher, H., Bancroft, G., Rawkins, A., Clark, S., Ho, M.M., McShane, H., Satti, I., Stylianou, E., Vordermeier, M., and Hogarth, P.
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bacille Calmette–Guérin ,biomarker ,clinical trial ,discovery ,portfolio management ,tuberculosis ,vaccination - Abstract
TBVAC2020 is a research project supported by the Horizon 2020 program of the European Commission (EC). It aims at the discovery and development of novel tuberculosis (TB) vaccines from preclinical research projects to early clinical assessment. The project builds on previous collaborations from 1998 onwards funded through the EC framework programs FP5, FP6, and FP7. It has succeeded in attracting new partners from outstanding laboratories from all over the world, now totaling 40 institutions. Next to the development of novel vaccines, TB biomarker development is also considered an important asset to facilitate rational vaccine selection and development. In addition, TBVAC2020 offers portfolio management that provides selection criteria for entry, gating, and priority settings of novel vaccines at an early developmental stage. The TBVAC2020 consortium coordinated by TBVI facilitates collaboration and early data sharing between partners with the common aim of working toward the development of an effective TB vaccine. Close links with funders and other consortia with shared interests further contribute to this goal.
- Published
- 2017
12. Bacterial diversity in Buruli ulcer skin lesions: Challenges in the clinical microbiome analysis of a skin disease
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Neyrolles, O, Van Leuvenhaege, C, Vandelannoote, K, Affolabi, D, Portaels, F, Sopoh, G, de Jong, BC, Eddyani, M, Meehan, CJ, Neyrolles, O, Van Leuvenhaege, C, Vandelannoote, K, Affolabi, D, Portaels, F, Sopoh, G, de Jong, BC, Eddyani, M, and Meehan, CJ
- Abstract
BACKGROUND: Buruli ulcer (BU) is an infectious disease caused by Mycobacterium ulcerans and considered the third most prevalent mycobacterial disease in humans. Secondary bacterial infections in open BU lesions are the main cause of pain, delayed healing and systemic illness, resulting in prolonged hospital stay. Thus, understanding the diversity of bacteria, termed the microbiome, in these open lesions is important for proper treatment. However, adequately studying the human microbiome in a clinical setting can prove difficult when investigating a neglected tropical skin disease due to its rarity and the setting. METHODOLOGY/PRINCIPAL FINDINGS: Using 16S rRNA sequencing, we determined the microbial composition of 5 BU lesions, 3 non-BU lesions and 3 healthy skin samples. Although no significant differences in diversity were found between BU and non-BU lesions, the former were characterized by an increase of Bacteroidetes compared to the non-BU wounds and the BU lesions also contained significantly more obligate anaerobes. With this molecular-based study, we were also able to detect bacteria that were missed by culture-based methods in previous BU studies. CONCLUSIONS/SIGNIFICANCE: Our study suggests that BU may lead to changes in the skin bacterial community within the lesions. However, in order to determine if such changes hold true across all BU cases and are either a cause or consequence of a specific wound environment, further microbiome studies are necessary. Such skin microbiome analysis requires large sample sizes and lesions from the same body site in many patients, both of which can be difficult for a rare disease. Our study proposes a pipeline for such studies and highlights several drawbacks that must be considered if microbiome analysis is to be utilized for neglected tropical diseases.
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- 2017
13. Spatial patterns of multidrug resistant tuberculosis and relationships to socioeconomic, demographic and household factors in northwest Ethiopia
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Neyrolles, O, Alene, KA, Viney, K, McBryde, ES, Clements, ACA, Neyrolles, O, Alene, KA, Viney, K, McBryde, ES, and Clements, ACA
- Abstract
BACKGROUND: Understanding the geographical distribution of multidrug-resistant tuberculosis (MDR-TB) in high TB burden countries such as Ethiopia is crucial for effective control of TB epidemics in these countries, and thus globally. We present the first spatial analysis of multidrug resistant tuberculosis, and its relationship to socio-economic, demographic and household factors in northwest Ethiopia. METHODS: An ecological study was conducted using data on patients diagnosed with MDR-TB at the University of Gondar Hospital MDR-TB treatment centre, for the period 2010 to 2015. District level population data were extracted from the Ethiopia National and Regional Census Report. Spatial autocorrelation was explored using Moran's I statistic, Local Indicators of Spatial Association (LISA), and the Getis-Ord statistics. A multivariate Poisson regression model was developed with a conditional autoregressive (CAR) prior structure, and with posterior parameters estimated using a Bayesian Markov chain Monte Carlo (MCMC) simulation approach with Gibbs sampling, in WinBUGS. RESULTS: A total of 264 MDR-TB patients were included in the analysis. The overall crude incidence rate of MDR-TB for the six-year period was 3.0 cases per 100,000 population. The highest incidence rate was observed in Metema (21 cases per 100,000 population) and Humera (18 cases per 100,000 population) districts; whereas nine districts had zero cases. Spatial clustering of MDR-TB was observed in districts located in the Ethiopia-Sudan and Ethiopia-Eritrea border regions, where large numbers of seasonal migrants live. Spatial clustering of MDR-TB was positively associated with urbanization (RR: 1.02; 95%CI: 1.01, 1.04) and the percentage of men (RR: 1.58; 95% CI: 1.26, 1.99) in the districts; after accounting for these factors there was no residual spatial clustering. CONCLUSION: Spatial clustering of MDR-TB, fully explained by demographic factors (urbanization and percent male), was detected in the border
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- 2017
14. Mycobacterial P1-Type ATPases Mediate Resistance to Zinc Poisoning in Human Macrophages
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Botella, H, Levillain, F, Poincloux, R, Poquet, Y, Brandli, I, Wang, C, Tailleux, L, Tilleul, S, Charriere, G, Waddel, S, Foti, M, Lugo Villarino, G, Gao, Q, Maridonneau Parini, I, Castagnoli, P, De Chastellier, C, Neyrolles, O, Botella HS, Levillain FP, Poquet YB, Charriere, GM, Waddel, SJ, Maridonneau Parini I, Neyrolles, O., FOTI, MARIA, CASTAGNOLI, PAOLA, Botella, H, Levillain, F, Poincloux, R, Poquet, Y, Brandli, I, Wang, C, Tailleux, L, Tilleul, S, Charriere, G, Waddel, S, Foti, M, Lugo Villarino, G, Gao, Q, Maridonneau Parini, I, Castagnoli, P, De Chastellier, C, Neyrolles, O, Botella HS, Levillain FP, Poquet YB, Charriere, GM, Waddel, SJ, Maridonneau Parini I, Neyrolles, O., FOTI, MARIA, and CASTAGNOLI, PAOLA
- Abstract
Mycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobacterial genes encoding heavy metal efflux P-type ATPases CtpC, CtpG, and CtpV, and host cell metallothioneins and zinc exporter ZnT1, were induced during infection. Consistent with this pattern of gene modulation, we observed a burst of free zinc inside macrophages, and intraphagosomal zinc accumulation within a few hours postinfection. Zinc exposure led to rapid CtpC induction, and ctpC deficiency caused zinc retention within the mycobacterial cytoplasm, leading to impaired intracellular growth of the bacilli. Thus, the use of P 1-type ATPases represents a M. tuberculosis strategy to neutralize the toxic effects of zinc in macrophages. We propose that heavy metal toxicity and its counteraction might represent yet another chapter in the host-microbe arms race. © 2011 Elsevier Inc.
- Published
- 2011
15. Probing host pathogen cross-talk by transcriptional profiling of both Mycobacterium tuberculosis and infected human dendritic cells and macrophages
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Tailleux, L, Waddell, S, Pelizzola, M, Mortellaro, A, Withers, M, Tanne, A, Castagnoli, P, Gicquel, B, Stoker, N, Butcher, P, Foti, M, Neyrolles, O, Waddell, SJ, Stoker, NG, Butcher, PD, Neyrolles, O., CASTAGNOLI, PAOLA, FOTI, MARIA, Tailleux, L, Waddell, S, Pelizzola, M, Mortellaro, A, Withers, M, Tanne, A, Castagnoli, P, Gicquel, B, Stoker, N, Butcher, P, Foti, M, Neyrolles, O, Waddell, SJ, Stoker, NG, Butcher, PD, Neyrolles, O., CASTAGNOLI, PAOLA, and FOTI, MARIA
- Abstract
BACKGROUND: Transcriptional profiling using microarrays provides a unique opportunity to decipher host pathogen cross-talk on the global level. Here, for the first time, we have been able to investigate gene expression changes in both Mycobacterium tuberculosis, a major human pathogen, and its human host cells, macrophages and dendritic cells. METHODOLOGY/PRINCIPAL FINDINGS: In addition to common responses, we could identify eukaryotic and microbial transcriptional signatures that are specific to the cell type involved in the infection process. In particular M. tuberculosis shows a marked stress response when inside dendritic cells, which is in accordance with the low permissivity of these specialized phagocytes to the tubercle bacillus and to other pathogens. In contrast, the mycobacterial transcriptome inside macrophages reflects that of replicating bacteria. On the host cell side, differential responses to infection in macrophages and dendritic cells were identified in genes involved in oxidative stress, intracellular vesicle trafficking and phagosome acidification. CONCLUSIONS/SIGNIFICANCE: This study provides the proof of principle that probing the host and the microbe transcriptomes simultaneously is a valuable means to accessing unique information on host pathogen interactions. Our results also underline the extraordinary plasticity of host cell and pathogen responses to infection, and provide a solid framework to further understand the complex mechanisms involved in immunity to M. tuberculosis and in mycobacterial adaptation to different intracellular environments.
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- 2008
16. Manipulation of the Mononuclear Phagocyte System by Mycobacterium tuberculosis
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Lugo-Villarino, G., primary and Neyrolles, O., additional
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- 2014
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17. Of Clots and Granulomas: Platelets are New Players in Immunity to Tuberculosis
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Lugo-Villarino, G., primary and Neyrolles, O., additional
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- 2014
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18. Host Responses to Melioidosis and Tuberculosis Are Both Dominated by Interferon-Mediated Signaling
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Neyrolles, O, Koh, GCKW, Schreiber, MF, Bautista, R, Maude, RR, Dunachie, S, Limmathurotsakul, D, Day, NPJ, Dougan, G, Peacock, SJ, Neyrolles, O, Koh, GCKW, Schreiber, MF, Bautista, R, Maude, RR, Dunachie, S, Limmathurotsakul, D, Day, NPJ, Dougan, G, and Peacock, SJ
- Abstract
Melioidosis (Burkholderia pseudomallei infection) is a common cause of community-acquired sepsis in Northeast Thailand and northern Australia. B. pseudomallei is a soil saprophyte endemic to Southeast Asia and northern Australia. The clinical presentation of melioidosis may mimic tuberculosis (both cause chronic suppurative lesions unresponsive to conventional antibiotics and both commonly affect the lungs). The two diseases have overlapping risk profiles (e.g., diabetes, corticosteroid use), and both B. pseudomallei and Mycobacterium tuberculosis are intracellular pathogens. There are however important differences: the majority of melioidosis cases are acute, not chronic, and present with severe sepsis and a mortality rate that approaches 50% despite appropriate antimicrobial therapy. By contrast, tuberculosis is characteristically a chronic illness with mortality <2% with appropriate antimicrobial chemotherapy. We examined the gene expression profiles of total peripheral leukocytes in two cohorts of patients, one with acute melioidosis (30 patients and 30 controls) and another with tuberculosis (20 patients and 24 controls). Interferon-mediated responses dominate the host response to both infections, and both type 1 and type 2 interferon responses are important. An 86-gene signature previously thought to be specific for tuberculosis is also found in melioidosis. We conclude that the host responses to melioidosis and to tuberculosis are similar: both are dominated by interferon-signalling pathways and this similarity means gene expression signatures from whole blood do not distinguish between these two diseases.
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- 2013
19. Mycobacterium tuberculosis 19 kDa lipoprotein inhibits mycobacterium induces cytokine production by human macrophages in vitro
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Fa, Post, Manca, C., Neyrolles, O., Ryffel, Bernhard, Db, Young, Kaplan, G., Immunologie et Embryologie Moléculaires (IEM), and Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)
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[SDV.IMM]Life Sciences [q-bio]/Immunology - Published
- 2001
20. Comparative Analysis of Mycobacterium tuberculosis pe and ppe Genes Reveals High Sequence Variation and an Apparent Absence of Selective Constraints
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Neyrolles, O, McEvoy, CRE, Cloete, R, Mueller, B, Schurch, AC, van Helden, PD, Gagneux, S, Warren, RM, Gey van Pittius, NC, Neyrolles, O, McEvoy, CRE, Cloete, R, Mueller, B, Schurch, AC, van Helden, PD, Gagneux, S, Warren, RM, and Gey van Pittius, NC
- Abstract
Mycobacterium tuberculosis complex (MTBC) genomes contain 2 large gene families termed pe and ppe. The function of pe/ppe proteins remains enigmatic but studies suggest that they are secreted or cell surface associated and are involved in bacterial virulence. Previous studies have also shown that some pe/ppe genes are polymorphic, a finding that suggests involvement in antigenic variation. Using comparative sequence analysis of 18 publicly available MTBC whole genome sequences, we have performed alignments of 33 pe (excluding pe_pgrs) and 66 ppe genes in order to detect the frequency and nature of genetic variation. This work has been supplemented by whole gene sequencing of 14 pe/ppe (including 5 pe_pgrs) genes in a cohort of 40 diverse and well defined clinical isolates covering all the main lineages of the M. tuberculosis phylogenetic tree. We show that nsSNP's in pe (excluding pgrs) and ppe genes are 3.0 and 3.3 times higher than in non-pe/ppe genes respectively and that numerous other mutation types are also present at a high frequency. It has previously been shown that non-pe/ppe M. tuberculosis genes display a remarkably low level of purifying selection. Here, we also show that compared to these genes those of the pe/ppe families show a further reduction of selection pressure that suggests neutral evolution. This is inconsistent with the positive selection pressure of "classical" antigenic variation. Finally, by analyzing such a large number of genes we were able to detect large differences in mutation type and frequency between both individual genes and gene sub-families. The high variation rates and absence of selective constraints provides valuable insights into potential pe/ppe function. Since pe/ppe proteins are highly antigenic and have been studied as potential vaccine components these results should also prove informative for aspects of M. tuberculosis vaccine design.
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- 2012
21. Innate immune response to Mycobacterium tuberculosis Beijing and other genotypes
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Wang, C., Peyron, P., Mestre, O., Kaplan, G., Soolingen, D. van, Gao, Q., Gicquel, B., Neyrolles, O., Wang, C., Peyron, P., Mestre, O., Kaplan, G., Soolingen, D. van, Gao, Q., Gicquel, B., and Neyrolles, O.
- Abstract
Contains fulltext : 124335.pdf (publisher's version ) (Open Access), BACKGROUND: As a species, Mycobacterium tuberculosis is more diverse than previously thought. In particular, the Beijing family of M. tuberculosis strains is spreading and evaluating throughout the world and this is giving rise to public health concerns. Genetic diversity within this family has recently been delineated further and a specific genotype, called Bmyc10, has been shown to represent over 60% of all Beijing clinical isolates in several parts of the world. How the host immune system senses and responds to various M. tuberculosis strains may profoundly influence clinical outcome and the relative epidemiological success of the different mycobacterial lineages. We hypothesised that the success of the Bmyc10 group may, at least in part, rely upon its ability to alter innate immune responses and the secretion of cytokines and chemokines by host phagocytes. METHODOLOGY/PRINCIPAL FINDINGS: We infected human macrophages and dendritic cells with a collection of genetically well-defined M. tuberculosis clinical isolates belonging to various mycobacterial families, including Beijing. We analyzed cytokine and chemokine secretion on a semi-global level using antibody arrays allowing the detection of sixty-five immunity-related soluble molecules. Our data indicate that Beijing strains induce significantly less interleukin (IL)-6, tumor necrosis factor (TNF), IL-10 and GRO-alpha than the H37Rv reference strain, a feature that is variously shared by other modern and ancient M. tuberculosis families and which constitutes a signature of the Beijing family as a whole. However, Beijing strains did not differ relative to each other in their ability to modulate cytokine secretion. CONCLUSIONS/SIGNIFICANCE: Our results confirm and expand upon previous reports showing that M. tuberculosis Beijing strains in general are poor in vitro cytokine inducers in human phagocytes. The results suggest that the epidemiological success of the Beijing Bmyc10 is unlikely to rely upon any specifi
- Published
- 2010
22. Sphingosine Kinase-1 (SphK-1) Regulates Mycobacterium smegmatis Infection in Macrophages
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Neyrolles, O, Prakash, H, Lueth, A, Grinkina, N, Holzer, D, Wadgaonkar, R, Gonzalez, AP, Anes, E, Kleuser, B, Neyrolles, O, Prakash, H, Lueth, A, Grinkina, N, Holzer, D, Wadgaonkar, R, Gonzalez, AP, Anes, E, and Kleuser, B
- Abstract
Sphingosine kinase-1 is known to mediate Mycobacterium smegmatis induced inflammatory responses in macrophages, but its role in controlling infection has not been reported to date. We aimed to unravel the significance of SphK-1 in controlling M. smegmatis infection in RAW 264.7 macrophages. Our results demonstrated for the first time that selective inhibition of SphK-1 by either D, L threo dihydrosphingosine (DHS; a competitive inhibitor of Sphk-1) or Sphk-1 siRNA rendered RAW macrophages sensitive to M. smegmatis infection. This was due to the reduction in the expression of iNOs, p38, pp-38, late phagosomal marker, LAMP-2 and stabilization of the RelA (pp-65) subunit of NF-kappaB. This led to a reduction in the generation of NO and secretion of TNF-alpha in infected macrophages. Congruently, overexpression of SphK-1 conferred resistance in macrophages to infection which was due to enhancement in the generation of NO and expression of iNOs, pp38 and LAMP-2. In addition, our results also unraveled a novel regulation of p38MAPK by SphK-1 during M. smegmatis infection and generation of NO in macrophages. Enhanced NO generation and expression of iNOs in SphK-1++ infected macrophages demonstrated their M-1(bright) phenotype of these macrophages. These findings thus suggested a novel antimycobacterial role of SphK-1 in macrophages.
- Published
- 2010
23. ClgR regulation of chaperone and protease systems is essential for Mycobacterium tuberculosis parasitism of the macrophage
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Estorninho, M., Smith, H.E., Thole, J.E.R., Harders-Westerveen, S.F., Kierzek, A., Butler, R.E., Neyrolles, O., Stewart, G.R., Estorninho, M., Smith, H.E., Thole, J.E.R., Harders-Westerveen, S.F., Kierzek, A., Butler, R.E., Neyrolles, O., and Stewart, G.R.
- Abstract
Chaperone and protease systems play essential roles in cellular homeostasis and have vital functions in controlling the abundance of specific cellular proteins involved in processes such as transcription, replication, metabolism and virulence. Bacteria have evolved accurate regulatory systems to control the expression and function of chaperones and potentially destructive proteases. Here, we have used a combination of transcriptomics, proteomics and targeted mutagenesis to reveal that the clp gene regulator (ClgR) of Mycobacterium tuberculosis activates the transcription of at least ten genes, including four that encode protease systems (ClpP1/C, ClpP2/C, PtrB and HtrA-like protease Rv1043c) and three that encode chaperones (Acr2, ClpB and the chaperonin Rv3269). Thus, M. tuberculosis ClgR controls a larger network of protein homeostatic and regulatory systems than ClgR in any other bacterium studied to date. We demonstrate that ClgR-regulated transcriptional activation of these systems is essential for M. tuberculosis to replicate in macrophages. Furthermore, we observe that this defect is manifest early in infection, as M. tuberculosis lacking ClgR is deficient in the ability to control phagosome pH 1 h post-phagocytosis.
- Published
- 2010
24. Editorial: How to play tag? DC-SIGN shows the way!
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Lugo-Villarino, G, primary and Neyrolles, O, additional
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- 2011
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25. Intracellular replication of attenuated Mycobacterium tuberculosis phoP mutant in the absence of host cell cytotoxicity
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FERRER, N, primary, GOMEZ, A, additional, SOTO, C, additional, NEYROLLES, O, additional, GICQUEL, B, additional, PORTILLO, F, additional, and MARTIN, C, additional
- Published
- 2009
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26. Ce que l’on sait de la réponse immunitaire antituberculeuse chez l’homme
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Neyrolles, O., primary and Volatron, A.-C., additional
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- 2008
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27. Contribution of Horizontally Acquired Genomic Islands to the Evolution of the Tubercle Bacilli
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Becq, J., primary, Gutierrez, M. C., additional, Rosas-Magallanes, V., additional, Rauzier, J., additional, Gicquel, B., additional, Neyrolles, O., additional, and Deschavanne, P., additional
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- 2007
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28. Deletion of the 19kDa antigen does not alter the protective efficacy of BCG
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Yeremeev, V.V., primary, Stewart, G.R., additional, Neyrolles, O., additional, Skrabal, K., additional, Avdienko, V.G., additional, Apt, A.S., additional, and Young, D.B., additional
- Published
- 2000
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29. Organization of Ureaplasma urealyticum urease gene cluster and expression in a suppressor strain of Escherichia coli
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Neyrolles, O, primary, Ferris, S, additional, Behbahani, N, additional, Montagnier, L, additional, and Blanchard, A, additional
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- 1996
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30. Emerging trends in the formation & function of tuberculosis granulomas.
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Lugo-Villarino, G., Hudrisier, D., Benard, A., and Neyrolles, O.
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CYTOLOGICAL research ,TUBERCULOSIS ,COMMUNICABLE diseases ,MYCOBACTERIAL diseases ,IMMUNE system ,GRANULOMA - Abstract
The granuloma is an elaborated aggregate of immune cells found in non-infectious as well as infectious diseases. It is a hallmark of tuberculosis (TB). Predominantly thought as a hostdriven strategy to constrain the bacilli and prevent dissemination, recent discoveries indicate the granuloma can also be modulated into an efficient tool to promote microbial pathogenesis. The aim of future studies will certainly focus on better characterization of the mechanisms driving the modulation of the granuloma functions. Here, we provide unique perspectives from both the innate and adaptive immune system in the formation and the role of the TB granuloma. As macrophages (MΦs) comprise the bulk of granulomas, we highlight the emerging concept of MΦ polarization and its potential impact in the microbicide response, and other activities, that may ultimately shape the fate of granulomas. Alternatively, we shed light on the ability of B cells to influence inflammatory status within the granuloma. [ABSTRACT FROM AUTHOR]
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- 2012
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31. Mycoplasma penetrans bacteremia and primary antiphospholipid syndrome.
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Yáñez, Antonio, Cedillo, Lilia, Neyrolles, Olivier, Alonso, Encarnación, Prévost, Marie-Christine, Rojas, Jorge, Watson, Harold L., Blanchard, Alain, Cassell, Gail H., Yáñez, A, Cedillo, L, Neyrolles, O, Alonso, E, Prévost, M C, Rojas, J, Watson, H L, Blanchard, A, and Cassell, G H
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ANTIPHOSPHOLIPID syndrome ,MYCOPLASMA ,BACTEREMIA ,COMPARATIVE studies ,RESEARCH methodology ,MEDICAL cooperation ,MYCOPLASMA diseases ,RESEARCH ,EVALUATION research ,DISEASE complications ,DIAGNOSIS - Abstract
Mycoplasma penetrans, a rare bacterium so far only found in HIV-infected persons, was isolated in the blood and throat of a non-HIV-infected patient with primary antiphospholipid syndrome (whose etiology and pathogenesis are unknown). [ABSTRACT FROM AUTHOR]
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- 1999
32. Key role for DsbA in cell-to-cell spread of Shigella flexneri, permitting secretion of Ipa proteins into interepithelial protrusions.
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Yu, J, Edwards-Jones, B, Neyrolles, O, and Kroll, J S
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DsbA, a disulfide bond catalyst, is necessary for realization of the pathogenic potential of Shigella flexneri. Sh42, a mutant strain differing from wild-type M90TS solely because it expresses nonfunctional DsbA33G (substitution for 33C at the active site), secreted less IpaB and IpaC than M90TS in response to various stimuli in vitro. A kinetic study demonstrated that Sh42 responded more slowly to Congo red than M90TS. By modulating relative concentrations of functional and nonfunctional DsbA within bacteria, functional enzyme has been shown to be necessary for intercellular spread. By confocal microscopy, M90TS dividing in protrusions was shown to secrete Ipa proteins from the septation furrow, anticipating lysis of protrusions, while Sh42 showed minimal Ipa secretion in this location. In the light of a previous demonstration that DsbA is not necessary for entry of epithelial cells, we conclude that a role in virulence of this disulfide bond catalyst lies in facilitating secretion of Ipa proteins specifically within epithelial protrusions, in turn allowing cell-to-cell spread of S. flexneri.
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- 2000
33. Phase variations of the Mycoplasma penetrans main surface lipoprotein increase antigenic diversity.
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Neyrolles, O, Chambaud, I, Ferris, S, Prevost, M C, Sasaki, T, Montagnier, L, and Blanchard, A
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Mycoplasma penetrans is a recently identified mycoplasma, isolated from urine samples collected from human immunodeficiency virus (HIV)-infected patients. Its presence is significantly associated with HIV infection. The major antigen recognized during natural and experimental infections is an abundant P35 lipoprotein which, upon extraction, segregates in the Triton X-114 detergent phase and is the basis of M. penetrans-specific serological assays. We report here that the P35 antigen undergoes spontaneous and reversible phase variation at high frequency, leading to heterogeneous populations of mycoplasmas, even when derived from a clonal lineage. This variation was found to be determined at the transcription level, and although this property is not unique among the members of the class Mollicutes, the mechanism by which it occurs in M. penetrans differs from those previously described for other Mycoplasma species. Indeed, the P35 phase variation was due neither to a p35 gene rearrangement nor to point mutations within the gene itself or its promoter. The P35 phase variation in the different variants obtained was concomitant with modifications in the pattern of other expressed lipoproteins, probably due to regulated expression of selected members of a gene family which was found to potentially encode similar lipoproteins. M. penetrans variants could be selected on the basis of their lack of colony immunoreactivity with a polyclonal antiserum against a Triton X-114 extract, strongly suggesting that the mechanisms involved in altering surface antigen expression might allow evasion of the humoral immune response of the infected host.
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- 1999
34. Rôle des cellules dendritiques humaines dans la tuberculose : protecteur ou non protecteur ?
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Jean-Louis Herrmann, Tailleux L, Nigou J, Giquel B, Puzo G, Ph, Lagrange, Neyrolles O, Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Génétique mycobactérienne - Mycobacterial genetics, Institut Pasteur [Paris] (IP), Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), and Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS)
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MESH: Humans ,MESH: Mycobacterium tuberculosis ,MESH: Dendritic Cells ,MESH: Antigen-Presenting Cells ,Polysaccharides, Bacterial ,Toll-Like Receptors ,Antigen-Presenting Cells ,Dendritic Cells ,Mycobacterium tuberculosis ,[SDV.IMM.II]Life Sciences [q-bio]/Immunology/Innate immunity ,[SDV.MHEP.MI]Life Sciences [q-bio]/Human health and pathology/Infectious diseases ,Humans ,Tuberculosis ,Lectins, C-Type ,MESH: Tuberculosis ,MESH: Polysaccharides, Bacterial ,MESH: Lectins, C-Type ,MESH: Toll-Like Receptors - Abstract
International audience; Mycobacterium tuberculosis, the cause of tuberculosis remains a pathogenic organism capable of infecting a large number of individuals and of resisting the immune response of the infected host. The main constituents of this response are the antigen presenting cells such as dendritic cells, macrophages and T lymphocytes.; IntroductionMycobacterium tuberculosis, agent de la tuberculose, reste un organisme pathogène capable d’infecter un grand nombre d’individus, et de résister à la réponse immune de l’hôte infecté. Les acteurs principaux de cette réponse immune sont les cellules présentatrices d’antigènes comme les cellules dendritiques, les macrophages et les lymphocytes T.État des connaissancesL’étude comparative des interactions entre M. tuberculosis et les cellules présentatrices d’antigène a permis de montrer que les cellules dendritiques ne permettent pas la croissance intracellulaire de M. tuberculosis, à la différence de ce que l’on observe dans les macrophages. Un compartiment intracellulaire hostile crée les conditions d’une bactériostase. M. tuberculosis st internalisé en se liant à un récepteur des cellules dendritiques de type lectine (DC-SIGN).PerspectivesCe récepteur reconnaît des composés sucrés que l’on retrouve à la surface de la paroi de M. tuberculosis. Ce lien sucres-lectine pourrait compenser le lien composés bactériens-récepteur de type Toll, inhibant partiellement la réaction inflammatoire protectrice, ou compensant une réaction inflammatoire excessive.ConclusionsCe lien favoriserait également la persistance de la bactérie à l’état quiescent dans les cellules dendritiques, et l’adaptation réciproque de l’hôte et de la bactérie au cours du temps.
35. Genetic determination of the effect of post-translational modification on the innate immune response to the 19 kDa lipoprotein of Mycobacterium tuberculosis
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Herrmann Jean-Louis, Sullivan Susan M, Patel Janisha, Martineau Adrian R, Stewart Graham R, Newton Sandra M, Wilkinson Katalin A, Neyrolles Olivier, Young Douglas B, and Wilkinson Robert J
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Microbiology ,QR1-502 - Abstract
Abstract Background The 19 kDa lipoprotein of Mycobacterium tuberculosis (MTB) is an important target of the innate immune response. To investigate the effect of post-translation modification of this protein on innate recognition in the context of the whole bacillus, we derived a recombinant M. tuberculosis H37Rv that lacked the 19 kDa gene (Δ19) and complemented this strain by reintroduction of the 19 kDa gene into the chromosome as a single copy to produce Δ19::19. We also reintroduced the 19 kDa gene in two modified forms that lacked motifs for acylation (Δ19::19NA) and O-glycosylation (Δ19::19NOG). Results Both acylation and O-glycosylation were necessary for the protein to remain within the cell. IL-1 Beta secretion from human monocytes was significantly reduced by deletion of the 19 kDa gene (p < 0.02). Complementation by the wild type, but not the mutagenised gene reversed this phenotype. The effect of deletion and complementation on IL-12p40 and TNF secretion was less marked with no statistically significant differences between strains. Although deletion of the 19 kDa reduced apoptosis, an effect that could also only be reversed by complementation with the wild type gene, the results were variable between donors and did not achieve statistical significance. Conclusion These results confirm in the context of the whole bacillus an important role for post-translational modification of the 19 kDa on both the cellular location and immune response to this protein.
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- 2009
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36. Sexual inequality in tuberculosis.
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Neyrolles O, Quintana-Murci L, Neyrolles, Olivier, and Quintana-Murci, Lluis
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- 2009
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37. Mycobacterial P1-Type ATPases Mediate Resistance to Zinc Poisoning in Human Macrophages
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Paola Ricciardi Castagnoli, Simon J. Waddell, Isabelle Maridonneau-Parini, Pascale Peyron, Sylvain Tilleul, Renaud Poincloux, Ludovic Tailleux, Yannick Poquet, Chantal de Chastellier, Qian Gao, Philip D. Butcher, Florence Levillain, Chuan Wang, Hélène Botella, Olivier Neyrolles, Guillaume M. Charrière, Brigitte Gicquel, Geanncarlo Lugo-Villarino, Irène Brandli, Maria Foti, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université de Toulouse (UT)-Université de Toulouse (UT)-Centre National de la Recherche Scientifique (CNRS), Dynamique de la membrane et du cytosquelette, Compartimentation et dynamique cellulaires (CDC), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut Curie [Paris]-Centre National de la Recherche Scientifique (CNRS), Centre d'Immunologie de Marseille - Luminy (CIML), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Department of Medical Sciences, Key Laboratory of Medical Molecular Virology - Fudan University, Fudan University [Shanghai], Génétique mycobactérienne - Mycobacterial genetics, Institut Pasteur [Paris] (IP), Neurobiologie, plasticité tissulaire et métabolisme énergétique (NPTME), Brighton and Sussex Medical School (BSMS), Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), St George's, University of London, Singapore Immunology Network (SIgN), Biomedical Sciences Institute (BMSI), Génétique et biochimie des microorganismes (GBM), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées, Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Aix Marseille Université (AMU), Institut Pasteur [Paris], Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), Università degli Studi di Milano-Bicocca [Milano] (UNIMIB), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Botella, H, Levillain, F, Poincloux, R, Poquet, Y, Brandli, I, Wang, C, Tailleux, L, Tilleul, S, Charriere, G, Waddel, S, Foti, M, Lugo Villarino, G, Gao, Q, Maridonneau Parini, I, Castagnoli, P, De Chastellier, C, and Neyrolles, O
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Cancer Research ,MESH: Mycobacterium tuberculosis ,ATPase ,medicine.disease_cause ,Q1 ,MESH: Zinc ,Mice ,Mycobacterium Tuberculosis, macrophages ,Metal poisoning ,MESH: Animals ,MESH: Tuberculosis ,Cells, Cultured ,Phagosome ,0303 health sciences ,Mice, Inbred BALB C ,MED/04 - PATOLOGIA GENERALE ,3. Good health ,Zinc ,QR180 ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,Female ,Efflux ,Intracellular ,MESH: Cells, Cultured ,MESH: Mice, Inbred BALB C ,chemistry.chemical_element ,Biology ,Microbiology ,Article ,03 medical and health sciences ,Virology ,Immunology and Microbiology(all) ,MESH: Bacterial Proton-Translocating ATPases ,medicine ,Animals ,Humans ,Tuberculosis ,MESH: Mice ,Molecular Biology ,030304 developmental biology ,QR0075 ,MESH: Humans ,030306 microbiology ,Macrophages ,MESH: Macrophages ,Mycobacterium tuberculosis ,chemistry ,Cytoplasm ,Bacterial Proton-Translocating ATPases ,Zinc toxicity ,biology.protein ,Parasitology ,MESH: Female - Abstract
Summary Mycobacterium tuberculosis thrives within macrophages by residing in phagosomes and preventing them from maturing and fusing with lysosomes. A parallel transcriptional survey of intracellular mycobacteria and their host macrophages revealed signatures of heavy metal poisoning. In particular, mycobacterial genes encoding heavy metal efflux P-type ATPases CtpC, CtpG, and CtpV, and host cell metallothioneins and zinc exporter ZnT1, were induced during infection. Consistent with this pattern of gene modulation, we observed a burst of free zinc inside macrophages, and intraphagosomal zinc accumulation within a few hours postinfection. Zinc exposure led to rapid CtpC induction, and ctpC deficiency caused zinc retention within the mycobacterial cytoplasm, leading to impaired intracellular growth of the bacilli. Thus, the use of P1-type ATPases represents a M. tuberculosis strategy to neutralize the toxic effects of zinc in macrophages. We propose that heavy metal toxicity and its counteraction might represent yet another chapter in the host-microbe arms race., Highlights ► Zinc accumulates in the M. tuberculosis (Mtb) phagosome in macrophages (Mϕ) ► Mtb P1-type ATPases, including CtpC, are induced upon exposure to zinc inside Mϕ ► CtpC enables Mtb resistance to zinc poisoning and intracellular survival in Mϕ ► P1-type zinc efflux ATPase ZntA null E. coli is highly susceptible to Mϕ killing
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- 2011
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38. Factors associated with adherence to treatment with isoniazid for the prevention of tuberculosis amongst people living with HIV/AIDS: a systematic review of qualitative data
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Andrew Booth, Henock B. Taddese, Titilola Makanjuola, and Neyrolles, O
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Bacterial Diseases ,HIV opportunistic infections ,Antitubercular Agents ,HIV Infections ,Global Health ,Social and Behavioral Sciences ,Sociology ,Health care ,Multidisciplinary ,Social Research ,Coinfection ,Socioeconomic Aspects of Health ,AIDS ,Systematic review ,Infectious diseases ,Medicine ,Public Health ,Behavioral and Social Aspects of Health ,Research Article ,medicine.medical_specialty ,Tuberculosis ,Systematic Reviews ,Clinical Research Design ,General Science & Technology ,Science ,Sexually Transmitted Diseases ,Qualitative property ,Viral diseases ,Medication Adherence ,Social support ,Acquired immunodeficiency syndrome (AIDS) ,MD Multidisciplinary ,medicine ,Isoniazid ,Humans ,Psychiatry ,Developing Countries ,Acquired Immunodeficiency Syndrome ,business.industry ,Tropical Diseases (Non-Neglected) ,HIV ,medicine.disease ,Critical appraisal ,Socioeconomic Factors ,Family medicine ,Preventive Medicine ,business ,Qualitative research - Abstract
Objective\ud \ud To systematically identify from qualitative data in the published literature the main barriers to adherence to isoniazid preventive therapy (IPT) for tuberculosis (TB) among people living with HIV/AIDS (PLWHA).\ud \ud Methods\ud \ud We searched ten data sources, including MEDLINE and EMBASE for articles published in peer-reviewed journals from inception through to December 2011 for evidence relevant to IPT for TB in relation to PLWHA. Studies were assessed for quality using the CASP critical appraisal tool for qualitative studies. Data extracted from studies were then analysed thematically using thematic synthesis.\ud \ud Results\ud \ud Eight studies, two of which were conducted within the same clinical trial, met the inclusion criteria. In addition to the influence of personal characteristics, five overarching themes were identified: Individual personal beliefs; HIV treatment and related issues; Socio-economic factors; Family and other social support factors, and Relationships with health providers. The review confirms current understanding of adherence to treatment as influenced by patients' understanding of, and beliefs related to treatment regimens. This is in-turn influenced by broader factors, namely: socio-economic factors such as poverty and lack of health facilities; the level of support available to patients from family and other networks and the stigma that emanates from these relationships; and relationships with health providers, which in-turn become a delicate issue given the sensitivity of dealing with two chronic diseases of significant morbidity and mortality toll. HIV treatment related issues also influence adherence to IPT, whereby challenges related to the acceptance, organisation and administration of these two long-term treatment regimens and stigma related to HIV/AIDS, are seen to be major factors.\ud \ud Conclusion\ud \ud Understanding this complex interplay of factors more clearly is essential for healthcare decision-makers to be able to achieve the level of adherence required to effectively mitigate the threat posed by co-infection with TB and HIV/AIDS in developing countries.
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- 2014
39. Probing Host Pathogen Cross-Talk by Transcriptional Profiling of Both Mycobacterium tuberculosis and Infected Human Dendritic Cells and Macrophages
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Mattia Pelizzola, Paola Ricciardi Castagnoli, Philip D. Butcher, Neil G. Stoker, Olivier Neyrolles, Alessandra Mortellaro, Simon J. Waddell, Antoine Tanne, Michael Withers, Maria Foti, Brigitte Gicquel, Ludovic Tailleux, Tailleux, L, Waddell, S, Pelizzola, M, Mortellaro, A, Withers, M, Tanne, A, Castagnoli, P, Gicquel, B, Stoker, N, Butcher, P, Foti, M, Neyrolles, O, Génétique mycobactérienne - Mycobacterial genetics, Institut Pasteur [Paris] (IP), St George's, University of London, Università degli Studi di Milano-Bicocca = University of Milano-Bicocca (UNIMIB), Royal Veterinary College [London], University of London [London], and This work was supported by a 6th Framework Programme Priority [1] grant (Molecular Markers of M. tuberculosis Early Interactions with Host Phagocytes, MM-TB, number LSHP-CT-2004-012187) from the European Community. The whole genome M. tuberculosis microarray was constructed and analysed at St George's University of London as part of the multi-collaborative microbial pathogen microarray facility BuGS, for which funding from The Wellcome Trust's Functional Genomics Resources Initiative is acknowledged (grant number 062511). P.Ricciardi-Castagnoli is a recipient of a EU M.Curie Chair Award.
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MESH: Mycobacterium tuberculosis ,Transcription, Genetic ,Macrophage ,[SDV]Life Sciences [q-bio] ,Immunology/Innate Immunity ,lcsh:Medicine ,Microbiology/Innate Immunity ,Mycobacterium tuberculosi ,Infectious Diseases/Bacterial Infections ,Transcriptome ,Immunology/Leukocyte Signaling and Gene Expression ,lcsh:Science ,Pathogen ,Multidisciplinary ,MESH: Dendritic Cells ,biology ,MED/04 - PATOLOGIA GENERALE ,Genetics and Genomics/Gene Expression ,Genetics and Genomics/Bioinformatics ,Microbiology/Immunity to Infections ,Cell biology ,QR180 ,[SDV.IMM]Life Sciences [q-bio]/Immunology ,DNA microarray ,Research Article ,Tuberculosis ,Cell Biology/Microbial Physiology and Metabolism ,Dendritic Cell ,Microbiology ,Mycobacterium tuberculosis ,MESH: Gene Expression Profiling ,Immunity ,Immunology/Immunity to Infections ,medicine ,Humans ,Cell Biology/Gene Expression ,QR0075 ,MESH: Humans ,Macrophages ,Infectious Diseases/Respiratory Infections ,MESH: Transcription, Genetic ,Gene Expression Profiling ,Intracellular parasite ,lcsh:R ,MESH: Macrophages ,Dendritic Cells ,medicine.disease ,biology.organism_classification ,[SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology ,R1 ,Gene expression profiling ,Immunology/Immune Response ,lcsh:Q - Abstract
BACKGROUND: Transcriptional profiling using microarrays provides a unique opportunity to decipher host pathogen cross-talk on the global level. Here, for the first time, we have been able to investigate gene expression changes in both Mycobacterium tuberculosis, a major human pathogen, and its human host cells, macrophages and dendritic cells. \ud \ud METHODOLOGY/PRINCIPAL FINDINGS: In addition to common responses, we could identify eukaryotic and microbial transcriptional signatures that are specific to the cell type involved in the infection process. In particular M. tuberculosis shows a marked stress response when inside dendritic cells, which is in accordance with the low permissivity of these specialized phagocytes to the tubercle bacillus and to other pathogens. In contrast, the mycobacterial transcriptome inside macrophages reflects that of replicating bacteria. On the host cell side, differential responses to infection in macrophages and dendritic cells were identified in genes involved in oxidative stress, intracellular vesicle trafficking and phagosome acidification. \ud \ud CONCLUSIONS/SIGNIFICANCE: This study provides the proof of principle that probing the host and the microbe transcriptomes simultaneously is a valuable means to accessing unique information on host pathogen interactions. Our results also underline the extraordinary plasticity of host cell and pathogen responses to infection, and provide a solid framework to further understand the complex mechanisms involved in immunity to M. tuberculosis and in mycobacterial adaptation to different intracellular environments.
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- 2008
40. Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells
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Rémi Planès, Miriam Pinilla, Karin Santoni, Audrey Hessel, Charlotte Passemar, Kenneth Lay, Perrine Paillette, Ana-Luiza Chaves Valadão, Kim Samirah Robinson, Paul Bastard, Nathaniel Lam, Ricardo Fadrique, Ida Rossi, David Pericat, Salimata Bagayoko, Stephen Adonai Leon-Icaza, Yoann Rombouts, Eric Perouzel, Michèle Tiraby, Qian Zhang, Pietro Cicuta, Emmanuelle Jouanguy, Olivier Neyrolles, Clare E. Bryant, Andres R. Floto, Caroline Goujon, Franklin Zhong Lei, Guillaume Martin-Blondel, Stein Silva, Jean-Laurent Casanova, Céline Cougoule, Bruno Reversade, Julien Marcoux, Emmanuel Ravet, Etienne Meunier, Institut de pharmacologie et de biologie structurale (IPBS), Université Toulouse III - Paul Sabatier (UT3), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Centre National de la Recherche Scientifique (CNRS), InvivoGen Europe, Institut de Recherche en Infectiologie de Montpellier (IRIM), Centre National de la Recherche Scientifique (CNRS)-Université de Montpellier (UM), Molecular Immunity Unit [Cambridge, UK] (Department of Medicine), University of Cambridge [UK] (CAM), Institute of Medical Biology [Singapore Singapore], Genome Institute of Singapore (GIS), Agency for science, technology and research [Singapore] (A*STAR), Human genetics of infectious diseases : Mendelian predisposition (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Department of Veterinary Medicine, University of Cambridge, Cambridge, UK, School of Clinical Medicine, Cavendish Laboratory, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Lee Kong Chian School of Medicine, Nanyang Technological University [Singapour], Skin Research Institute of Singapore [Singapore, Singapore] (SRIS / A*STAR), Service Maladies infectieuses et tropicales [CHU Toulouse], Pôle Inflammation, infection, immunologie et loco-moteur [CHU Toulouse] (Pôle I3LM Toulouse), Centre Hospitalier Universitaire de Toulouse (CHU Toulouse)-Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Institut Toulousain des Maladies Infectieuses et Inflammatoires (Infinity), Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Service de réanimation infantile [CHU Purpan], Centre Hospitalier Universitaire de Toulouse (CHU Toulouse), Howard Hughes Medical Institute [New York] (HHMI), Howard Hughes Medical Institute (HHMI)-New York University School of Medicine, NYU System (NYU)-NYU System (NYU)-Rockefeller University [New York]-Columbia University Irving Medical Center (CUIMC), Institute of Molecular and Cell Biology, National University of Singapore (NUS)-Agency for science, technology and research [Singapore] (A*STAR), Yong Loo Lin School of Medicine [Singapore], Koç University, This project was funded by grants from the Fondation pour la Recherche Médicale (F.R.M.) and the ERC StG (INFLAME) to E.M., the ERC StG (ANTIViR) to C.G., and the French Ministry of Health with the participation of the Groupement Interrégional de Recherche Clinique et d’Innovation Sud-Ouest Outre-Mer (PHRCI 2020 IMMUNOMARK-COV) to G.-M.B. The ASB3 structure is supported by LABEX, Investissement d’Avenir and foundation Bettencourt grants to O.N. M.P. and R.P. were, respectively, funded by a CIFRE PhD fellowship and a research grant from InvivoGen. S.B. is supported by a PhD fellowship from Mali Ministry of Education and from the FRM (FDT 12794)., ANR-12-BSV3-0002,B-TB,Rôle des lymphocytes B dans l'immunité et l'inflammation tuberculeuse(2012), ANR-18-CE44-0005,DCIR-TB,Etude des mécanismes impliqués dans la modulation de la signalisation par les interférons de type I et l'immunité anti-tuberculeuse par la lectine de type C DCIR(2018), Cougoule, Céline, BLANC - Rôle des lymphocytes B dans l'immunité et l'inflammation tuberculeuse - - B-TB2012 - ANR-12-BSV3-0002 - BLANC - VALID, APPEL À PROJETS GÉNÉRIQUE 2018 - Etude des mécanismes impliqués dans la modulation de la signalisation par les interférons de type I et l'immunité anti-tuberculeuse par la lectine de type C DCIR - - DCIR-TB2018 - ANR-18-CE44-0005 - AAPG2018 - VALID, Center for Reproductive Medicine, ACS - Heart failure & arrhythmias, Amsterdam Reproduction & Development, Reversade, Bruno, Planes, R., Pinilla, M., Santoni, K., Hessel, A., Passemar, C., Lay, K., Paillette, P., Valadao, A.C., Robinson, K.S., Bastard, P., Lam, N., Fadrique, R., Rossi, I., Pericat, D., Bagayoko, S., Leon-Icaza, S.A., Rombouts, Y., Perouzel, E., Tiraby, M., COVID Human Genetic Effort, Zhang, Q., Cicuta, P., Jouanguy, E., Neyrolles, O., Bryant, C.E., Floto, A.R., Goujon, C., Lei, F.Z., Martin-Blondel, G., Silva, S., Casanova, J.L., Cougoule, C., Marcoux, J., Ravet, E., Meunier, E., and School of Medicine
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Pore Forming Cytotoxic Proteins ,Caspase 3 ,Inflammasomes ,SARS-CoV-2 ,[SDV]Life Sciences [q-bio] ,pyroptosis ,COVID-19 ,NLR Proteins ,Cell Biology ,3CL proteases ,Epithelial cells ,Gasdermins ,NLRP1 inflammasome ,Pyroptosis ,Phosphate-Binding Proteins ,epithelial cells ,[SDV] Life Sciences [q-bio] ,Humans ,Biochemistry and molecular biology ,Cell biology ,Lung ,Molecular Biology ,Coronavirus 3C Proteases ,Peptide Hydrolases - Abstract
Inflammation observed in SARS-CoV-2-infected patients suggests that inflammasomes, proinflammatory intracellular complexes, regulate various steps of infection. Lung epithelial cells express inflammasome-forming sensors and constitute the primary entry door of SARS-CoV-2. Here, we describe that the NLRP1 in-flammasome detects SARS-CoV-2 infection in human lung epithelial cells. Specifically, human NLRP1 is cleaved at the Q333 site by multiple coronavirus 3CL proteases, which triggers inflammasome assembly and cell death and limits the production of infectious viral particles. Analysis of NLRP1-associated pathways unveils that 3CL proteases also inactivate the pyroptosis executioner Gasdermin D (GSDMD). Subsequently, caspase-3 and GSDME promote alternative cell pyroptosis. Finally, analysis of pyroptosis markers in plasma from COVID-19 patients with characterized severe pneumonia due to autoantibodies against, or inborn errors of, type I interferons (IFNs) highlights GSDME/caspase-3 as potential markers of disease severity. Overall, our findings identify NLRP1 as a sensor of SARS-CoV-2 infection in lung epithelia., Fondation pour la Recherche Med-icale (F.R.M.); European Union (EU); Horizon 2020; ERC StG (INFLAME); ERC StG (ANTIViR); French Ministry of Health; Goupe-ment Interregional de Recherche Clinique et d’Innovation Sud-Ouest Outre-Mer (PHRCI 2020 IMMUNOMARK-COV); LABEX; CIFRE PhD Fellowship; Investissement d'Avenir and foundation Bettencourt; InvivoGen; Mali Ministry of Education; Vaincre La Mucoviscidose (VLM); InvivoGen
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41. Maintenance of cell wall remodeling and vesicle production are connected in Mycobacterium tuberculosis .
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Salgueiro V, Bertol J, Gutierrez C, Serrano-Mestre JL, Ferrer-Luzon N, Palacios A, Pasquina-Lemonche L, Espalliat A, Lerma L, Weinrick B, Lavin JL, Elortza F, Azkalgorta M, Prieto A, Buendía-Nacarino P, Luque-García JL, Neyrolles O, Cava F, Hobbs JK, Sanz J, and Prados-Rosales R
- Abstract
Pathogenic and nonpathogenic mycobacteria secrete extracellular vesicles (EVs) under various conditions. EVs produced by Mycobacterium tuberculosis ( Mtb ) have raised significant interest for their potential in cell communication, nutrient acquisition, and immune evasion. However, the relevance of vesicle secretion during tuberculosis infection remains unknown due to the limited understanding of mycobacterial vesicle biogenesis. We have previously shown that a transposon mutant in the LCP-related gene virR ( virR
mut ) manifested a strong attenuated phenotype during experimental macrophage and murine infections, concomitant to enhanced vesicle release. In this study, we aimed to understand the role of VirR in the vesicle production process in Mtb . We employ genetic, transcriptional, proteomics, ultrastructural and biochemical methods to investigate the underlying processes explaining the enhanced vesiculogenesis phenomenon observed in the virRmut . Our results establish that VirR is critical to sustain proper cell permeability via regulation of cell envelope remodeling possibly through the interaction with similar cell envelope proteins, which control the link between peptidoglycan and arabinogalactan. These findings advance our understanding of mycobacterial extracellular vesicle biogenesis and suggest that these set of proteins could be attractive targets for therapeutic intervention.- Published
- 2024
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42. Mycobacterial D-serine impairs TB control.
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Caouaille M, Hudrisier D, and Neyrolles O
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- Humans, Animals, Tuberculosis immunology, Mice, Serine metabolism, Mycobacterium tuberculosis immunology
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- 2024
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43. Elevated glycolytic metabolism of monocytes limits the generation of HIF1A-driven migratory dendritic cells in tuberculosis.
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Maio M, Barros J, Joly M, Vahlas Z, Marín Franco JL, Genoula M, Monard SC, Vecchione MB, Fuentes F, Gonzalez Polo V, Quiroga MF, Vermeulen M, Vu Manh TP, Argüello RJ, Inwentarz S, Musella R, Ciallella L, González Montaner P, Palmero D, Lugo Villarino G, Sasiain MDC, Neyrolles O, Vérollet C, and Balboa L
- Subjects
- Humans, Animals, Mice, Toll-Like Receptor 2 metabolism, Mice, Inbred C57BL, Female, Dendritic Cells metabolism, Dendritic Cells immunology, Glycolysis, Monocytes metabolism, Monocytes immunology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Mycobacterium tuberculosis immunology, Cell Movement, Tuberculosis immunology, Tuberculosis metabolism, Tuberculosis microbiology
- Abstract
During tuberculosis (TB), migration of dendritic cells (DCs) from the site of infection to the draining lymph nodes is known to be impaired, hindering the rapid development of protective T-cell-mediated immunity. However, the mechanisms involved in the delayed migration of DCs during TB are still poorly defined. Here, we found that infection of DCs with Mycobacterium tuberculosis (Mtb) triggers HIF1A-mediated aerobic glycolysis in a TLR2-dependent manner, and that this metabolic profile is essential for DC migration. In particular, the lactate dehydrogenase inhibitor oxamate and the HIF1A inhibitor PX-478 abrogated Mtb-induced DC migration in vitro to the lymphoid tissue-specific chemokine CCL21, and in vivo to lymph nodes in mice. Strikingly, we found that although monocytes from TB patients are inherently biased toward glycolysis metabolism, they differentiate into poorly glycolytic and poorly migratory DCs compared with healthy subjects. Taken together, these data suggest that because of their preexisting glycolytic state, circulating monocytes from TB patients are refractory to differentiation into migratory DCs, which may explain the delayed migration of these cells during the disease and opens avenues for host-directed therapies for TB., Competing Interests: MM, JB, MJ, ZV, JM, MG, SM, MV, FF, VG, MQ, MV, TV, RA, SI, RM, LC, PG, DP, GL, MS, ON, CV, LB No competing interests declared, (© 2023, Maio et al.)
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- 2024
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44. A host-directed oxadiazole compound potentiates antituberculosis treatment via zinc poisoning in human macrophages and in a mouse model of infection.
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Maure A, Lawarée E, Fiorentino F, Pawlik A, Gona S, Giraud-Gatineau A, Eldridge MJG, Danckaert A, Hardy D, Frigui W, Keck C, Gutierrez C, Neyrolles O, Aulner N, Mai A, Hamon M, Barreiro LB, Brodin P, Brosch R, Rotili D, and Tailleux L
- Subjects
- Animals, Humans, Mice, Mice, Inbred C57BL, Female, Drug Synergism, Oxadiazoles pharmacology, Antitubercular Agents pharmacology, Antitubercular Agents therapeutic use, Mycobacterium tuberculosis drug effects, Zinc metabolism, Macrophages drug effects, Macrophages metabolism, Disease Models, Animal, Tuberculosis drug therapy
- 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., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Maure et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2024
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45. Dual-action compounds unleash a one-two punch against tuberculosis.
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Le Mouëllic W, Poquet Y, and Neyrolles O
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- Humans, Bacterial Proteins metabolism, Virulence, Mycobacterium tuberculosis metabolism, Tuberculosis drug therapy
- Abstract
In this issue of Cell Chemical Biology, Gries et al.
1 employ an innovative screening approach to identify anti-tuberculosis compounds with dual modes of action: anti-virulence against the type VII secretion system ESX-1 and enhanced ethionamide efficacy. These compounds hold promise for developing multi-target tuberculosis drugs with potential clinical applications., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)- Published
- 2024
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46. The C-type lectin DCIR contributes to the immune response and pathogenesis of colorectal cancer.
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Trimaglio G, Sneperger T, Raymond BBA, Gilles N, Näser E, Locard-Paulet M, Ijsselsteijn ME, Brouwer TP, Ecalard R, Roelands J, Matsumoto N, Colom A, Habch M, de Miranda NFCC, Vergnolle N, Devaud C, Neyrolles O, and Rombouts Y
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- Animals, Humans, Mice, Dendritic Cells, Immunity, Lectins, C-Type metabolism, Tumor Microenvironment, CD8-Positive T-Lymphocytes metabolism, Colorectal Neoplasms metabolism
- Abstract
Development and progression of malignancies are accompanied and influenced by alterations in the surrounding immune microenvironment. Understanding the cellular and molecular interactions between immune cells and cancer cells has not only provided important fundamental insights into the disease, but has also led to the development of new immunotherapies. The C-type lectin Dendritic Cell ImmunoReceptor (DCIR) is primarily expressed by myeloid cells and is an important regulator of immune homeostasis, as demonstrated in various autoimmune, infectious and inflammatory contexts. Yet, the impact of DCIR on cancer development remains largely unknown. Analysis of available transcriptomic data of colorectal cancer (CRC) patients revealed that high DCIR gene expression is associated with improved patients' survival, immunologically "hot" tumors and high immunologic constant of rejection, thus arguing for a protective and immunoregulatory role of DCIR in CRC. In line with these correlative data, we found that deficiency of DCIR1, the murine homologue of human DCIR, leads to the development of significantly larger tumors in an orthotopic murine model of CRC. This phenotype is accompanied by an altered phenotype of tumor-associated macrophages (TAMs) and a reduction in the percentage of activated effector CD4
+ and CD8+ T cells in CRC tumors of DCIR1-deficient mice. Overall, our results show that DCIR promotes antitumor immunity in CRC, making it an attractive target for the future development of immunotherapies to fight the second deadliest cancer in the world., (© 2024. The Author(s).)- Published
- 2024
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47. Modulation of bacterial membrane proteins activity by clustering into plasma membrane nanodomains.
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Dupuy P, Gutierrez C, and Neyrolles O
- Abstract
Recent research has demonstrated specific protein clustering within membrane subdomains in bacteria, challenging the long-held belief that prokaryotes lack these subdomains. This mini review provides examples of bacterial membrane protein clustering, discussing the benefits of protein assembly in membranes and highlighting how clustering regulates protein activity., (© 2023 John Wiley & Sons Ltd.)
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- 2023
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48. MenT nucleotidyltransferase toxins extend tRNA acceptor stems and can be inhibited by asymmetrical antitoxin binding.
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Xu X, Usher B, Gutierrez C, Barriot R, Arrowsmith TJ, Han X, Redder P, Neyrolles O, Blower TR, and Genevaux P
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- Humans, Nucleotidyltransferases, Nucleotides, RNA, Transfer genetics, Antitoxins genetics, Toxins, Biological, Mycobacterium tuberculosis
- Abstract
Mycobacterium tuberculosis, the bacterium responsible for human tuberculosis, has a genome encoding a remarkably high number of toxin-antitoxin systems of largely unknown function. We have recently shown that the M. tuberculosis genome encodes four of a widespread, MenAT family of nucleotidyltransferase toxin-antitoxin systems. In this study we characterize MenAT1, using tRNA sequencing to demonstrate MenT1 tRNA modification activity. MenT1 activity is blocked by MenA1, a short protein antitoxin unrelated to the MenA3 kinase. X-ray crystallographic analysis shows blockage of the conserved MenT fold by asymmetric binding of MenA1 across two MenT1 protomers, forming a heterotrimeric toxin-antitoxin complex. Finally, we also demonstrate tRNA modification by toxin MenT4, indicating conserved activity across the MenT family. Our study highlights variation in tRNA target preferences by MenT toxins, selective use of nucleotide substrates, and diverse modes of MenA antitoxin activity., (© 2023. The Author(s).)
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- 2023
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49. A Mycobacterium tuberculosis Effector Targets Mitochondrion, Controls Energy Metabolism, and Limits Cytochrome c Exit.
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Martin M, deVisch A, Boudehen YM, Barthe P, Gutierrez C, Turapov O, Aydogan T, Heriaud L, Gracy J, Neyrolles O, Mukamolova GV, Letourneur F, and Cohen-Gonsaud M
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- Humans, Cytochromes c metabolism, Energy Metabolism, Mitochondria metabolism, Host-Pathogen Interactions, Mycobacterium tuberculosis metabolism, Tuberculosis microbiology
- Abstract
Host metabolism reprogramming is a key feature of Mycobacterium tuberculosis ( Mtb ) infection that enables the survival of this pathogen within phagocytic cells and modulates the immune response facilitating the spread of the tuberculosis disease. Here, we demonstrate that a previously uncharacterized secreted protein from Mtb , Rv1813c, manipulates the host metabolism by targeting mitochondria. When expressed in eukaryotic cells, the protein is delivered to the mitochondrial intermembrane space and promotes the enhancement of host ATP production by boosting the oxidative phosphorylation metabolic pathway. Furthermore, the release of cytochrome c from mitochondria, an early apoptotic event in response to short-term oxidative stress, is delayed in Rv1813c-expressing cells. This study reveals a novel class of mitochondria targeting effectors from Mtb that might participate in host cell metabolic reprogramming and apoptosis control during Mtb infections. IMPORTANCE In this article, using a combination of techniques (bioinformatics, structural biology, and cell biology), we identified and characterized a new class of effectors present only in intracellular mycobacteria. These proteins specifically target host cell mitochondria when ectopically expressed in cells. We showed that one member of this family (Rv1813c) affects mitochondria metabolism in a way that might twist the immune response. This effector also inhibits the cytochrome c exit from mitochondria, suggesting that it might alter normal host cell apoptotic capacities, one of the first defenses of immune cells against Mtb infection., Competing Interests: The authors declare no conflict of interest.
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- 2023
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50. The fat is in the lysosome: how Mycobacterium tuberculosis tricks macrophages into storing lipids.
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Rombouts Y and Neyrolles O
- Subjects
- Humans, Macrophages metabolism, Lysosomes metabolism, Mycobacterium tuberculosis, Tuberculosis metabolism
- Abstract
Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), infects primarily macrophages, causing them to differentiate into lipid-laden foamy macrophages that are a primary source of tissue destruction in patients with TB. In this issue of the JCI, Bedard et al. demonstrate that 1-tuberculosinyladenosine, a virulence factor produced by M. tuberculosis, caused lysosomal dysfunction associated with lipid storage in the phagolysosome of macrophages in a manner that mimicked lysosomal storage diseases. This work sheds light on how M. tuberculosis manipulates host lipid metabolism for its survival and opens avenues toward host-directed therapy against TB.
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- 2023
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