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9 results on '"MESH: Mycobacterium Infections"'

1. Human T-bet Governs Innate and Innate-like Adaptive IFN-γ Immunity against Mycobacteria

Author

Laurent Abel, Laurie H. Glimcher, Lluis Quintana-Murci, Nico Marr, Fatima Al Ali, Jean Marc Doisne, David Langlais, Jacinta Bustamante, Marc Weisshaar, Jing Han, Jamila El Baghdadi, Frédéric Batteux, Manon Roynard, Yichao Shen, Mathieu Bourgey, Flore Rozenberg, Federica Sallusto, Peng Zhang, David Jarrossay, Carmen Oleaga-Quintas, Jean-Laurent Casanova, Daniela Latorre, Gaspard Kerner, Mahbuba Rahman, Houda Elarabi, Federico Mele, Yoann Seeleuthner, James P. Di Santo, Stuart G. Tangye, Michael S. Kobor, Janet Markle, Dusan Bogunovic, Stéphanie Boisson-Dupuis, Julia L. Maclsaac, Lucas T. Husquin, Lisa Worley, Conor Gruber, Cindy S. Ma, Jérémie Rosain, Taushif Khan, Thomas L. Carroll, Mohamed Jeljeli, Abderrahmane Errami, Anne Puel, Qiang Pan-Hammarström, Philippe Gros, Ibithal Benhsaien, Aziz Bousfiha, Fatima Ailal, Carys A. Croft, Rui Yang, Masato Ogishi, Rockefeller University [New York], Università della Svizzera italiana = University of Italian Switzerland (USI), Garvan Institute of medical research, McGill University = Université McGill [Montréal, Canada], Laboratory of Human Genetics of Infectious Diseases (Necker Branch - INSERM U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Université Hassan II [Casablanca] (UH2MC), Immunité Innée - Innate Immunity, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Paris Cité (UPCité), Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Icahn School of Medicine at Mount Sinai [New York] (MSSM), We thank the patients and families, members of the laboratory, Cecilia Lindestam Arlehamn and Alessandro Sette, NIH Tetramer Core Facility (NTCF), James McCluskey, Jamie Rossjohn, and David Fairlie, the Genomics and the Flow Cytometry Resource Center of Rockefeller University, National Center for Advancing Translational Sciences of the National Institutes of Health (UL1TR001866 to Rockefeller University), Steven Elledge, National Institute of Allergy and Infectious Diseases (R37AI095983 to J.L.C. and U19AI118626 to F.S.), Sackler Center for Biomedicine and Nutrition at the Center for Clinical and Translational Science (CCTS), Shapiro-Silverberg Fund for the Advancement of Translational Research at CCTS, Rockefeller University (to R.Y.), Research Grant Program of the Immune Deficiency Foundation (to R.Y.), Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), French National Research Agency under the 'Investments for the future' program (ANR-10-IAHU-01), ANR-GENMSMD (ANR-16-CE17-0005-01 to J.B.), ANR-LTh-MSMD-CMCD (ANR-18-CE93-0008-01 to A.P and F.S.), Fonds de Recherche en Santé Respiratoire (SRC2017 to J.B.), French Foundation for Medical Research (FRM) (EQU201903007798), the SCOR Corporate Foundation for Science, ECOS Nord (C19S01-63407 to J.B.), Swiss National Science Foundation (310030L_182728 to F.S.), French Foundation for Medical Research (FRM) (EQU201903007798), Helmut Horten Foundation, Canadian Center for Computational Genomics (C3G), Genomics Technology Platform (GTP), and Genome Canada. J. R. was supported by INSERM Poste d’accueil and and Imagine Institute, T.K. by Qatar National Research Fund (PPM1-1220-150017). S.G.T. by Program grant (1113904), Principal Research Fellowship (1042925), and Leadership 3 Investigator grant (1176665) from the National Health and Medical Research Council of Australia, C.S.M. by an Early/Mid-Career Development Research Fellowship, Ministry of Health, NSW Government, R.Y. by Stony Wold-Herbert Fund., ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010), ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), ANR-16-CE17-0005,GENMSMD,Dissection génétique de la Susceptibilité Mendélienne aux infections mycobactériennes chez l'homme(2016), ANR-18-CE93-0008,LTh-MSMD-CMCD,Différenciation des lymphocytes T-helper (Th) dans les défauts génétiques de l'immunité contre Mycobacterium et/ou Candida species.(2018), Garvan Institute of Medical Research [Darlinghurst, Australia], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM), and Université de Paris (UP)

Subjects
Male, inborn errors of immunity, [SDV]Life Sciences [q-bio], Mendelian susceptibility to mycobacterial disease, MESH: Amino Acid Sequence, Adaptive Immunity, MESH: Base Sequence, Epigenesis, Genetic, mycobacterium, MESH: INDEL Mutation, 0302 clinical medicine, MESH: DNA Methylation, INDEL Mutation, Loss of Function Mutation, Interferon gamma, MESH: Epigenesis, Genetic, MESH: CpG Islands, IFN-γ, Immunodeficiency, 0303 health sciences, biology, MESH: Dendritic Cells, Homozygote, T-Lymphocytes, Helper-Inducer, MESH: Infant, Chromatin, Pedigree, 3. Good health, Killer Cells, Natural, Child, Preschool, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, MESH: Immunity, Innate, medicine.drug, MESH: Homozygote, MESH: Killer Cells, Natural, MESH: Pedigree, MESH: T-Box Domain Proteins, MESH: Interferon-gamma, T-bet, Article, General Biochemistry, Genetics and Molecular Biology, MESH: Chromatin, Interferon-gamma, 03 medical and health sciences, Immunity, medicine, MESH: Mycobacterium, Humans, Cell Lineage, Amino Acid Sequence, MESH: Mycobacterium Infections, MESH: T-Lymphocytes, Helper-Inducer, Transcription factor, 030304 developmental biology, Mycobacterium Infections, MESH: Humans, Base Sequence, MESH: Transcriptome, MESH: Child, Preschool, Infant, MESH: Loss of Function Mutation, Dendritic Cells, DNA Methylation, Mycobacterial disease, MESH: Cell Lineage, medicine.disease, biology.organism_classification, Immunity, Innate, MESH: Male, innate-like adaptive lymphocyte, Mycobacterial antigen, Immunology, CpG Islands, innate lymphocyte, T-Box Domain Proteins, Transcriptome, immunodeficiency, MESH: Female, 030217 neurology & neurosurgery, CD8, MESH: Adaptive Immunity, Mycobacterium
Abstract

International audience; Inborn errors of human interferon gamma (IFN-γ) immunity underlie mycobacterial disease. We report a patient with mycobacterial disease due to inherited deficiency of the transcription factor T-bet. The patient has extremely low counts of circulating Mycobacterium-reactive natural killer (NK), invariant NKT (iNKT), mucosal-associated invariant T (MAIT), and Vδ2+ γδ T lymphocytes, and of Mycobacterium-non reactive classic TH1 lymphocytes, with the residual populations of these cells also producing abnormally small amounts of IFN-γ. Other lymphocyte subsets develop normally but produce low levels of IFN-γ, with the exception of CD8+ αβ T and non-classic CD4+ αβ TH1∗ lymphocytes, which produce IFN-γ normally in response to mycobacterial antigens. Human T-bet deficiency thus underlies mycobacterial disease by preventing the development of innate (NK) and innate-like adaptive lymphocytes (iNKT, MAIT, and Vδ2+ γδ T cells) and IFN-γ production by them, with mycobacterium-specific, IFN-γ-producing, purely adaptive CD8+ αβ T, and CD4+ αβ TH1∗ cells unable to compensate for this deficit.

Published
2020
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2. Nitazoxanide Analogs Require Nitroreduction for Antimicrobial Activity in Mycobacterium smegmatis

Author

Gerald Larrouy-Maumus, Sandrine Favre-Rochex, Alessandro Cascioferro, Hélène Munier-Lehmann, Sonia Rebollo-Ramirez, Claire Beauvineau, Delphine Naud-Martin, Mena Cimino, Brigitte Gicquel, Maria Virginia Buchieri, Olivier Helynck, Génétique mycobactérienne - Mycobacterial genetics, Institut Pasteur [Paris], Imperial College London, Chimie, Modélisation et Imagerie pour la Biologie [Orsay], Université Paris-Sud - Paris 11 (UP11)-Institut Curie [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Pathogénomique mycobactérienne intégrée, Chimie et Biocatalyse, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), This work is part of the European Seventh Framework Program Nanotherapeutics against Resistant Emerging Bacterial Pathogens (NAREB Project 604237). This work was also supported by the 'Programme de Recherche sur les Nouvelles Molécules Intervenant dans la Lutte Contre la Tuberculose' of the Gabonese Republic, the Department of Life Sciences and the Faculty of Natural Sciences kick-start funding award from Imperial College London, U.K., and Agilent Technologies, U.K., concerning all LC–MS experiments performed on the Agilent 6545 QToF., We thank Yves Janin for fruitful discussions and technical support., European Project: 604237,EC:FP7:NMP,FP7-NMP-2013-LARGE-7,NAREB(2014), Institut Pasteur [Paris] (IP), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Mycobacterium smegmatis, 030106 microbiology, Down-Regulation, Mycobacterium Infections, Nontuberculous, MESH: Thiazoles, MESH: Down-Regulation, Mycobacterium aurum, Mycobacterium, Microbiology, 03 medical and health sciences, Nitroreductase, chemistry.chemical_compound, Hydroxylamine, MESH: Anti-Bacterial Agents, Drug Resistance, Bacterial, MESH: Drug Resistance, Bacterial, Drug Discovery, MESH: Mycobacterium, medicine, Humans, [CHIM]Chemical Sciences, MESH: Mycobacterium Infections, Gene, MESH: Mycobacterium smegmatis, Mycobacterium Infections, MESH: Humans, biology, Nitazoxanide, Nitroreductases, Nitro Compounds, MESH: Mycobacterium Infections, Nontuberculous, Antimicrobial, biology.organism_classification, Anti-Bacterial Agents, 3. Good health, Thiazoles, MESH: Nitroreductases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, 030104 developmental biology, chemistry, Biochemistry, Molecular Medicine, Antibacterial activity, medicine.drug
Abstract

International audience; In this study, we aimed to decipher the natural resistance mechanisms of mycobacteria against novel compounds isolated by whole-cell-based high-throughput screening (HTS). We identified active compounds using Mycobacterium aurum. Further analyses were performed to determine the resistance mechanism of M. smegmatis against one hit, 3-bromo-N-(5-nitrothiazol-2-yl)-4-propoxybenzamide (3), which turned out to be an analog of the drug nitazoxanide (1). We found that the repression of the gene nfnB coding for the nitroreductase NfnB was responsible for the natural resistance of M. smegmatis against 3. The overexpression of nfnB resulted in sensitivity of M. smegmatis to 3. This compound must be metabolized into hydroxylamine intermediate for exhibiting antibacterial activity. Thus, we describe, for the first time, the activity of a mycobacterial nitroreductase against 1 analogs, highlighting the differences in the metabolism of nitro compounds among mycobacterial species and emphasizing the potential of nitro drugs as antibacterials in various bacterial species.

Published
2017
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3. Mycobacterial disease in patients with chronic granulomatous disease: A retrospective analysis of 71 cases

Author

Capucine Picard, Anastasia Bondarenko, Marjorie Hubeau, Lorena Regairaz, Caroline Deswarte, Imen Ben-Mustapha, Antoine Guérin, Joseph Hertecant, Guillaume Vogt, Rose-Marie Herbigneaux, Fatima Ailal, Davood Mansouri, Guzide Aksu, Antonio Condino-Neto, Laurent Abel, Carolina Prando, Ambre Czarna, Lizbeth Blancas Galicia, Saul Oswaldo Lugo-Reyes, Isil Barlan, Mussaret B. Zaidi, Liliana Bezrodnik, Daniela Di Giovanni, Laura Perez, Laila Ait Baba, Sigifredo Pedraza-Sánchez, Miguel Galicchio, Gehad ElGhazali, Aminata Diabate, Sara Espinosa, Matías Oleastro, Francesca Conti, Necil Kutukculer, Edgar Oliveira, Héctor Eduardo Guidos Morales, Edith Gonzalez Serrano, Fatma Nur Öz, Ahmed Aziz Bousfiha, Jalel Chemli, Özden Anal, Peter Ciznar, Nizar Mahlaoui, Francisco J. Espinosa-Rosales, Silvia Danielian, Gloria G. Guerrero, Saleh Al-Muhsen, Marco Antonio Yamazaki Nakashimada, Nadia Kechout, Ridha Barbouche, Maria Claudia Ortega, Susana Soto Lavin, Liudmyla Chernyshova, Ghassan Dbaibo, Melike Emiroglu, Stéphane Blanche, Jacinta Bustamante, Mélanie Migaud, Jean-Laurent Casanova, Maylis de Suremain, Barik Konte, Neslihan Edeer Karaca, Jianxin He, Stéphanie Ndaga, Nestor Proenza Pérez, Stéphanie Boisson-Dupuis, Eman Al-Idrissi, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Public Health and Cellular Biology [Rome], Università degli Studi di Roma Tor Vergata [Roma], Génétique Humaine des Maladies Infectieuses (Inserm U980), Immunodeficiencies Research Unit [Mexico city], National Institute of Pediatrics, Mexico, Beijing Childrens Hospital, Department of Pediatrics [Izmir], Ege University, Institute of Biomedical Sciences - Department of Immunology [Sao Paulo], University of São Paulo (USP), Laboratory of Biology and Health UARC34–Metabolic and Immunologic Pathology Research Team, Faculté des Sciences Ben M'sik [Casablanca], Université Hassan II [Casablanca] (UH2MC)-Université Hassan II [Casablanca] (UH2MC), Bioinformatics Laboratory [Curitiba], Pelé Pequeno Principe Research Institute, Curitiba, Department of Pediatric Infectious Diseases [Konya], Necmettin Erbakan University, Meram Medical Faculty, Pediatric Infectious Diseases Department [Ankara], Dr Sami Ulus Matern & Childrens Res & Training Ho, Department of Immunology [Mexico City], Natl Inst Pediat, Immunodeficiencies Res Unit, Mexico City, DF, Mexico, Marmara University [Kadıköy - İstanbul], Childrens Hosp Super Sor Maria Ludovica, Allergy and Immunology Unit [San Salvador], Natl Childrens Hosp Benjamin Bloom San Salvador, Immunology Unit [Buenos Aires], Childrens Hosp Ricardo Gutierrez Buenos Aires, Department of Pediatrics [Beirut], American University of Beirut [Beyrouth] (AUB), Clinical Immunology Unit, Casablanca Children's Hospital, Ibn Rochd Hospital King Hassan II University-Aïn Chok, Childrens Hosp Victor J Vilela Rosario, Department of Immunology [Buenos Aires], 'Juan Pedro Garrahan' National Hospital of Pediatrics, Buenos Aires, Department of Pediatrics [Sousse], Sahloul Hospital, Childrens Hosp San Jose Colombia, Concepcion Regional Hospital [Concepción], Department of Pediatrics [Abu Dhabi], Tawam Hospital, Al Ain, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Institut Pasteur d'Algérie, Réseau International des Instituts Pasteur (RIIP), Department of Pediatrics [Riyadh], King Fahad Medical City, Department of Pediatrics Infectious Diseases and Clinical Immunology [Kiev], Department of Pediatrics, Comenius University Medical School [Bratislava], University Children's Hospital, Bratislava, Centre Hospitalier Universitaire de La Réunion (CHU La Réunion), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Unit of Biochemistry [Tlalpan], Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran [Mexico], Microbiology Research Laboratory, Hospital General O'Horan and Infectious Diseases Research Unit [Merida], Hosp Reg Alta Especialidad Peninsula Yucatan, Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur de Tunis, Shahid Beheshti University of Medical Sciences [Tehran] (SBUMS), Shahid Beheshti University, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], French Reference Center for Primary Immune Deficiencies (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Department of Pediatrics, Prince Naif Center for Immunology Research, College of Medicine, King Saud University [Riyadh] (KSU), F.C. was supported by the Department of Public Health and Cellular Biology, University of Rome Tor Vergata. A.G. was supported by the French National Research Agency (ANR). The Laboratory of Human Genetics of Infectious Diseases is supported by institutional grants from INSERM, University Paris Descartes, the Rockefeller University, and the St Giles Foundation and grants from the French National Research Agency (ANR) under the 'Investments for the Future' program (grant no. ANR-10-IAHU-01) and grant IFNGPHOX (no. ANR13-ISV3-0001-01). E.B.d.O. and A.C.-N. are supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP grants 2012/11757-2, 2010/51814-0, and 2012/51094-2) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPQ grant 303809/2010-8). S.P.-S. is supported by Consejo Nacional de Ciencia y Tecnología (CONACYT, grant 182817)., Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Rome Tor Vergata, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Dokuz Eylul University, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán - National Institute of Medical Science and Nutrition Salvador Zubiran, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Shahid Beheshti University of Medical Sciences, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, rockefeller university, Imagine - Institut des maladies génétiques ( IMAGINE - U1163 ), Centre National de la Recherche Scientifique ( CNRS ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), University of São Paulo ( USP ), Faculty of Science of Ben M'sik, King Hassan II University–Mohammedia, Casablanca, American University of Beirut [Beyrouth], Faculty of Medicine, Dokuz Eylül University, Izmir, Institut Pasteur d'Algérie-Réseau International des Instituts Pasteur ( RIIP ), Centre Hospitalier Universitaire de La Réunion ( CHU La Réunion ), Natl Inst Med Sci & Nutr Salvador Zubiran, Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institut Pasteur de Tunis-Réseau International des Instituts Pasteur ( RIIP ), and King Saud University [Riyadh] ( KSU )

Subjects
0301 basic medicine, Male, MESH : Retrospective Studies, [SDV]Life Sciences [q-bio], Disease, MESH : Child, Preschool, chronic granulomatous disease, Granulomatous Disease, Chronic, 0302 clinical medicine, Chronic granulomatous disease, MESH : Child, MESH: Granulomatous Disease, Chronic, MESH: Child, Immunology and Allergy, Disseminated disease, MESH : Female, BCG, MESH: Tuberculosis, MESH : BCG Vaccine, Child, biology, MESH: Patient Outcome Assessment, MESH : Infant, Bacterial Infections, MESH : Tuberculosis, MESH: Infant, MESH : Patient Outcome Assessment, 3. Good health, Vaccination, MESH : Bacterial Infections, MESH: BCG Vaccine, tuberculosis, Mycobacterium ulcerans, Child, Preschool, BCG Vaccine, Female, Tuberculosis, MESH: Bacterial Infections, MESH : Male, Immunology, primary immunodeficiency, 03 medical and health sciences, MESH: Mycoses, medicine, Humans, MESH: Mycobacterium Infections, Retrospective Studies, MESH : Mycoses, Mycobacterium Infections, MESH: Humans, [ SDV ] Life Sciences [q-bio], business.industry, MESH : Humans, MESH: Child, Preschool, Infant, Mycobacteria, MESH: Retrospective Studies, medicine.disease, biology.organism_classification, MESH: Male, Patient Outcome Assessment, 030104 developmental biology, Mycoses, MESH : Mycobacterium Infections, Primary immunodeficiency, MESH : Granulomatous Disease, Chronic, business, BCG vaccine, MESH: Female, 030215 immunology
Abstract

International audience; Background : Chronic granulomatous disease (CGD) is a rare primary immunodeficiency caused by inborn errors of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase complex. From the first year of life onward, most affected patients display multiple, severe, and recurrent infections caused by bacteria and fungi. Mycobacterial infections have also been reported in some patients.Objective : Our objective was to assess the effect of mycobacterial disease in patients with CGD.Methods : We analyzed retrospectively the clinical features of mycobacterial disease in 71 patients with CGD. Tuberculosis and BCG disease were diagnosed on the basis of microbiological, pathological, and/or clinical criteria.Results : Thirty-one (44%) patients had tuberculosis, and 53 (75%) presented with adverse effects of BCG vaccination; 13 (18%) had both tuberculosis and BCG infections. None of these patients displayed clinical disease caused by environmental mycobacteria, Mycobacterium leprae, or Mycobacterium ulcerans. Most patients (76%) also had other pyogenic and fungal infections, but 24% presented solely with mycobacterial disease. Most patients presented a single localized episode of mycobacterial disease (37%), but recurrence (18%), disseminated disease (27%), and even death (18%) were also observed. One common feature in these patients was an early age at presentation for BCG disease. Mycobacterial disease was the first clinical manifestation of CGD in 60% of these patients.Conclusion : Mycobacterial disease is relatively common in patients with CGD living in countries in which tuberculosis is endemic, BCG vaccine is mandatory, or both. Adverse reactions to BCG and severe forms of tuberculosis should lead to a suspicion of CGD. BCG vaccine is contraindicated in patients with CGD.

Published
2016
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4. Structural and functional characterization of an arylamineN-acetyltransferase from the pathogenMycobacterium abscessus: differences from other mycobacterial isoforms and implications for selective inhibition

Author

Linh Chi-Bui, Xavier Kubiak, Julien Dairou, Ahmed Haouz, Guillaume Garnier, Jean Marie Dupret, Florent Busi, Jean-Louis Herrmann, Angélique Cocaign, Inès Li de la Sierra-Gallay, Areej Abuhammad, Ximing Xu, Fernando Rodrigues-Lima, Unité de Biologie Fonctionnelle et Adaptative (BFA (UMR_8251 / U1133)), Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Hôpital Raymond Poincaré [AP-HP], Institut de biochimie et biophysique moléculaire et cellulaire (IBBMC), Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS), University of Oxford, The University of Jordan (JU), Cristallogenèse et Diffraction des Rayons X (Plate-forme/PF6), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Ribierre, Hélène

Subjects
Models, Molecular, [SDV]Life Sciences [q-bio], Molecular Sequence Data, MESH: Amino Acid Sequence, Mycobacterium abscessus, Crystallography, X-Ray, arylamine N-acetyltransferase, Mycobacterium, Substrate Specificity, Microbiology, Structural Biology, medicine, MESH: Mycobacterium, Humans, Amino Acid Sequence, MESH: Mycobacterium Infections, MESH: Phylogeny, Pathogen, Phylogeny, Nocardia farcinica, chemistry.chemical_classification, Mycobacterium Infections, MESH: Humans, MESH: Molecular Sequence Data, biology, Arylamine N-acetyltransferase, Isoniazid, Acetylation, General Medicine, biology.organism_classification, bacterial infections and mycoses, MESH: Crystallography, X-Ray, MESH: Arylamine N-Acetyltransferase, [SDV] Life Sciences [q-bio], Enzyme, chemistry, Biochemistry, Docking (molecular), bacteria, MESH: Substrate Specificity, MESH: Acetylation, MESH: Models, Molecular, medicine.drug
Abstract

Mycobacterium abscessusis the most pathogenic rapid-growing mycobacterium and is one of the most resistant organisms to chemotherapeutic agents. However, structural and functional studies ofM. abscessusproteins that could modify/inactivate antibiotics remain nonexistent. Here, the structural and functional characterization of an arylamineN-acetyltransferase (NAT) fromM. abscessus[(MYCAB)NAT1] are reported. This novel prokaryotic NAT displays significantN-acetyltransferase activity towards aromatic substrates, including antibiotics such as isoniazid andp-aminosalicylate. The enzyme is endogenously expressed and functional in both the rough and smoothM. abscessusmorphotypes. The crystal structure of (MYCAB)NAT1 at 1.8 Å resolution reveals that it is more closely related toNocardia farcinicaNAT than to mycobacterial isoforms. In particular, structural and physicochemical differences from other mycobacterial NATs were found in the active site. Peculiarities of (MYCAB)NAT1 were further supported by kinetic and docking studies showing that the enzyme was poorly inhibited by the piperidinol inhibitor of mycobacterial NATs. This study describes the first structure of an antibiotic-modifying enzyme fromM. abscessusand provides bases to better understand the substrate/inhibitor-binding specificities among mycobacterial NATs and to identify/optimize specific inhibitors. These data should also contribute to the understanding of the mechanisms that are responsible for the pathogenicity and extensive chemotherapeutic resistance ofM. abscessus.

Published
2014
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5. A 1,100-year-old founder effect mutation in IL12B gene is responsible for Mendelian susceptibility to mycobacterial disease in Tunisian patients

Author

Mohamed Bejaoui, Lamia Boughammoura, Abdelaziz Harbi, Christine Harmant, J. Bouguila, Jalel Chemli, Najla Mekki, Etienne Patin, Houda Elloumi-Zghal, Mohamed-Ridha Barbouche, Meriem Ben-Ali, Imen Ben-Mustapha, Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Université de Tunis El Manar (UTM), Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Department of Pediatrics, Sahloul Hospital, Sousse, Tunisia, Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia., This work has been supported partially by the Tunisian Ministry of Higher Education, Research and Technology (grant to the LR11IPT02), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH: Mycobacterium bovis, [SDV]Life Sciences [q-bio], MESH: Founder Effect, MESH: Genotype, 0302 clinical medicine, MESH: Child, Genotype, Child, Genetics, 0303 health sciences, Interleukin-12 Subunit p40, MESH: Genetic Predisposition to Disease, Mycobacterium bovis, Founder Effect, 3. Good health, Pedigree, MESH: BCG Vaccine, Mutation (genetic algorithm), symbols, BCG Vaccine, Female, MESH: Tunisia, Adult, Tunisia, MESH: Mutation, MESH: Pedigree, Genetic counseling, Immunology, Consanguinity, Biology, 03 medical and health sciences, symbols.namesake, Humans, Genetic Predisposition to Disease, Allele, MESH: Mycobacterium Infections, Alleles, 030304 developmental biology, Mycobacterium Infections, [SDV.GEN]Life Sciences [q-bio]/Genetics, MESH: Humans, MESH: Alleles, MESH: Adult, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Human genetics, MESH: Male, MESH: Interleukin-12 Subunit p40, Mutation, Mendelian inheritance, MESH: Female, 030215 immunology, Founder effect
Abstract

International audience; Mendelian susceptibility to mycobacterial disease (MSMD) is a rare disorder predisposing apparently healthy individuals to infections caused by weakly virulent mycobacteria such as bacille Calmette-Guerin (BCG), environmental mycobacteria, and poorly virulent Salmonella strains. IL-12p40 deficiency is the first reported human disease due to a cytokine gene defect and is one of the deficiencies that cause MSMD. Nine mutant alleles only have been identified in the IL12B gene, and three of them are recurrent mutations due to a founder effect in specific populations. IL-12p40 deficiency has been identified especially in countries where consanguinity is high and where BCG vaccination at birth is universal. We investigated, in such settings, the clinical, cellular, and molecular features of six IL-12p40-deficient Tunisian patients having the same mutation in IL12B gene (c.298_305del). We found that this mutation is inherited as a common founder mutation arousing ~1,100 years ago. This finding facilitates the development of a preventive approach by genetic counseling and prenatal diagnosis especially in affected families.

Published
2014
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6. Phagosomal Rupture by Mycobacterium tuberculosis Results in Toxicity and Host Cell Death

Author

Jost Enninga, Roxane Simeone, Roland Brosch, Juliane Lippmann, Alexandre Bobard, Wilbert Bitter, Laleh Majlessi, Pathogénomique mycobactérienne intégrée, Institut Pasteur [Paris] (IP), Dynamique des Interactions Hôte-Pathogène - Dynamics of Host-Pathogen Interactions, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Vrije Universiteit Amsterdam [Amsterdam] (VU), Régulation Immunitaire et Vaccinologie, Institut Pasteur [Paris] (IP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), This work was supported by the Institut Pasteur PTR372 (to R.B.), the European Community's Seventh Framework Program under grant agreements n°201762 (to L.M., W.B. and R.B.) and n°241745 (to R.B.), a European Research Council Starting Grant Award n° 261166 (to J.E.), and a grant n° ANR-09-MIEN-020-01 from the Agence Nationale pour la Recherche (to J.E.)., We would like to thank Alexandre Pawlik for help with the figure layout, ANR-09-MIEN-0020,SignRupVac,Signalisation cellulaire associée à la rupture vacuolaire des bactéries à réplication intracytoplasmique(2009), European Project: 201762,EC:FP7:HEALTH,FP7-HEALTH-2007-A,NOVSEC-TB(2008), Institut Pasteur [Paris], Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Institut Pasteur [Paris]-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Langlais, Laurence, MIE : Maladies infectieuses, immunité et environnement - Signalisation cellulaire associée à la rupture vacuolaire des bactéries à réplication intracytoplasmique - - SignRupVac2009 - ANR-09-MIEN-0020 - MIE - VALID, Novel secretion systems of Mycobacterium tuberculosis and their role in host-pathogen interaction - NOVSEC-TB - - EC:FP7:HEALTH2008-01-01 - 2011-06-30 - 201762 - VALID, Medical Microbiology and Infection Prevention, CCA - Immuno-pathogenesis, Vrije universiteit = Free university of Amsterdam [Amsterdam] (VU), Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Pasteur [Paris], Molecular Microbiology, AIMMS, and VU University Amsterdam

Subjects
MESH: Cell Death, MESH: Mycobacterium tuberculosis, MESH: Shigella flexneri, MESH: Fluorescence Resonance Energy Transfer, Host cells, [SDV.BC.IC] Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], Fluorescence imaging, Cytosol, Fluorescence resonance energy transfer, [SDV.BC.IC]Life Sciences [q-bio]/Cellular Biology/Cell Behavior [q-bio.CB], MESH: Immune Evasion, Pathogen, [SDV.BBM.BC] Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], lcsh:QH301-705.5, Phagosome, Fluorescence microscopy, 0303 health sciences, biology, 3. Good health, Research Article, lcsh:Immunologic diseases. Allergy, Programmed cell death, Tuberculosis, Immunology, Virulence, Microbiology, MESH: Mycobacterium marinum, Mycobacterium tuberculosis, 03 medical and health sciences, Necrosis, MESH: Phagosomes, SDG 3 - Good Health and Well-being, Virology, MESH: Homeodomain Proteins, Genetics, medicine, Secretion, MESH: Mycobacterium Infections, [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM], Molecular Biology, Biology, Mycobacterium marinum, 030304 developmental biology, MESH: Humans, 030306 microbiology, Macrophages, MESH: Macrophages, MESH: Salmonella typhimurium, medicine.disease, biology.organism_classification, MESH: Cell Line, lcsh:Biology (General), Parasitology, lcsh:RC581-607
Abstract

Survival within macrophages is a central feature of Mycobacterium tuberculosis pathogenesis. Despite significant advances in identifying new immunological parameters associated with mycobacterial disease, some basic questions on the intracellular fate of the causative agent of human tuberculosis in antigen-presenting cells are still under debate. To get novel insights into this matter, we used a single-cell fluorescence resonance energy transfer (FRET)-based method to investigate the potential cytosolic access of M. tuberculosis and the resulting cellular consequences in an unbiased, quantitative way. Analysis of thousands of THP-1 macrophages infected with selected wild-type or mutant strains of the M. tuberculosis complex unambiguously showed that M. tuberculosis induced a change in the FRET signal after 3 to 4 days of infection, indicating phagolysosomal rupture and cytosolic access. These effects were not seen for the strains M. tuberculosisΔRD1 or BCG, both lacking the ESX-1 secreted protein ESAT-6, which reportedly shows membrane-lysing properties. Complementation of these strains with the ESX-1 secretion system of M. tuberculosis restored the ability to cause phagolysosomal rupture. In addition, control experiments with the fish pathogen Mycobacterium marinum showed phagolysosomal translocation only for ESX-1 intact strains, further validating our experimental approach. Most importantly, for M. tuberculosis as well as for M. marinum we observed that phagolysosomal rupture was followed by necrotic cell death of the infected macrophages, whereas ESX-1 deletion- or truncation-mutants that remained enclosed within phagolysosomal compartments did not induce such cytotoxicity. Hence, we provide a novel mechanism how ESX-1 competent, virulent M. tuberculosis and M. marinum strains induce host cell death and thereby escape innate host defenses and favor their spread to new cells. In this respect, our results also open new research directions in relation with the extracellular localization of M. tuberculosis inside necrotic lesions that can now be tackled from a completely new perspective., Author Summary Mycobacterium tuberculosis is one of the most life-threatening pathogens of all time. Despite the development of vaccines and antibiotics, this pathogen is still a major public health problem. Also the HIV epidemic has an important impact on the rise of M. tuberculosis infections since immunodeficient people are highly susceptible. Commonly, M. tuberculosis has been thought to reside in a membrane-bound compartment within its host cells during the entire infection cycle from invasion to cell death. Using a fluorescence-based method, we provide evidence that M. tuberculosis is able to rupture its membrane-bound compartment and gain access to the host cytosol, where it can elicit cell death. Furthermore, we show that this effect is dependent on a functional type VII secretion system named ESX-1. Most importantly, we were able to track the dynamics of infection to understand the consequences of M. tuberculosis phagosomal rupture. This revealed that phagosomal rupture results in cell toxicity and host cell death involving necrosis. Together, our data provide a new angle in the worldwide fight against M. tuberculosis and could lead to new approaches in the development of innovative treatments.

Published
2012
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7. Spoligotyping of Mycobacterium africanum, Burkina Faso

Author

Guislaine Refrégier, Adama Ouiminga, Christophe Sola, Michel K. Gomgnimbou, Sanou Adama, Serge Diagbouga, Antoinette Kaboré, Institut de génétique et microbiologie [Orsay] (IGM), and Université Paris-Sud - Paris 11 (UP11)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Epidemiology, lcsh:Medicine, MESH: Genotype, fluids and secretions, Genotype, bacteria, health care economics and organizations, 0303 health sciences, biology, spoligotyping, Dispatch, Genomic signature, Mycobacterium Infections, 3. Good health, Bacterial Typing Techniques, Infectious Diseases, [SDV.MP]Life Sciences [q-bio]/Microbiology and Parasitology, population characteristics, geographic locations, Microbiology (medical), DNA, Bacterial, Tuberculosis, MESH: Bacterial Typing Techniques, Microbiology, lcsh:Infectious and parasitic diseases, Mycobacterium, 03 medical and health sciences, parasitic diseases, Burkina Faso, medicine, MESH: Mycobacterium, Humans, MESH: Burkina Faso, [SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology, lcsh:RC109-216, MESH: Mycobacterium Infections, 030304 developmental biology, MESH: Humans, Mycobacterium africanum, 030306 microbiology, lcsh:R, biology.organism_classification, medicine.disease, Virology, MESH: DNA, Bacterial, tuberculosis and other mycobacteria
Abstract

International audience; Using Ziehl-Neelsen-positive slides collected from tuberculosis diagnostic centers in Burkina Faso, we showed that 20% of 80 spoligotyping-positive DNA samples had a characteristic Mycobacterium africanum-specific genomic signature. This result suggests that M. africanum is still present in Burkina Faso at almost the same prevalence as 15-20 years ago.

Published
2012
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8. Lipids of pathogenic Mycobacteria: contributions to virulence and host immune suppression

Author

L Guenin-Macé, Caroline Demangel, Roxane Simeone, Pathogénomique mycobactérienne intégrée - Integrated Mycobacterial Pathogenomics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), and Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS)

Subjects
MESH: Signal Transduction, Lipopolysaccharides, [SDV]Life Sciences [q-bio], MESH: Virulence, Phagosomes, MESH: Glycolipids, 0303 health sciences, Antigen Presentation, Immunity, Cellular, biology, Virulence, General Medicine, Lipids, 3. Good health, Signal Transduction, Tuberculosis, MESH: Immune Tolerance, Virulence Factors, Antigen presentation, Microbiology, MESH: Immunity, Cellular, Mycobacterium, Mycobacterium tuberculosis, 03 medical and health sciences, Immune system, MESH: Phagosomes, Antigen, Immunity, medicine, MESH: Mycobacterium, Immune Tolerance, Humans, MESH: Mycobacterium Infections, 030304 developmental biology, MESH: Virulence Factors, Antigens, Bacterial, Mycobacterium Infections, MESH: Humans, General Veterinary, General Immunology and Microbiology, 030306 microbiology, biology.organism_classification, medicine.disease, Virology, MESH: Lipids, MESH: Antigen Presentation, MESH: Lipopolysaccharides, Glycolipids, MESH: Antigens, Bacterial
Abstract

International audience; Mycobacteria are characterized by a complex cell wall, the lipid nature of which confers to the bacilli resistance to drying, acid or alkaline conditions, and to chemical disinfectants and therapeutic agents. Pathogenic species, such as Mycobacterium tuberculosis, M. leprae and M. ulcerans, have evolved various strategies to establish residence in their hosts and provoke long-term infections. There is mounting evidence that the unique lipids composing their envelopes, strategically located at the host-pathogen interface, contribute to their escape from immune surveillance. Here, the chemical structure, host cell receptors and biological actions of this emerging class of mycobacterial virulence factors are reviewed.

Published
2009
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9. Novel STAT1 alleles in otherwise healthy patients with mycobacterial disease

Author

Claire Soudais, Capucine Picard, Angela Rösen-Wolff, Guillaume Vogt, C. Rolinck-Werninghaus, Emmanuelle Jouanguy, Jacqueline Feinberg, Jean-Laurent Casanova, Klaus Magdorf, Jacinta Bustamante, Kun Yang, Ada Prochnicka-Chalufour, Claire Fieschi, Orchidée Filipe Santos, Peter D. Arkwright, Joachim Roesler, Jean-François Emile, Robert D. Schreiber, Ludovic de Beaucoudrey, Stéphanie Boisson-Dupuis, Ariane Chapgier, Armanda Casrouge, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), French Chinese laboratory of Genetics (FRENCH CHINESE LABORATORY OF GENETICS), Rujin ospital, Shanghai II University, Résonance Magnétique Nucléaire des Biomolécules, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Service d'immunologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Service d'anatomie pathologique [CHU Ambroise-Paré], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Ambroise Paré [AP-HP], University of Manchester [Manchester], Department of Pathology and Immunology (DEPARTMENT OF PATHOLOGY AND IMMUNOLOGY), Washington University in Saint Louis (WUSTL), Department of Pediatric Pneumology and Immunology (DEPARTMENT OF PEDIATRIC PNEUMOLOGY AND IMMUNOLOGY), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], Department of Pediatrics (DEPARTMENT OF PEDIATRICS), University Clinic Carl Gustav Carus, Dresden, Service d'immuno-hématologie pédiatrique [CHU Necker], Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7)-Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], Service d'anatomie pathologique, Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Hôpital Ambroise Paré, Washington University in St Louis, Charité - Universitätsmedizin Berlin / Charite - University Medicine Berlin, Génétique Humaine des Maladies Infectieuses ( Inserm U980 ), Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Paris Descartes - Paris 5 ( UPD5 ), French Chinese laboratory of Genetics ( FRENCH CHINESE LABORATORY OF GENETICS ), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique ( CNRS ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Groupe Hospitalier Saint Louis - Lariboisière - Fernand Widal [Paris], Centre de Référence Déficits Immunitaires Héréditaires ( CEREDIH ), Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Université de Versailles Saint-Quentin-en-Yvelines ( UVSQ ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Ambroise Paré, Department of Pathology and Immunology ( DEPARTMENT OF PATHOLOGY AND IMMUNOLOGY ), Washington University Saint Louis Missouri, Department of Pediatric Pneumology and Immunology ( DEPARTMENT OF PEDIATRIC PNEUMOLOGY AND IMMUNOLOGY ), Charité, Humboldt University of Berlin, Department of Pediatrics ( DEPARTMENT OF PEDIATRICS ), and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Male, MESH : Mutant Proteins, Transcription, Genetic, DNA Mutational Analysis, Cell Cycle Proteins, 0302 clinical medicine, MESH : Cell Cycle Proteins, MESH : Child, MESH: Child, MESH : Interferon-Stimulated Gene Factor 3, gamma Subunit, STAT1, MESH: DNA Mutational Analysis, Child, Cells, Cultured, 0303 health sciences, MESH : Gene Expression Regulation, MESH : Infant, MESH : Interferon Type II, MESH : Protein Binding, MESH : Genes, Dominant, MESH: Infant, 3. Good health, Pedigree, STAT1 Transcription Factor, [SDV.IMM.IA]Life Sciences [q-bio]/Immunology/Adaptive immunology, 030220 oncology & carcinogenesis, Child, Preschool, MESH : DNA-Binding Proteins, MESH: Membrane Proteins, MESH: Models, Molecular, MESH: Cells, Cultured, MESH : Heterozygote, MESH: Pedigree, Immunology, Alpha interferon, MESH : DNA Mutational Analysis, GPI-Linked Proteins, Transfection, 03 medical and health sciences, Interferon-gamma, MESH: Cell Cycle Proteins, MESH : Adolescent, Genetics, MESH: Protein Binding, Humans, Molecular Biology, Ecology, Evolution, Behavior and Systematics, MESH: Genes, Recessive, Alleles, MESH: Adolescent, Mycobacterium Infections, MESH: Humans, MESH: STAT1 Tra, MESH : Immunity, Active, MESH : Humans, MESH: Child, Preschool, MESH : Genes, Recessive, Infant, MESH: Adult, Interferon-Stimulated Gene Factor 3, gamma Subunit, MESH : Membrane Proteins, MESH : Mycobacterium Infections, Mutation, MESH : Alleles, MESH: Genes, Dominant, MESH: Female, MESH: Immunity, Active, Models, Molecular, Cancer Research, MESH : Models, Biological, MESH : Child, Preschool, [ SDV.IMM.IA ] Life Sciences [q-bio]/Immunology/Adaptive immunology, Loss of heterozygosity, MESH: Mutant Proteins, Homo (Human), Interferon gamma, MESH : Female, Genetics (clinical), MESH: Heterozygote, Genes, Dominant, MESH : Adult, MESH: Gene Expression Regulation, DNA-Binding Proteins, Immunity, Active, Infectious Diseases, MESH : Interferon-alpha, MESH: Interferon-Stimulated Gene Factor 3, gamma Subunit, Female, MESH : Mutation, MESH: Interferon-alpha, medicine.drug, Protein Binding, Research Article, MESH : STAT1 Tra, Adult, Heterozygote, MESH: Mutation, lcsh:QH426-470, Adolescent, MESH : Models, Molecular, MESH: Interferon Type II, MESH : Male, Genetics/Genetics of Disease, Genes, Recessive, Biology, Models, Biological, Immunity, MESH : Cells, Cultured, medicine, Allele, MESH: Mycobacterium Infections, Gene, 030304 developmental biology, MESH: Alleles, MESH: Models, Biological, Interferon-alpha, Membrane Proteins, Heterozygote advantage, MESH: Male, lcsh:Genetics, Gene Expression Regulation, MESH : Pedigree, biology.protein, Mutant Proteins, MESH: DNA-Binding Proteins
Abstract

The transcription factor signal transducer and activator of transcription-1 (STAT1) plays a key role in immunity against mycobacterial and viral infections. Here, we characterize three human STAT1 germline alleles from otherwise healthy patients with mycobacterial disease. The previously reported L706S, like the novel Q463H and E320Q alleles, are intrinsically deleterious for both interferon gamma (IFNG)–induced gamma-activating factor–mediated immunity and interferon alpha (IFNA)–induced interferon-stimulated genes factor 3–mediated immunity, as shown in STAT1-deficient cells transfected with the corresponding alleles. Their phenotypic effects are however mediated by different molecular mechanisms, L706S affecting STAT1 phosphorylation and Q463H and E320Q affecting STAT1 DNA-binding activity. Heterozygous patients display specifically impaired IFNG-induced gamma-activating factor–mediated immunity, resulting in susceptibility to mycobacteria. Indeed, IFNA-induced interferon-stimulated genes factor 3–mediated immunity is not affected, and these patients are not particularly susceptible to viral disease, unlike patients homozygous for other, equally deleterious STAT1 mutations recessive for both phenotypes. The three STAT1 alleles are therefore dominant for IFNG-mediated antimycobacterial immunity but recessive for IFNA-mediated antiviral immunity at the cellular and clinical levels. These STAT1 alleles define two forms of dominant STAT1 deficiency, depending on whether the mutations impair STAT1 phosphorylation or DNA binding., Synopsis Mendelian susceptibility to mycobacterial disease is a rare syndrome. It is defined by the occurrence of severe disease caused by low virulence mycobacteria in otherwise healthy individuals, in whom antiviral immune response is not affected. Eleven known genetic defects, affecting five genes, have been involved in this type of deficient response to infection, involving immune-mediator molecules IL12 and interferon gamma: IL12B, IL12RB1, IFNGR1, IFNGR2, and STAT1. The signal transducer and activator of transcription-1 (STAT1) amino acid change L706S was previously shown to cause disease by impairing STAT1 phosphorylation. Here, we report two new STAT1 mutations that impair STAT1 DNA-binding activity. We show, by functional analysis of the three STAT1 mutant alleles, that they are intrinsically deleterious for both interferon gamma–induced antimycobacterial immunity, which is mediated through gamma-activated factor and for interferon alpha–induced antiviral immunity, which is mediated through interferon-stimulated genes factor 3. Interestingly, the three alleles are dominant for interferon gamma–induced gamma-activated factor–mediated antimycobacterial immunity, but recessive for interferon alpha–induced interferon-stimulated genes factor 3–mediated antiviral immunity at the cellular and clinical levels. These two new STAT1 alleles, which affect the binding of STAT1 to DNA, define distinct novel genetic causes of Mendelian susceptibility to mycobacterial disease and provide further insight into the molecular mechanism of disease.

Published
2006
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