165 results on '"Neyrolles O"'
Search Results
2. MRC1 deficiency rewires bone marrow and circulating immune profile in diet-induced obesity
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Nour, J., Moregola, A., Svecla, M., Da Dalt, L., Bellini, R., Neyrolles, O., Fadini, G.P., Rombouts, Y., Albiero, M., Bonacina, F., and Norata, G.
- Published
- 2023
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3. 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.
- Published
- 2012
4. 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.
- Published
- 2012
5. 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.
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- 2017
6. 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
7. 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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8. 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]
- Published
- 1999
9. WS16.04 When cystic fibrosis triggers a protective immunity against tuberculosis: loss of CFTR confers resistance to Mycobacterium marinum infections in cystic fibrosis zebrafish models.
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Cornelie, S., Renshaw, S., Neyrolles, O., Floto, A., and Bernut, A.
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MYCOBACTERIAL diseases , *CYSTIC fibrosis , *TUBERCULOSIS , *CYSTIC fibrosis transmembrane conductance regulator , *BRACHYDANIO - Published
- 2024
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10. 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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11. 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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12. 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.
- Published
- 2014
13. 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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14. 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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15. 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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16. 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
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- 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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17. 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
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- 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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18. 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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19. 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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20. Modulation of bacterial membrane proteins activity by clustering into plasma membrane nanodomains.
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Dupuy P, Gutierrez C, and Neyrolles O
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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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21. 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).)
- Published
- 2023
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22. A Mycobacterium tuberculosis Effector Targets Mitochondrion, Controls Energy Metabolism, and Limits Cytochrome c Exit.
- Author
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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
- Subjects
- 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.
- Published
- 2023
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23. The fat is in the lysosome: how Mycobacterium tuberculosis tricks macrophages into storing lipids.
- Author
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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.
- Published
- 2023
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24. The molecular basis and downstream immune consequences of mycobacteria-host cell interactions.
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Daher W, Pichler V, Karam J, Neyrolles O, and Kremer L
- Subjects
- Macrophages microbiology, Cell Communication, Host-Pathogen Interactions, Mycobacterium
- Abstract
Pathogenic mycobacteria gain entry to their hosts by inhalation or ingestion where they adhere to different cell types and are subsequently internalized by professional phagocytic cells, such as macrophages or dendritic cells. Multiple pathogen-associated molecular patterns present on the mycobacterial surface are recognized by and interact with a diverse panel of phagocytic pattern recognition receptors, representing the first step of the infection process. This review summarizes the current knowledge on the numerous host cell receptors and their associated mycobacterial ligands or adhesins. It further discusses the downstream molecular and cellular events resulting from the engagement of the various receptor-mediated pathways, leading to either intracellular survival of mycobacteria or to activation of host immune defenses. The content presented herein on adhesins and host receptors may serve as a resource for those developing novel therapeutic approaches, e.g. in the design of antiadhesin molecules to prevent bacterial attachment and infection. The collection of mycobacterial surface molecules highlighted in this review may also provide potential new therapeutic targets, diagnostic markers, or vaccine candidates to combat these notoriously challenging and persistent pathogens., (© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.)
- Published
- 2023
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25. Dendritic cell marker Clec4a4 deficiency limits atherosclerosis progression.
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Bellini R, Moregola A, Nour J, Rombouts Y, Neyrolles O, Uboldi P, Bonacina F, and Norata GD
- Abstract
Background and Aims: Atherogenesis results from altered lipid metabolism and impaired immune response. Emerging evidence has suggested that dendritic cells (DCs) participate to atherosclerosis-related immune response, but their impact is scarcely characterized. Clec4a4 or DCIR2 (Dendritic cell immunoreceptor 2) is a C-type lectin receptor, mainly expressed by CD8α
- DCs, able to modulate T cell immunity. However, whether this DC subset could play a role in the atherogenesis is still poorly understood. Thus, the aim of this study is to investigate whether the absence of Clec4a4 could affect atherosclerosis-related immune response and atherosclerosis itself., Methods: Dcir2-/- Ldlr-/- and Ldlr-/- mice were fed a standard diet or cholesterol-enriched diet for 12 weeks. Subsequently, the profile of circulating and lymph nodes-resident immune cells was investigated together with the analysis of plasma lipid levels and atherosclerotic plaque extension in the aorta., Results: Here, we show that Clec4a4 expression is downregulated under hypercholesterolemia and its deficiency in Ldlr-/- mice results in the reduction of atherosclerotic plaque formation, together with altered lipid metabolism and impaired myeloid immune cell distribution., Conclusions: Our findings suggest a pro-atherosclerotic role of Clec4a4 in experimental atherosclerosis., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)- Published
- 2022
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26. Mannose Receptor Deficiency Impacts Bone Marrow and Circulating Immune Cells during High Fat Diet Induced Obesity.
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Nour J, Moregola A, Svecla M, Da Dalt L, Bellini R, Neyrolles O, Fadini GP, Rombouts Y, Albiero M, Bonacina F, and Norata GD
- Abstract
The mannose receptor C-type 1 (Mrc1) is a C-type lectin receptor expressed on the immune cells and sinusoidal endothelial cells (ECs) of several tissues, including the bone marrow (BM). Parallel to systemic metabolic alterations and hematopoietic cell proliferation, high-fat diet (HFD) feeding increases the expression of Mrc1 in sinusoidal ECs, thus calling for the investigation of its role in bone marrow cell reprogramming and the metabolic profile during obesity. Mrc1
-/- mice and wild-type (WT) littermates were fed an HFD (45% Kcal/diet) for 20 weeks. Weight gain was monitored during the diet regimen and glucose and insulin tolerance were assessed. Extensive flow cytometry profiling, histological, and proteomic analyses were performed. After HFD feeding, Mrc1-/- mice presented impaired medullary hematopoiesis with reduced myeloid progenitors and mature cells in parallel with an increase in BM adipocytes compared to controls. Accordingly, circulating levels of neutrophils and pro-inflammatory monocytes decreased in Mrc1-/- mice together with reduced infiltration of macrophages in the visceral adipose tissue and the liver compared to controls. Liver histological profiling coupled with untargeted proteomic analysis revealed that Mrc1-/- mice presented decreased liver steatosis and the downregulation of proteins belonging to pathways involved in liver dysfunction. This profile was reflected by improved glucose and insulin response and reduced weight gain during HFD feeding in Mrc1-/- mice compared to controls. Our data show that during HFD feeding, mannose receptor deficiency impacts BM and circulating immune cell subsets, which is associated with reduced systemic inflammation and resistance to obesity development., Competing Interests: The authors declare no conflict of interest.- Published
- 2022
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27. Antiviral and Anti-Inflammatory Activities of Fluoxetine in a SARS-CoV-2 Infection Mouse Model.
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Péricat D, Leon-Icaza SA, Sanchez Rico M, Mühle C, Zoicas I, Schumacher F, Planès R, Mazars R, Gros G, Carpinteiro A, Becker KA, Izopet J, Strub-Wourgaft N, Sjö P, Neyrolles O, Kleuser B, Limosin F, Gulbins E, Kornhuber J, Meunier E, Hoertel N, and Cougoule C
- Subjects
- Animals, Mice, Anti-Inflammatory Agents pharmacology, Anti-Inflammatory Agents therapeutic use, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Ceramides, Disease Models, Animal, Fluoxetine pharmacology, Fluoxetine therapeutic use, SARS-CoV-2, COVID-19 Drug Treatment
- Abstract
The coronavirus disease 2019 (COVID-19) pandemic continues to cause significant morbidity and mortality worldwide. Since a large portion of the world's population is currently unvaccinated or incompletely vaccinated and has limited access to approved treatments against COVID-19, there is an urgent need to continue research on treatment options, especially those at low cost and which are immediately available to patients, particularly in low- and middle-income countries. Prior in vitro and observational studies have shown that fluoxetine, possibly through its inhibitory effect on the acid sphingomyelinase/ceramide system, could be a promising antiviral and anti-inflammatory treatment against COVID-19. In this report, we evaluated the potential antiviral and anti-inflammatory activities of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and against variants of concern in vitro, i.e., SARS-CoV-2 ancestral strain, Alpha B.1.1.7, Gamma P1, Delta B1.617 and Omicron BA.5. Fluoxetine, administrated after SARS-CoV-2 infection, significantly reduced lung tissue viral titres and expression of several inflammatory markers (i.e., IL-6, TNFα, CCL2 and CXCL10). It also inhibited the replication of all variants of concern in vitro. A modulation of the ceramide system in the lung tissues, as reflected by the increase in the ratio HexCer 16:0/Cer 16:0 in fluoxetine-treated mice, may contribute to explain these effects. Our findings demonstrate the antiviral and anti-inflammatory properties of fluoxetine in a K18-hACE2 mouse model of SARS-CoV-2 infection, and its in vitro antiviral activity against variants of concern, establishing fluoxetine as a very promising candidate for the prevention and treatment of SARS-CoV-2 infection and disease pathogenesis.
- Published
- 2022
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28. Dysregulation of the IFN-I signaling pathway by Mycobacterium tuberculosis leads to exacerbation of HIV-1 infection of macrophages.
- Author
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Dupont M, Rousset S, Manh TV, Monard SC, Pingris K, Souriant S, Vahlas Z, Velez T, Poincloux R, Maridonneau-Parini I 1st, Neyrolles O, Lugo-Villarino G, and Vérollet C
- Subjects
- Humans, HIV-1, Signal Transduction, Coinfection, HIV Infections, Macrophages metabolism, Macrophages virology, Mycobacterium tuberculosis, Tuberculosis metabolism, Interferon Type I metabolism
- Abstract
While tuberculosis (TB) is a risk factor in HIV-1-infected individuals, the mechanisms by which Mycobacterium tuberculosis (Mtb), the agent of TB in humans, worsens HIV-1 pathogenesis still need to be fully elucidated. Recently, we showed that HIV-1 infection and spread are exacerbated in macrophages exposed to TB-associated microenvironments. Transcriptomic analysis of macrophages conditioned with medium of Mtb-infected human macrophages (cmMTB) revealed an up-regulation of the typeI interferon (IFN-I) pathway, characterized by the overexpression of IFN-inducible genes. Historically, IFN-I are well known for their antiviral functions, but our previous work showed that this is not the case in the context of coinfection with HIV-1. Here, we show that the IFN-I response signature in cmMTB-treated macrophages matches the one observed in the blood of active TB patients, and depends on the timing of incubation with cmMTB. This suggests that the timing of macrophage's exposure to IFN-I can impact their capacity to control HIV-1 infection. Strikingly, we found that cmMTB-treated macrophages are hyporesponsive to extrastimulation with exogenous IFN-I, used to mimic HIV-1 infection. Yet, depleting STAT1 by gene silencing to block the IFN-I signaling pathway reduced TB-induced exacerbation of HIV-1 infection. Altogether, by aiming to understand why TB-derived IFN-I preexposure of macrophages did not induce antiviral immunity against HIV-1, we demonstrated that these cells are hyporesponsive to exogenous IFN-I, a phenomenon that prevents macrophage activation against HIV-1., (©2022 Society for Leukocyte Biology.)
- Published
- 2022
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29. Mycobacterial resistance to zinc poisoning requires assembly of P-ATPase-containing membrane metal efflux platforms.
- Author
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Boudehen YM, Faucher M, Maréchal X, Miras R, Rech J, Rombouts Y, Sénèque O, Wallat M, Demange P, Bouet JY, Saurel O, Catty P, Gutierrez C, and Neyrolles O
- Subjects
- Biological Transport, Humans, Metals metabolism, Zinc metabolism, Adenosine Triphosphatases metabolism, Mycobacterium tuberculosis genetics, Mycobacterium tuberculosis metabolism
- Abstract
The human pathogen Mycobacterium tuberculosis requires a P
1B -ATPase metal exporter, CtpC (Rv3270), for resistance to zinc poisoning. Here, we show that zinc resistance also depends on a chaperone-like protein, PacL1 (Rv3269). PacL1 contains a transmembrane domain, a cytoplasmic region with glutamine/alanine repeats and a C-terminal metal-binding motif (MBM). PacL1 binds Zn2+ , but the MBM is required only at high zinc concentrations. PacL1 co-localizes with CtpC in dynamic foci in the mycobacterial plasma membrane, and the two proteins form high molecular weight complexes. Foci formation does not require flotillin nor the PacL1 MBM. However, deletion of the PacL1 Glu/Ala repeats leads to loss of CtpC and sensitivity to zinc. Genes pacL1 and ctpC appear to be in the same operon, and homologous gene pairs are found in the genomes of other bacteria. Furthermore, PacL1 colocalizes and functions redundantly with other PacL orthologs in M. tuberculosis. Overall, our results indicate that PacL proteins may act as scaffolds that assemble P-ATPase-containing metal efflux platforms mediating bacterial resistance to metal poisoning., (© 2022. The Author(s).)- Published
- 2022
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30. Human NLRP1 is a sensor of pathogenic coronavirus 3CL proteases in lung epithelial cells.
- Author
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Planès R, Pinilla M, Santoni K, Hessel A, Passemar C, Lay K, Paillette P, Valadão AC, Robinson KS, Bastard P, Lam N, Fadrique R, Rossi I, Pericat D, Bagayoko S, Leon-Icaza SA, Rombouts Y, Perouzel E, Tiraby M, Zhang Q, Cicuta P, Jouanguy E, Neyrolles O, Bryant CE, Floto AR, Goujon C, Lei FZ, Martin-Blondel G, Silva S, Casanova JL, Cougoule C, Reversade B, Marcoux J, Ravet E, and Meunier E
- Subjects
- Caspase 3 metabolism, Humans, Lung metabolism, Lung virology, Peptide Hydrolases genetics, Peptide Hydrolases metabolism, Phosphate-Binding Proteins genetics, Phosphate-Binding Proteins metabolism, Pore Forming Cytotoxic Proteins genetics, Pore Forming Cytotoxic Proteins metabolism, Pyroptosis, COVID-19 genetics, COVID-19 metabolism, COVID-19 virology, Coronavirus 3C Proteases genetics, Coronavirus 3C Proteases metabolism, Epithelial Cells metabolism, Inflammasomes genetics, Inflammasomes metabolism, NLR Proteins genetics, NLR Proteins metabolism, SARS-CoV-2 enzymology, SARS-CoV-2 genetics, SARS-CoV-2 metabolism, SARS-CoV-2 pathogenicity
- 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 inflammasome 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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)
- Published
- 2022
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31. A lentiviral vector expressing a dendritic cell-targeting multimer induces mucosal anti-mycobacterial CD4 + T-cell immunity.
- Author
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Anna F, Lopez J, Moncoq F, Blanc C, Authié P, Noirat A, Fert I, Souque P, Nevo F, Pawlik A, Hardy D, Goyard S, Hudrisier D, Brosch R, Guinet F, Neyrolles O, Charneau P, and Majlessi L
- Subjects
- Mice, Animals, Dendritic Cells, Mice, Inbred C57BL, Genetic Vectors genetics, CD8-Positive T-Lymphocytes, CD4-Positive T-Lymphocytes
- Abstract
Most viral vectors, including the potently immunogenic lentiviral vectors (LVs), only poorly direct antigens to the MHC-II endosomal pathway and elicit CD4
+ T cells. We developed a new generation of LVs encoding antigen-bearing monomers of collectins substituted at their C-terminal domain with the CD40 ligand ectodomain to target and activate antigen-presenting cells. Host cells transduced with such optimized LVs secreted soluble collectin-antigen polymers with the potential to be endocytosed in vivo and reach the MHC-II pathway. In the murine tuberculosis model, such LVs induced efficient MHC-II antigenic presentation and triggered both CD8+ and CD4+ T cells at the systemic and mucosal levels. They also conferred a significant booster effect, consistent with the importance of CD4+ T cells for protection against Mycobacterium tuberculosis. Given the pivotal role of CD4+ T cells in orchestrating innate and adaptive immunity, this strategy could have a broad range of applications in the vaccinology field., (© 2022. The Author(s).)- Published
- 2022
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32. ILC precursors differentiate into metabolically distinct ILC1-like cells during Mycobacterium tuberculosis infection.
- Author
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Corral D, Charton A, Krauss MZ, Blanquart E, Levillain F, Lefrançais E, Sneperger T, Vahlas Z, Girard JP, Eberl G, Poquet Y, Guéry JC, Argüello RJ, Belkaid Y, Mayer-Barber KD, Hepworth MR, Neyrolles O, and Hudrisier D
- Subjects
- Cytokines, Humans, Inflammation, Lymphocytes, Immunity, Innate, Tuberculosis
- Abstract
Tissue-resident innate lymphoid cells (ILCs) regulate tissue homeostasis, protect against pathogens at mucosal surfaces, and are key players at the interface of innate and adaptive immunity. How ILCs adapt their phenotype and function to environmental cues within tissues remains to be fully understood. Here, we show that Mycobacterium tuberculosis (Mtb) infection alters the phenotype and function of lung IL-18Rα
+ ILC toward a protective interferon-γ-producing ILC1-like population. This differentiation is controlled by type 1 cytokines and is associated with a glycolytic program. Moreover, a BCG-driven type I milieu enhances the early generation of ILC1-like cells during secondary challenge with Mtb. Collectively, our data reveal how tissue-resident ILCs adapt to type 1 inflammation toward a pathogen-tailored immune response., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2022
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33. Mycobacteria-host interactions in human bronchiolar airway organoids.
- Author
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Iakobachvili N, Leon-Icaza SA, Knoops K, Sachs N, Mazères S, Simeone R, Peixoto A, Bernard C, Murris-Espin M, Mazières J, Cam K, Chalut C, Guilhot C, López-Iglesias C, Ravelli RBG, Neyrolles O, Meunier E, Lugo-Villarino G, Clevers H, Cougoule C, and Peters PJ
- Subjects
- Humans, Macrophages microbiology, Nontuberculous Mycobacteria, Organoids, Mycobacterium abscessus, Mycobacterium tuberculosis, Tuberculosis microbiology
- Abstract
Respiratory infections remain a major global health concern. Tuberculosis is one of the top 10 causes of death worldwide, while infections with Non-Tuberculous Mycobacteria are rising globally. Recent advances in human tissue modeling offer a unique opportunity to grow different human "organs" in vitro, including the human airway, that faithfully recapitulates lung architecture and function. Here, we have explored the potential of human airway organoids (AOs) as a novel system in which to assess the very early steps of mycobacterial infection. We reveal that Mycobacterium tuberculosis (Mtb) and Mycobacterium abscessus (Mabs) mainly reside as extracellular bacteria and infect epithelial cells with very low efficiency. While the AO microenvironment was able to control, but not eliminate Mtb, Mabs thrives. We demonstrate that AOs responded to infection by modulating cytokine, antimicrobial peptide, and mucin gene expression. Given the importance of myeloid cells in mycobacterial infection, we co-cultured infected AOs with human monocyte-derived macrophages and found that these cells interact with the organoid epithelium. We conclude that adult stem cell (ASC)-derived AOs can be used to decipher very early events of mycobacteria infection in human settings thus offering new avenues for fundamental and therapeutic research., (© 2021 The Authors. Molecular Microbiology published by John Wiley & Sons Ltd.)
- Published
- 2022
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34. 100 years of the Bacillus Calmette-Guérin vaccine.
- Author
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Bettencourt PJG, Joosten SA, Lindestam Arlehamn CS, Behr MA, Locht C, and Neyrolles O
- Subjects
- Adjuvants, Immunologic, BCG Vaccine
- Published
- 2021
- Full Text
- View/download PDF
35. Modulation of Cystatin C in Human Macrophages Improves Anti-Mycobacterial Immune Responses to Mycobacterium tuberculosis Infection and Coinfection With HIV.
- Author
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Pires D, Calado M, Velez T, Mandal M, Catalão MJ, Neyrolles O, Lugo-Villarino G, Vérollet C, Azevedo-Pereira JM, and Anes E
- Subjects
- CD4-Positive T-Lymphocytes immunology, Cells, Cultured, Cystatin C genetics, HIV-1, Humans, Interferon-gamma immunology, Macrophages microbiology, Mycobacterium tuberculosis, Coinfection immunology, Cystatin C immunology, HIV Infections immunology, Macrophages immunology, Tuberculosis immunology
- Abstract
Tuberculosis owes its resurgence as a major global health threat mostly to the emergence of drug resistance and coinfection with HIV. The synergy between HIV and Mycobacterium tuberculosis (Mtb) modifies the host immune environment to enhance both viral and bacterial replication and spread. In the lung immune context, both pathogens infect macrophages, establishing favorable intracellular niches. Both manipulate the endocytic pathway in order to avoid destruction. Relevant players of the endocytic pathway to control pathogens include endolysosomal proteases, cathepsins, and their natural inhibitors, cystatins. Here, a mapping of the human macrophage transcriptome for type I and II cystatins during Mtb, HIV, or Mtb-HIV infection displayed different profiles of gene expression, revealing cystatin C as a potential target to control mycobacterial infection as well as HIV coinfection. We found that cystatin C silencing in macrophages significantly improves the intracellular killing of Mtb, which was concomitant with an increased general proteolytic activity of cathepsins. In addition, downmodulation of cystatin C led to an improved expression of the human leukocyte antigen (HLA) class II in macrophages and an increased CD4
+ T-lymphocyte proliferation along with enhanced IFN-γ secretion. Overall, our results suggest that the targeting of cystatin C in human macrophages represents a promising approach to improve the control of mycobacterial infections including multidrug-resistant (MDR) TB., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Pires, Calado, Velez, Mandal, Catalão, Neyrolles, Lugo-Villarino, Vérollet, Azevedo-Pereira and Anes.)- Published
- 2021
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36. A Pulmonary Lactobacillus murinus Strain Induces Th17 and RORγt + Regulatory T Cells and Reduces Lung Inflammation in Tuberculosis.
- Author
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Bernard-Raichon L, Colom A, Monard SC, Namouchi A, Cescato M, Garnier H, Leon-Icaza SA, Métais A, Dumas A, Corral D, Ghebrendrias N, Guilloton P, Vérollet C, Hudrisier D, Remot A, Langella P, Thomas M, Cougoule C, Neyrolles O, and Lugo-Villarino G
- Subjects
- Animals, Cells, Cultured, Disease Models, Animal, Humans, Lung microbiology, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Pneumonia, Lactobacillus physiology, Lung immunology, Mycobacterium tuberculosis physiology, Nuclear Receptor Subfamily 1, Group F, Member 3 metabolism, T-Lymphocytes, Regulatory immunology, Th17 Cells immunology, Tuberculosis, Pulmonary immunology
- Abstract
The lungs harbor multiple resident microbial communities, otherwise known as the microbiota. There is an emerging interest in deciphering whether the pulmonary microbiota modulate local immunity, and whether this knowledge could shed light on mechanisms operating in the response to respiratory pathogens. In this study, we investigate the capacity of a pulmonary Lactobacillus strain to modulate the lung T cell compartment and assess its prophylactic potential upon infection with Mycobacterium tuberculosis , the etiological agent of tuberculosis. In naive mice, we report that a Lactobacillus murinus ( Lagilactobacillus murinus ) strain (CNCM I-5314) increases the presence of lung Th17 cells and of a regulatory T cell (Treg) subset known as RORγt
+ Tregs. In particular, intranasal but not intragastric administration of CNCM I-5314 increases the expansion of these lung leukocytes, suggesting a local rather than systemic effect. Resident Th17 and RORγt+ Tregs display an immunosuppressive phenotype that is accentuated by CNCM I-5314. Despite the well-known ability of M. tuberculosis to modulate lung immunity, the immunomodulatory effect by CNCM I-5314 is dominant, as Th17 and RORγt+ Tregs are still highly increased in the lung at 42-d postinfection. Importantly, CNCM I-5314 administration in M. tuberculosis -infected mice results in reduction of pulmonary inflammation, without increasing M. tuberculosis burden. Collectively, our findings provide evidence for an immunomodulatory capacity of CNCM I-5314 at steady state and in a model of chronic inflammation in which it can display a protective role, suggesting that L. murinus strains found in the lung may shape local T cells in mice and, perhaps, in humans., (Copyright © 2021 by The American Association of Immunologists, Inc.)- Published
- 2021
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37. Antimicrobial zinc toxicity in Mϕs: ZnT1 pays the toll.
- Author
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Neyrolles O
- Subjects
- Zinc metabolism, Anti-Infective Agents, Cation Transport Proteins
- Abstract
Transition metals, including zinc, are essential to all living organisms. They are also toxic in high amounts, and their intracellular concentration must be tightly regulated. In this edition of JLB, Stocks et al. report that the zinc transporter, ZnT1 (SLC30A1) is induced by TLR4 activation in Mϕs, in which it contributes to zinc accumulation in Escherichia coli-containing phagosomes, resulting in increased bacterial clearance., (©2020 Society for Leukocyte Biology.)
- Published
- 2021
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38. Dissemination of Mycobacterium tuberculosis is associated to a SIGLEC1 null variant that limits antigen exchange via trafficking extracellular vesicles.
- Author
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Benet S, Gálvez C, Drobniewski F, Kontsevaya I, Arias L, Monguió-Tortajada M, Erkizia I, Urrea V, Ong RY, Luquin M, Dupont M, Chojnacki J, Dalmau J, Cardona P, Neyrolles O, Lugo-Villarino G, Vérollet C, Julián E, Furrer H, Günthard HF, Crocker PR, Tapia G, Borràs FE, Fellay J, McLaren PJ, Telenti A, Cardona PJ, Clotet B, Vilaplana C, Martinez-Picado J, and Izquierdo-Useros N
- Subjects
- Animals, Antigen Presentation immunology, Humans, Immunity genetics, Lung microbiology, Lung pathology, Mice, Mycobacterium tuberculosis pathogenicity, Sialic Acid Binding Ig-like Lectin 1 immunology, Tuberculosis, Lymph Node microbiology, Tuberculosis, Lymph Node pathology, Tuberculosis, Pulmonary microbiology, Tuberculosis, Pulmonary pathology, Extracellular Vesicles immunology, Mycobacterium tuberculosis immunology, Sialic Acid Binding Ig-like Lectin 1 genetics
- Abstract
The identification of individuals with null alleles enables studying how the loss of gene function affects infection. We previously described a non-functional variant in SIGLEC1 , which encodes the myeloid-cell receptor Siglec-1/CD169 implicated in HIV-1 cell-to-cell transmission. Here we report a significant association between the SIGLEC1 null variant and extrapulmonary dissemination of Mycobacterium tuberculosis (Mtb) in two clinical cohorts comprising 6,256 individuals. Local spread of bacteria within the lung is apparent in Mtb-infected Siglec-1 knockout mice which, despite having similar bacterial load, developed more extensive lesions compared to wild type mice. We find that Siglec-1 is necessary to induce antigen presentation through extracellular vesicle uptake. We postulate that lack of Siglec-1 delays the onset of protective immunity against Mtb by limiting antigen exchange via extracellular vesicles, allowing for an early local spread of mycobacteria that increases the risk for extrapulmonary dissemination., Competing Interests: The authors declare that no competing financial interests exist., (© 2021 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.)
- Published
- 2021
- Full Text
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39. Host-Derived Lipids from Tuberculous Pleurisy Impair Macrophage Microbicidal-Associated Metabolic Activity.
- Author
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Marín Franco JL, Genoula M, Corral D, Duette G, Ferreyra M, Maio M, Dolotowicz MB, Aparicio-Trejo OE, Patiño-Martínez E, Charton A, Métais A, Fuentes F, Soldan V, Moraña EJ, Palmero D, Ostrowski M, Schierloh P, Sánchez-Torres C, Hernández-Pando R, Pedraza-Chaverri J, Rombouts Y, Hudrisier D, Layre E, Vérollet C, Maridonneau-Parini I, Neyrolles O, Sasiain MDC, Lugo-Villarino G, and Balboa L
- Subjects
- Animals, Bacterial Load, Eicosanoids pharmacology, Female, Glycolysis drug effects, Host-Pathogen Interactions, Humans, Macrophage Activation, Mice, Mice, Inbred C57BL, Mitochondria drug effects, Mitochondria metabolism, Oxidative Phosphorylation drug effects, Oxygen Consumption drug effects, Pleural Effusion, Tuberculosis, Pleural microbiology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Lipids pharmacology, Macrophages drug effects, Macrophages metabolism, Mycobacterium tuberculosis metabolism, Tuberculosis, Pleural metabolism
- Abstract
Mycobacterium tuberculosis (Mtb) regulates the macrophage metabolic state to thrive in the host, yet the responsible mechanisms remain elusive. Macrophage activation toward the microbicidal (M1) program depends on the HIF-1α-mediated metabolic shift from oxidative phosphorylation (OXPHOS) toward glycolysis. Here, we ask whether a tuberculosis (TB) microenvironment changes the M1 macrophage metabolic state. We expose M1 macrophages to the acellular fraction of tuberculous pleural effusions (TB-PEs) and find lower glycolytic activity, accompanied by elevated levels of OXPHOS and bacillary load, compared to controls. The eicosanoid fraction of TB-PE drives these metabolic alterations. HIF-1α stabilization reverts the effect of TB-PE by restoring M1 metabolism. Furthermore, Mtb-infected mice with stabilized HIF-1α display lower bacillary loads and a pronounced M1-like metabolic profile in alveolar macrophages (AMs). Collectively, we demonstrate that lipids from a TB-associated microenvironment alter the M1 macrophage metabolic reprogramming by hampering HIF-1α functions, thereby impairing control of Mtb infection., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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40. Fatty acid oxidation of alternatively activated macrophages prevents foam cell formation, but Mycobacterium tuberculosis counteracts this process via HIF-1α activation.
- Author
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Genoula M, Marín Franco JL, Maio M, Dolotowicz B, Ferreyra M, Milillo MA, Mascarau R, Moraña EJ, Palmero D, Matteo M, Fuentes F, López B, Barrionuevo P, Neyrolles O, Cougoule C, Lugo-Villarino G, Vérollet C, Sasiain MDC, and Balboa L
- Subjects
- Animals, Lipid Droplets metabolism, Macrophage Activation physiology, Macrophages metabolism, Male, Mice, Inbred BALB C, Mycobacterium tuberculosis physiology, Tuberculosis microbiology, Foam Cells microbiology, Hypoxia-Inducible Factor 1, alpha Subunit metabolism, Lipid Metabolism, Macrophages microbiology, Mycobacterium tuberculosis pathogenicity
- Abstract
The ability of Mycobacterium tuberculosis (Mtb) to persist inside host cells relies on metabolic adaptation, like the accumulation of lipid bodies (LBs) in the so-called foamy macrophages (FM), which are favorable to Mtb. The activation state of macrophages is tightly associated to different metabolic pathways, such as lipid metabolism, but whether differentiation towards FM differs between the macrophage activation profiles remains unclear. Here, we aimed to elucidate whether distinct macrophage activation states exposed to a tuberculosis-associated microenvironment or directly infected with Mtb can form FM. We showed that the triggering of signal transducer and activator of transcription 6 (STAT6) in interleukin (IL)-4-activated human macrophages (M(IL-4)) prevents FM formation induced by pleural effusion from patients with tuberculosis. In these cells, LBs are disrupted by lipolysis, and the released fatty acids enter the β-oxidation (FAO) pathway fueling the generation of ATP in mitochondria. Accordingly, murine alveolar macrophages, which exhibit a predominant FAO metabolism, are less prone to become FM than bone marrow derived-macrophages. Interestingly, direct infection of M(IL-4) macrophages with Mtb results in the establishment of aerobic glycolytic pathway and FM formation, which could be prevented by FAO activation or inhibition of the hypoxia-inducible factor 1-alpha (HIF-1α)-induced glycolytic pathway. In conclusion, our results demonstrate that Mtb has a remarkable capacity to induce FM formation through the rewiring of metabolic pathways in human macrophages, including the STAT6-driven alternatively activated program. This study provides key insights into macrophage metabolism and pathogen subversion strategies., Competing Interests: The authors have declared that no competing interests exist.
- Published
- 2020
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41. A nucleotidyltransferase toxin inhibits growth of Mycobacterium tuberculosis through inactivation of tRNA acceptor stems.
- Author
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Cai Y, Usher B, Gutierrez C, Tolcan A, Mansour M, Fineran PC, Condon C, Neyrolles O, Genevaux P, and Blower TR
- Subjects
- Bacterial Proteins metabolism, Humans, Nucleotidyltransferases metabolism, RNA, Transfer metabolism, Mycobacterium tuberculosis genetics, Toxin-Antitoxin Systems genetics, Tuberculosis
- Abstract
Toxin-antitoxin systems are widespread stress-responsive elements, many of whose functions remain largely unknown. Here, we characterize the four DUF1814-family nucleotidyltransferase-like toxins (MenT
1-4 ) encoded by the human pathogen Mycobacterium tuberculosis . Toxin MenT3 inhibited growth of M. tuberculosis when not antagonized by its cognate antitoxin, MenA3 . We solved the structures of toxins MenT3 and MenT4 to 1.6 and 1.2 Å resolution, respectively, and identified the biochemical activity and target of MenT3 . MenT3 blocked in vitro protein expression and prevented tRNA charging in vivo. MenT3 added pyrimidines (C or U) to the 3'-CCA acceptor stems of uncharged tRNAs and exhibited strong substrate specificity in vitro, preferentially targeting tRNASer from among the 45 M . tuberculosis tRNAs. Our study identifies a previously unknown mechanism that expands the range of enzymatic activities used by bacterial toxins, uncovering a new way to block protein synthesis and potentially treat tuberculosis and other infections., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)- Published
- 2020
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42. Colon-specific immune microenvironment regulates cancer progression versus rejection.
- Author
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Trimaglio G, Tilkin-Mariamé AF, Feliu V, Lauzéral-Vizcaino F, Tosolini M, Valle C, Ayyoub M, Neyrolles O, Vergnolle N, Rombouts Y, and Devaud C
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Humans, Immunotherapy, Mice, Colonic Neoplasms, Tumor Microenvironment
- Abstract
Immunotherapies have achieved clinical benefit in many types of cancer but remain limited to a subset of patients in colorectal cancer (CRC). Resistance to immunotherapy can be attributed in part to tissue-specific factors constraining antitumor immunity. Thus, a better understanding of how the colon microenvironment shapes the immune response to CRC is needed to identify mechanisms of resistance to immunotherapies and guide the development of novel therapeutics. In an orthotopic mouse model of MC38-CRC, tumor progression was monitored by bioluminescence imaging and the immune signatures were assessed at a transcriptional level using NanoString and at a cellular level by flow cytometry. Despite initial tumor growth in all mice, only 25% to 35% of mice developed a progressive lethal CRC while the remaining animals spontaneously rejected their solid tumor. No tumor rejection was observed in the absence of adaptive immunity, nor when MC38 cells were injected in non-orthotopic locations, subcutaneously or into the liver. We observed that progressive CRC tumors exhibited a protumor immune response, characterized by a regulatory T-lymphocyte pattern, discernible shortly post-tumor implantation, as well as suppressive myeloid cells. In contrast, tumor-rejecting mice presented an early inflammatory response and an antitumor microenvironment enriched in CD8
+ T cells. Taken together, our data demonstrate the role of the colon microenvironment in regulating the balance between anti or protumor immune responses. While emphasizing the relevance of the CRC orthotopic model, they set the basis for exploring the impact of the identified signatures in colon cancer response to immunotherapy., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2020
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43. Efficacy of Bedaquiline, Alone or in Combination with Imipenem, against Mycobacterium abscessus in C3HeB/FeJ Mice.
- Author
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Le Moigne V, Raynaud C, Moreau F, Dupont C, Nigou J, Neyrolles O, Kremer L, and Herrmann JL
- Subjects
- Animals, Anti-Bacterial Agents pharmacology, Diarylquinolines, Imipenem pharmacology, Mice, Microbial Sensitivity Tests, Mycobacterium Infections, Nontuberculous drug therapy, Mycobacterium abscessus
- Abstract
Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics, such as bedaquiline and imipenem, although in vitro data have questioned this combination. We report that the efficacy of bedaquiline-imipenem combination treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of M. abscessus The addition of imipenem contributed to clearing the infection in the spleen., (Copyright © 2020 American Society for Microbiology.)
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- 2020
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44. Multi-Stress Induction of the Mycobacterium tuberculosis MbcTA Bactericidal Toxin-Antitoxin System.
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Ariyachaokun K, Grabowska AD, Gutierrez C, and Neyrolles O
- Subjects
- Animals, Bacterial Proteins metabolism, Bacterial Toxins metabolism, Cells, Cultured, Female, Genes, Reporter, Humans, Hydrogen Peroxide pharmacology, Macrophages microbiology, Mice, Inbred C57BL, Microbial Viability, Monocytes microbiology, Mycobacterium smegmatis drug effects, Mycobacterium smegmatis metabolism, Mycobacterium tuberculosis drug effects, Mycobacterium tuberculosis metabolism, NAD metabolism, Operon, Promoter Regions, Genetic, Toxin-Antitoxin Systems drug effects, Transcription, Genetic, Triazenes pharmacology, Bacterial Proteins genetics, Bacterial Toxins genetics, Gene Expression Regulation, Bacterial drug effects, Mycobacterium smegmatis genetics, Mycobacterium tuberculosis genetics, Oxidative Stress drug effects, Toxin-Antitoxin Systems genetics
- Abstract
MbcTA is a type II toxin/antitoxin (TA) system of Mycobacterium tuberculosis . The MbcT toxin triggers mycobacterial cell death in vitro and in vivo through the phosphorolysis of the essential metabolite NAD
+ and its bactericidal activity is neutralized by physical interaction with its cognate antitoxin MbcA. Therefore, the MbcTA system appears as a promising target for the development of novel therapies against tuberculosis, through the identification of compounds able to antagonize or destabilize the MbcA antitoxin. Here, the expression of the mbcAT operon and its regulation were investigated. A dual fluorescent reporter system was developed, based on an integrative mycobacterial plasmid that encodes a constitutively expressed reporter, serving as an internal standard for monitoring mycobacterial gene expression, and an additional reporter, dependent on the promoter under investigation. This system was used both in M. tuberculosis and in the fast growing model species Mycobacterium smegmatis to: (i) assess the autoregulation of mbcAT ; (ii) perform a genetic dissection of the mbcA promoter/operator region; and (iii) explore the regulation of mbcAT transcription from the mbcA promoter (PmbcA ) in a variety of stress conditions, including in vivo in mice and in macrophages.- Published
- 2020
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45. Characterization of Macrophage Galactose-type Lectin (MGL) ligands in colorectal cancer cell lines.
- Author
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Pirro M, Rombouts Y, Stella A, Neyrolles O, Burlet-Schiltz O, van Vliet SJ, de Ru AH, Mohammed Y, Wuhrer M, van Veelen PA, and Hensbergen PJ
- Subjects
- Binding Sites, Flow Cytometry, Humans, Lectins, C-Type genetics, Ligands, Mutation, Proteomics, Tumor Cells, Cultured, Colorectal Neoplasms metabolism, Lectins, C-Type metabolism, Macrophages metabolism
- Abstract
Background: The Ca
2+ -dependent C-type lectin receptor Macrophage Galactose-type Lectin (MGL) is highly expressed by tolerogenic dendritic cells (DC) and macrophages. MGL exhibits a high binding specificity for terminal alpha- and beta-linked GalNAc residues found in Tn, sTn and LacdiNAc antigens. These glycan epitopes are often overexpressed in colorectal cancer (CRC), and, as such, MGL can be used to discriminate tumor from the corresponding healthy tissues. Moreover, the high expression of MGL ligands is associated with poor disease-free survival in stage III of CRC tumors. Nonetheless, the glycoproteins expressed by tumor cells that are recognized by MGL have hitherto remained elusive., Methods: Using a panel of three CRC cell lines (HCT116, HT29 and LS174T), recapitulating CRC diversity, we performed FACS staining and pull-down assays using a recombinant soluble form of MGL (and a mutant MGL as control) combined with mass spectrometry-based (glyco)proteomics., Results: HCT116 and HT29, but not LS174T, are high MGL-binding CRC cell lines. On these cells, the major cell surface binding proteins are receptors (e.g. MET, PTK7, SORL1, PTPRF) and integrins (ITGB1, ITGA3). From these proteins, several N- and/or O-glycopeptides were identified, of which some carried either a LacdiNAc or Tn epitope., Conclusions: We have identified cell surface MGL-ligands on CRC cell lines., General Significance: Advances in (glyco)proteomics have led to identification of candidate key mediators of immune-evasion and tumor growth in CRC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2020
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46. Tuberculosis-associated IFN-I induces Siglec-1 on tunneling nanotubes and favors HIV-1 spread in macrophages.
- Author
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Dupont M, Souriant S, Balboa L, Vu Manh TP, Pingris K, Rousset S, Cougoule C, Rombouts Y, Poincloux R, Ben Neji M, Allers C, Kaushal D, Kuroda MJ, Benet S, Martinez-Picado J, Izquierdo-Useros N, Sasiain MDC, Maridonneau-Parini I, Neyrolles O, Vérollet C, and Lugo-Villarino G
- Subjects
- Animals, Cells, Cultured, Coinfection immunology, Female, Gene Expression Profiling, HIV Infections, Humans, Macaca mulatta, Male, Nanotubes, Sialic Acid Binding Ig-like Lectin 1 immunology, HIV-1 pathogenicity, Interferon Type I immunology, Macrophages, Alveolar immunology, Macrophages, Alveolar virology, Sialic Acid Binding Ig-like Lectin 1 genetics, Tuberculosis, Pulmonary immunology
- Abstract
While tuberculosis (TB) is a risk factor in HIV-1-infected individuals, the mechanisms by which Mycobacterium tuberculosis (Mtb) worsens HIV-1 pathogenesis remain scarce. We showed that HIV-1 infection is exacerbated in macrophages exposed to TB-associated microenvironments due to tunneling nanotube (TNT) formation. To identify molecular factors associated with TNT function, we performed a transcriptomic analysis in these macrophages, and revealed the up-regulation of Siglec-1 receptor. Siglec-1 expression depends on Mtb-induced production of type I interferon (IFN-I). In co-infected non-human primates, Siglec-1 is highly expressed by alveolar macrophages, whose abundance correlates with pathology and activation of IFN-I/STAT1 pathway. Siglec-1 localizes mainly on microtubule-containing TNT that are long and carry HIV-1 cargo. Siglec-1 depletion decreases TNT length, diminishes HIV-1 capture and cell-to-cell transfer, and abrogates the exacerbation of HIV-1 infection induced by Mtb. Altogether, we uncover a deleterious role for Siglec-1 in TB-HIV-1 co-infection and open new avenues to understand TNT biology., Competing Interests: MD, SS, LB, TV, KP, SR, CC, YR, RP, MB, CA, DK, MK, SB, JM, NI, MS, IM, ON, CV, GL No competing interests declared, (© 2020, Dupont et al.)
- Published
- 2020
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47. Preclinical assessment of a new live attenuated Mycobacterium tuberculosis Beijing-based vaccine for tuberculosis.
- Author
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Levillain F, Kim H, Woong Kwon K, Clark S, Cia F, Malaga W, Lanni F, Brodin P, Gicquel B, Guilhot C, Bancroft GJ, Williams A, Jae Shin S, Poquet Y, and Neyrolles O
- Subjects
- Animals, BCG Vaccine, Guinea Pigs, Mice, Mice, SCID, Mycobacterium tuberculosis genetics, Mycobacterium tuberculosis immunology, Vaccines, Attenuated immunology, Tuberculosis prevention & control, Tuberculosis Vaccines immunology
- Abstract
Tuberculosis still claims more lives than any other pathogen, and a vaccine better than BCG is urgently needed. One of the challenges for novel TB vaccines is to protect against all Mycobacterium tuberculosis lineages, including the most virulent ones, such as the Beijing lineage. Here we developed a live attenuated M. tuberculosis mutant derived from GC1237, a Beijing strain responsible for tuberculosis outbreaks in the Canary Islands. The mutant strain is inactivated both in the Rv1503c gene, responsible for surface glycolipid synthesis, and in the two-component global regulator PhoPR. This double mutant is as safe as BCG in immunodeficient SCID mice. In immune-competent mice and guinea pigs, the mutant is as protective as BCG against M. tuberculosis strains of common lineage 4 (Euro-American). By contrast, in mice the vaccine is protective against a M. tuberculosis strain of lineage 2 (East-Asian, Beijing), while BCG is not. These results highlight differences in protection efficacy of live attenuated M. tuberculosis-derived vaccine candidates depending on their genetic background, and provide insights for the development of novel live vaccines against TB, especially in East-Asian countries where M. tuberculosis strains of the Beijing family are highly dominant., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2019. Published by Elsevier Ltd.)
- Published
- 2020
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48. An improved Xer-cise technology for the generation of multiple unmarked mutants in Mycobacteria.
- Author
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Boudehen YM, Wallat M, Rousseau P, Neyrolles O, and Gutierrez C
- Subjects
- Genetic Engineering methods, Mutagenesis, Mycobacterium smegmatis genetics, Mycobacterium tuberculosis genetics
- Abstract
Xer-cise is a technique using antibiotic resistance cassettes flanked by dif sites allowing spontaneous and accurate excision from bacterial chromosomes with a high frequency through the action of the cellular recombinase XerCD. Here, we report a significant improvement of Xer-cise in Mycobacteria. Zeocin resistance cassettes flanked by variants of the natural Mycobacterium tuberculosis dif site were constructed and shown to be effective tools to construct multiple unmarked mutations in M. tuberculosis and in the model species Mycobacterium smegmatis . The dif site variants harbor mutations in the central region and can therefore not recombine with the wild-type or other variants, resulting in mutants of increased genetic stability. The herein described method should be generalizable to virtually any transformable bacterial species.
- Published
- 2020
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- View/download PDF
49. C-type Lectins in Immunity to Lung Pathogens.
- Author
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Raymond BBA, Neyrolles O, and Rombouts Y
- Subjects
- Immunity, Innate, Pathogen-Associated Molecular Pattern Molecules, Signal Transduction, Lectins, C-Type genetics, Lectins, C-Type metabolism, Receptors, Pattern Recognition genetics
- Abstract
The respiratory tract is tasked with responding to a constant and vast influx of foreign agents. It acts as an important first line of defense in the innate immune system and as such plays a crucial role in preventing the entry of invading pathogens. While physical barriers like the mucociliary escalator exert their effects through the clearance of these pathogens, diverse and dynamic cellular mechanisms exist for the activation of the innate immune response through the recognition of pathogen-associated molecular patterns (PAMPs). These PAMPs are recognized by pattern recognition receptors (PRRs) that are expressed on a number of myeloid cells such as dendritic cells, macrophages, and neutrophils found in the respiratory tract. C-type lectin receptors (CLRs) are PRRs that play a pivotal role in the innate immune response and its regulation to a variety of respiratory pathogens such as viruses, bacteria, and fungi. This chapter will describe the function of both activating and inhibiting myeloid CLRs in the recognition of a number of important respiratory pathogens as well as the signaling events initiated by these receptors.
- Published
- 2020
- Full Text
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50. The synthesis and in vitro biological evaluation of novel fluorinated tetrahydrobenzo[j]phenanthridine-7,12-diones against Mycobacterium tuberculosis.
- Author
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Cappoen D, Torfs E, Meiresonne T, Claes P, Semina E, Holvoet F, de Macedo MB, Cools F, Piller T, Matheeussen A, Van Calster K, Caljon G, Delputte P, Maes L, Neyrolles O, De Kimpe N, Mangelinckx S, and Cos P
- Subjects
- Animals, Antitubercular Agents chemical synthesis, Antitubercular Agents chemistry, Benzophenanthridines chemical synthesis, Benzophenanthridines chemistry, Cell Line, Dose-Response Relationship, Drug, Humans, Hydrocarbons, Fluorinated chemical synthesis, Hydrocarbons, Fluorinated chemistry, Macrophages drug effects, Mice, Microbial Sensitivity Tests, Molecular Structure, Mycobacterium tuberculosis growth & development, Structure-Activity Relationship, Antitubercular Agents pharmacology, Benzophenanthridines pharmacology, Hydrocarbons, Fluorinated pharmacology, Mycobacterium tuberculosis drug effects
- Abstract
Tuberculosis (TB) still has a major impact on public health. In order to efficiently eradicate this life-threatening disease, the exploration of novel anti-TB drugs is of paramount importance. As part of our program to design new 2-azaanthraquinones with anti-mycobacterial activity, various "out-of-plane" tetrahydro- and octahydrobenzo[j]phenanthridinediones were synthesized. In this study, the scaffold of the most promising hits was further optimized in an attempt to improve the bioactivity and to decrease enzymatic degradation. The rudiment bio-evaluation of a small library of fluorinated tetrahydrobenzo[j]phenanthridine-7,12-dione derivatives indicated no significant improvement of the bio-activity against intracellular and extracellular Mycobacterium tuberculosis (Mtb). Though, the derivatives showed an acceptable toxicity against J774A.1 macrophages and early signs of genotoxicity were absent. All derivatives showed to be metabolic stabile in the presence of both phase I and phase II murine or human microsomes. Finally, the onset of reactive oxygen species within Mtb after exposure to the derivatives was measured by electron paramagnetic resonance (EPR). Results showed that the most promising fluorinated derivative is still a possible candidate for the subversive inhibition of mycothione reductase., (Copyright © 2019 Elsevier Masson SAS. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
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