Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.158
Filtrar
Más filtros

Intervalo de año de publicación
1.
Cell ; 186(23): 5114-5134.e27, 2023 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-37875108

RESUMEN

Human inherited disorders of interferon-gamma (IFN-γ) immunity underlie severe mycobacterial diseases. We report X-linked recessive MCTS1 deficiency in men with mycobacterial disease from kindreds of different ancestries (from China, Finland, Iran, and Saudi Arabia). Complete deficiency of this translation re-initiation factor impairs the translation of a subset of proteins, including the kinase JAK2 in all cell types tested, including T lymphocytes and phagocytes. JAK2 expression is sufficiently low to impair cellular responses to interleukin-23 (IL-23) and partially IL-12, but not other JAK2-dependent cytokines. Defective responses to IL-23 preferentially impair the production of IFN-γ by innate-like adaptive mucosal-associated invariant T cells (MAIT) and γδ T lymphocytes upon mycobacterial challenge. Surprisingly, the lack of MCTS1-dependent translation re-initiation and ribosome recycling seems to be otherwise physiologically redundant in these patients. These findings suggest that X-linked recessive human MCTS1 deficiency underlies isolated mycobacterial disease by impairing JAK2 translation in innate-like adaptive T lymphocytes, thereby impairing the IL-23-dependent induction of IFN-γ.


Asunto(s)
Interferón gamma , Janus Quinasa 2 , Infecciones por Mycobacterium , Humanos , Masculino , Proteínas de Ciclo Celular/metabolismo , Interferón gamma/inmunología , Interleucina-12 , Interleucina-23 , Janus Quinasa 2/metabolismo , Mycobacterium/fisiología , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/metabolismo , Proteínas Oncogénicas/metabolismo
2.
Cell ; 183(7): 1826-1847.e31, 2020 12 23.
Artículo en Inglés | MEDLINE | ID: mdl-33296702

RESUMEN

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+ αß T and non-classic CD4+ αß 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+ αß T, and CD4+ αß TH1∗ cells unable to compensate for this deficit.


Asunto(s)
Inmunidad Adaptativa , Inmunidad Innata , Interferón gamma/inmunología , Mycobacterium/inmunología , Proteínas de Dominio T Box/metabolismo , Secuencia de Aminoácidos , Secuencia de Bases , Linaje de la Célula , Preescolar , Cromatina/metabolismo , Islas de CpG/genética , Metilación de ADN/genética , Células Dendríticas/metabolismo , Epigénesis Genética , Femenino , Homocigoto , Humanos , Mutación INDEL/genética , Lactante , Interferón gamma/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Mutación con Pérdida de Función/genética , Masculino , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/microbiología , Linaje , Proteínas de Dominio T Box/química , Proteínas de Dominio T Box/deficiencia , Proteínas de Dominio T Box/genética , Linfocitos T Colaboradores-Inductores/inmunología , Transcriptoma/genética
3.
Cell ; 166(4): 920-934, 2016 Aug 11.
Artículo en Inglés | MEDLINE | ID: mdl-27499022

RESUMEN

Understanding how membrane nanoscale organization controls transmembrane receptors signaling activity remains a challenge. We studied interferon-γ receptor (IFN-γR) signaling in fibroblasts from homozygous patients with a T168N mutation in IFNGR2. By adding a neo-N-glycan on IFN-γR2 subunit, this mutation blocks IFN-γ activity by unknown mechanisms. We show that the lateral diffusion of IFN-γR2 is confined by sphingolipid/cholesterol nanodomains. In contrast, the IFN-γR2 T168N mutant diffusion is confined by distinct actin nanodomains where conformational changes required for Janus-activated tyrosine kinase/signal transducer and activator of transcription (JAK/STAT) activation by IFN-γ could not occur. Removing IFN-γR2 T168N-bound galectins restored lateral diffusion in lipid nanodomains and JAK/STAT signaling in patient cells, whereas adding galectins impaired these processes in control cells. These experiments prove the critical role of dynamic receptor interactions with actin and lipid nanodomains and reveal a new function for receptor glycosylation and galectins. Our study establishes the physiological relevance of membrane nanodomains in the control of transmembrane receptor signaling in vivo. VIDEO ABSTRACT.


Asunto(s)
Fibroblastos/metabolismo , Mutación Missense , Receptores de Interferón/genética , Receptores de Interferón/metabolismo , Transducción de Señal , Actinas/química , Actinas/metabolismo , Animales , Células COS , Membrana Celular/química , Membrana Celular/metabolismo , Chlorocebus aethiops , Difusión , Endocitosis , Activación Enzimática , Glicosilación , Humanos , Interferón gamma/metabolismo , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/inmunología , Receptores de Interferón/química
4.
Cell ; 165(1): 139-152, 2016 Mar 24.
Artículo en Inglés | MEDLINE | ID: mdl-27015311

RESUMEN

A zebrafish genetic screen for determinants of susceptibility to Mycobacterium marinum identified a hypersusceptible mutant deficient in lysosomal cysteine cathepsins that manifests hallmarks of human lysosomal storage diseases. Under homeostatic conditions, mutant macrophages accumulate undigested lysosomal material, which disrupts endocytic recycling and impairs their migration to, and thus engulfment of, dying cells. This causes a buildup of unengulfed cell debris. During mycobacterial infection, macrophages with lysosomal storage cannot migrate toward infected macrophages undergoing apoptosis in the tuberculous granuloma. The unengulfed apoptotic macrophages undergo secondary necrosis, causing granuloma breakdown and increased mycobacterial growth. Macrophage lysosomal storage similarly impairs migration to newly infecting mycobacteria. This phenotype is recapitulated in human smokers, who are at increased risk for tuberculosis. A majority of their alveolar macrophages exhibit lysosomal accumulations of tobacco smoke particulates and do not migrate to Mycobacterium tuberculosis. The incapacitation of highly microbicidal first-responding macrophages may contribute to smokers' susceptibility to tuberculosis.


Asunto(s)
Susceptibilidad a Enfermedades , Lisosomas/metabolismo , Macrófagos/inmunología , Macrófagos/patología , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/patología , Animales , Granuloma/metabolismo , Macrófagos/citología , Macrófagos Alveolares/inmunología , Mycobacterium marinum , Alveolos Pulmonares/inmunología , Fumar , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Vesículas Transportadoras/metabolismo , Tuberculosis/inmunología , Tuberculosis/patología , Pez Cebra , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo
5.
Nat Immunol ; 19(9): 973-985, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-30127434

RESUMEN

Human inborn errors of IFN-γ immunity underlie mycobacterial diseases. We describe patients with Mycobacterium bovis (BCG) disease who are homozygous for loss-of-function mutations of SPPL2A. This gene encodes a transmembrane protease that degrades the N-terminal fragment (NTF) of CD74 (HLA invariant chain) in antigen-presenting cells. The CD74 NTF therefore accumulates in the HLA class II+ myeloid and lymphoid cells of SPPL2a-deficient patients. This toxic fragment selectively depletes IL-12- and IL-23-producing CD1c+ conventional dendritic cells (cDC2s) and their circulating progenitors. Moreover, SPPL2a-deficient memory TH1* cells selectively fail to produce IFN-γ when stimulated with mycobacterial antigens in vitro. Finally, Sppl2a-/- mice lack cDC2s, have CD4+ T cells that produce small amounts of IFN-γ after BCG infection, and are highly susceptible to infection with BCG or Mycobacterium tuberculosis. These findings suggest that inherited SPPL2a deficiency in humans underlies mycobacterial disease by decreasing the numbers of cDC2s and impairing IFN-γ production by mycobacterium-specific memory TH1* cells.


Asunto(s)
Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Células Dendríticas/inmunología , Proteínas de la Membrana/metabolismo , Infecciones por Mycobacterium/inmunología , Mycobacterium bovis/fisiología , Mycobacterium tuberculosis/fisiología , Células TH1/inmunología , Tuberculosis/inmunología , Animales , Antígenos de Diferenciación de Linfocitos B/metabolismo , Células Cultivadas , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunidad , Memoria Inmunológica , Lactante , Interferón gamma/metabolismo , Linfadenopatía , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación/genética , Infecciones por Mycobacterium/genética , Vacunación
6.
Cell ; 148(3): 434-46, 2012 Feb 03.
Artículo en Inglés | MEDLINE | ID: mdl-22304914

RESUMEN

Susceptibility to tuberculosis is historically ascribed to an inadequate immune response that fails to control infecting mycobacteria. In zebrafish, we find that susceptibility to Mycobacterium marinum can result from either inadequate or excessive acute inflammation. Modulation of the leukotriene A(4) hydrolase (LTA4H) locus, which controls the balance of pro- and anti-inflammatory eicosanoids, reveals two distinct molecular routes to mycobacterial susceptibility converging on dysregulated TNF levels: inadequate inflammation caused by excess lipoxins and hyperinflammation driven by excess leukotriene B(4). We identify therapies that specifically target each of these extremes. In humans, we identify a single nucleotide polymorphism in the LTA4H promoter that regulates its transcriptional activity. In tuberculous meningitis, the polymorphism is associated with inflammatory cell recruitment, patient survival and response to adjunctive anti-inflammatory therapy. Together, our findings suggest that host-directed therapies tailored to patient LTA4H genotypes may counter detrimental effects of either extreme of inflammation.


Asunto(s)
Infecciones por Mycobacterium/tratamiento farmacológico , Infecciones por Mycobacterium/inmunología , Tuberculosis Meníngea/tratamiento farmacológico , Tuberculosis Meníngea/inmunología , Animales , Modelos Animales de Enfermedad , Humanos , Inflamación/inmunología , Leucotrieno A4/genética , Leucotrieno A4/inmunología , Leucotrieno B4/genética , Leucotrieno B4/inmunología , Lipoxinas/inmunología , Mitocondrias/metabolismo , Infecciones por Mycobacterium/genética , Mycobacterium marinum , Polimorfismo Genético , Polimorfismo de Nucleótido Simple , Regiones Promotoras Genéticas , Transducción de Señal , Transcripción Genética , Tuberculosis Meníngea/genética , Factor de Necrosis Tumoral alfa/metabolismo , Pez Cebra/embriología , Pez Cebra/inmunología
7.
Nat Immunol ; 14(7): 706-13, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23727893

RESUMEN

Human T cell antigen receptors (TCRs) pair in millions of combinations to create complex and unique T cell repertoires for each person. Through the use of tetramers to analyze TCRs reactive to the antigen-presenting molecule CD1b, we detected T cells with highly stereotyped TCR α-chains present among genetically unrelated patients with tuberculosis. The germline-encoded, mycolyl lipid-reactive (GEM) TCRs had an α-chain bearing the variable (V) region TRAV1-2 rearranged to the joining (J) region TRAJ9 with few nontemplated (N)-region additions. Analysis of TCRs by high-throughput sequencing, binding and crystallography showed linkage of TCRα sequence motifs to high-affinity recognition of antigen. Thus, the CD1-reactive TCR repertoire is composed of at least two compartments: high-affinity GEM TCRs, and more-diverse TCRs with low affinity for CD1b-lipid complexes. We found high interdonor conservation of TCRs that probably resulted from selection by a nonpolymorphic antigen-presenting molecule and an immunodominant antigen.


Asunto(s)
Antígenos CD1/inmunología , Infecciones por Mycobacterium/inmunología , Mycobacterium/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T/inmunología , Secuencia de Aminoácidos , Secuencia de Bases , Células Clonales , Cristalografía por Rayos X , Citometría de Flujo , Humanos , Modelos Moleculares , Datos de Secuencia Molecular , Infecciones por Mycobacterium/microbiología , ARN/química , ARN/genética , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Análisis de Secuencia de ADN , Subgrupos de Linfocitos T/citología , Linfocitos T/citología
8.
Immunity ; 45(6): 1245-1257, 2016 12 20.
Artículo en Inglés | MEDLINE | ID: mdl-27887882

RESUMEN

Phosphatidyl-inositol mannosides (PIM) are glycolipids unique to mycobacteria and other related bacteria that stimulate host immune responses and are implicated in mycobacteria pathogenicity. Here, we found that the FcRγ-coupled C-type lectin receptor DCAR (dendritic cell immunoactivating receptor; gene symbol Clec4b1) is a direct receptor for PIM. Mycobacteria activated reporter cells expressing DCAR, and delipidation of mycobacteria abolished this activity. Acylated PIMs purified from mycobacteria were identified as ligands for DCAR. DCAR was predominantly expressed in small peritoneal macrophages and monocyte-derived inflammatory cells in lungs and spleen. These cells produced monocyte chemoattractant protein-1 (MCP-1) upon PIM treatment, and absence of DCAR or FcRγ abrogated MCP-1 production. Upon mycobacterial infection, Clec4b1-deficient mice showed reduced numbers of monocyte-derived inflammatory cells at the infection site, impaired IFNγ production by T cells, and an increased bacterial load. Thus, DCAR is a critical receptor for PIM that functions to promote T cell responses against mycobacteria.


Asunto(s)
Proteínas Bacterianas/inmunología , Lectinas Tipo C/inmunología , Fosfatidilinositoles/inmunología , Receptores Inmunológicos/inmunología , Células TH1/inmunología , Animales , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium/inmunología , Infecciones por Mycobacterium/inmunología
9.
Nature ; 567(7746): 56-60, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30814731

RESUMEN

The cytokine interferon-γ (IFNγ) is a central coordinator of innate and adaptive immunity, but its highly pleiotropic actions have diminished its prospects for use as an immunotherapeutic agent. Here, we took a structure-based approach to decoupling IFNγ pleiotropy. We engineered an affinity-enhanced variant of the ligand-binding chain of the IFNγ receptor IFNγR1, which enabled us to determine the crystal structure of the complete hexameric (2:2:2) IFNγ-IFNγR1-IFNγR2 signalling complex at 3.25 Å resolution. The structure reveals the mechanism underlying deficits in IFNγ responsiveness in mycobacterial disease syndrome resulting from a T168N mutation in IFNγR2, which impairs assembly of the full signalling complex. The topology of the hexameric complex offers a blueprint for engineering IFNγ variants to tune IFNγ receptor signalling output. Unexpectedly, we found that several partial IFNγ agonists exhibited biased gene-expression profiles. These biased agonists retained the ability to induce upregulation of major histocompatibility complex class I antigen expression, but exhibited impaired induction of programmed death-ligand 1 expression in a wide range of human cancer cell lines, offering a route to decoupling immunostimulatory and immunosuppressive functions of IFNγ for therapeutic applications.


Asunto(s)
Diseño de Fármacos , Interferón gamma/agonistas , Interferón gamma/inmunología , Receptores de Interferón/química , Receptores de Interferón/metabolismo , Antígeno B7-H1/biosíntesis , Antígeno B7-H1/genética , Línea Celular Tumoral , Agonismo Parcial de Drogas , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/efectos de los fármacos , Antígenos de Histocompatibilidad Clase I/biosíntesis , Antígenos de Histocompatibilidad Clase I/genética , Humanos , Interferón gamma/química , Interferón gamma/genética , Ligandos , Modelos Moleculares , Mutación , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/inmunología , Estabilidad Proteica , Receptores de Interferón/genética , Transducción de Señal , Relación Estructura-Actividad , Receptor de Interferón gamma
10.
Cell Mol Life Sci ; 81(1): 380, 2024 Sep 02.
Artículo en Inglés | MEDLINE | ID: mdl-39222120

RESUMEN

The cytokine IFNγ is a principal effector of macrophage activation and immune resistance to mycobacterial infection; however, pathogenic mycobacteria are capable of surviving in IFNγ-activated macrophages by largely unknown mechanisms. In this study, we find that pathogenic mycobacteria, including M. bovis BCG and M. tuberculosis can sense IFNγ to promote their proliferative activity and virulence phenotype. Moreover, interaction with the host intracellular environment increases the susceptibility of mycobacteria to IFNγ through upregulating expression of mmpL10, a mycobacterial IFNγ receptor, thereby facilitating IFNγ-dependent survival and growth of mycobacteria in macrophages. Transmission electron microscopy analysis reveals that IFNγ triggers the secretion of extracellular vesicles, an essential virulence strategy of intracellular mycobacteria, while proteomics identifies numerous pivotal IFNγ-induced effectors required for mycobacterial infection in macrophages. Our study suggests that sensing host IFNγ is a crucial virulence mechanism used by pathogenic mycobacteria to survive and proliferate inside macrophages.


Asunto(s)
Interferón gamma , Macrófagos , Ratones Endogámicos C57BL , Mycobacterium tuberculosis , Interferón gamma/metabolismo , Interferón gamma/inmunología , Macrófagos/microbiología , Macrófagos/metabolismo , Macrófagos/inmunología , Animales , Ratones , Mycobacterium tuberculosis/patogenicidad , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/metabolismo , Mycobacterium bovis/inmunología , Mycobacterium bovis/metabolismo , Humanos , Interacciones Huésped-Patógeno/inmunología , Virulencia , Receptores de Interferón/metabolismo , Receptores de Interferón/genética , Receptor de Interferón gamma , Vesículas Extracelulares/metabolismo , Vesículas Extracelulares/inmunología , Activación de Macrófagos , Infecciones por Mycobacterium/microbiología , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/metabolismo , Infecciones por Mycobacterium/patología
11.
J Allergy Clin Immunol ; 153(5): 1432-1444, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38341181

RESUMEN

BACKGROUND: Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare clinical syndrome characterized by vulnerability to weakly virulent mycobacterial species, including Bacillus Calmette-Guérin (BCG) vaccines and environmental mycobacteria. OBJECTIVE: We sought to perform a systematic review of the genetic, immunologic, and clinical findings for reported patients with MSMD. METHODS: We searched PubMed, Web of Science, and Scopus databases for publications in English relating to MSMD. All full texts were evaluated for eligibility for inclusion. Two reviewers independently selected the publications, with a third reviewer consulted in cases of disagreement. RESULTS: A primary systematic search and searches of other resources identified 16,155 articles. In total, 158 articles from 63 countries were included in qualitative and quantitative analyses. In total, 830 patients-436 males (52.5%), 369 females (44.5%), and 25 patients of unknown sex (3.0%)-from 581 families were evaluated. A positive family history was reported in 347 patients (45.5%). The patients had a mean age of 10.41 ± 0.42 (SEM) years. The frequency of MSMD was highest in Iran, Turkey, and Saudi Arabia. Lymphadenopathy was the most common clinical manifestation of MSMD, reported in 378 (45.5%) cases and multifocal in 35.1%. Fever, organomegaly, and sepsis were the next most frequent findings, reported in 251 (30.2%), 206 (24.8%), and 171 (20.8%) cases, respectively. In total, 299 unique mutations in 21 genes known to be involved in MSMD were reported: 100 missense (34%), 80 indel-frameshift (insertion or deletion, 27%), 53 nonsense (18%), 35 splice site (12%), 10 indel-in frame (2.7%), 6 indel (2%), and 15 large deletion/duplication mutations. Finally, 61% of the reported patients with MSMD had mutations of IL12RB1 (41%) or IFNGR1 (20%). At the time of the report, 177 of the patients (21.3%) were dead and 597 (71.9%) were still alive. CONCLUSIONS: MSMD is associated with a high mortality rate, mostly due to impaired control of infection. Preexposure strategies, such as changes in vaccination policy in endemic areas, the establishment of a worldwide registry of patients with MSMD, and precise follow-up over generations in affected families, appear to be vital to decrease MSMD-related mortality.


Asunto(s)
Predisposición Genética a la Enfermedad , Infecciones por Mycobacterium , Humanos , Infecciones por Mycobacterium/genética , Infecciones por Mycobacterium/inmunología , Masculino , Femenino , Niño , Vacuna BCG/inmunología
12.
Cell ; 136(1): 17-9, 2009 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-19135882

RESUMEN

By investigating host-pathogen interactions in zebrafish using intravital imaging, Davis and Ramakrishnan (2009) provide evidence that aggregates of immune cells known as granulomas, long thought to constrain mycobacterial infection, may instead facilitate its spread.


Asunto(s)
Granuloma/inmunología , Granuloma/microbiología , Interacciones Huésped-Patógeno , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/microbiología , Animales , Mycobacterium/inmunología , Pez Cebra
13.
Cell ; 136(1): 37-49, 2009 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-19135887

RESUMEN

Granulomas, organized aggregates of immune cells, form in response to persistent stimuli and are hallmarks of tuberculosis. Tuberculous granulomas have long been considered host-protective structures formed to contain infection. However, work in zebrafish infected with Mycobacterium marinum suggests that granulomas contribute to early bacterial growth. Here we use quantitative intravital microscopy to reveal distinct steps of granuloma formation and assess their consequence for infection. Intracellular mycobacteria use the ESX-1/RD1 virulence locus to induce recruitment of new macrophages to, and their rapid movement within, nascent granulomas. This motility enables multiple arriving macrophages to efficiently find and phagocytose infected macrophages undergoing apoptosis, leading to rapid, iterative expansion of infected macrophages and thereby bacterial numbers. The primary granuloma then seeds secondary granulomas via egress of infected macrophages. Our direct observations provide insight into how pathogenic mycobacteria exploit the granuloma during the innate immune phase for local expansion and systemic dissemination.


Asunto(s)
Granuloma/inmunología , Granuloma/microbiología , Interacciones Huésped-Patógeno , Infecciones por Mycobacterium no Tuberculosas/inmunología , Tuberculosis/inmunología , Animales , Apoptosis , Quimiotaxis , Granuloma/patología , Humanos , Macrófagos/citología , Macrófagos/inmunología , Macrófagos/microbiología , Infecciones por Mycobacterium/inmunología , Infecciones por Mycobacterium/patología , Infecciones por Mycobacterium no Tuberculosas/patología , Mycobacterium marinum/inmunología , Mycobacterium tuberculosis , Fagocitosis , Tuberculosis/patología , Factores de Virulencia , Pez Cebra
14.
Immunity ; 41(3): 402-413, 2014 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-25176311

RESUMEN

Mycobacteria possess various immunomodulatory molecules on the cell wall. Mannose-capped lipoarabinomannan (Man-LAM), a major lipoglycan of Mycobacterium tuberculosis, has long been known to have both inhibitory and stimulatory effects on host immunity. However, the direct Man-LAM receptor that explains its pleiotropic activities has not been clearly identified. Here, we report that a C-type lectin receptor Dectin-2 (gene symbol Clec4n) is a direct receptor for Man-LAM. Man-LAM activated bone-marrow-derived dendritic cells (BMDCs) to produce pro- and anti-inflammatory cytokines, whereas it was completely abrogated in Clec4n(-/-) BMDCs. Man-LAM promoted antigen-specific T cell responses through Dectin-2 on DCs. Furthermore, Man-LAM induced experimental autoimmune encephalitis (EAE) as an adjuvant in mice, whereas Clec4n(-/-) mice were resistant. Upon mycobacterial infection, Clec4n(-/-) mice showed augmented lung pathology. These results demonstrate that Dectin-2 contributes to host immunity against mycobacterial infection through the recognition of Man-LAM.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Lectinas Tipo C/inmunología , Lipopolisacáridos/inmunología , Infecciones por Mycobacterium/inmunología , Animales , Antígenos CD/genética , Moléculas de Adhesión Celular/genética , Citocinas/biosíntesis , Células Dendríticas/inmunología , Encefalomielitis Autoinmune Experimental/genética , Inflamación/inmunología , Interferón gamma/biosíntesis , Interleucina-10/biosíntesis , Lectinas Tipo C/genética , Lipopolisacáridos/química , Manosa/química , Receptor de Manosa , Lectinas de Unión a Manosa/inmunología , Ratones , Ratones Noqueados , Infecciones por Mycobacterium/genética , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/inmunología , Factor 88 de Diferenciación Mieloide/genética , Unión Proteica/inmunología , Receptores de Superficie Celular/genética , Receptores de Superficie Celular/inmunología , Receptores Inmunológicos/genética , Linfocitos T/inmunología
15.
Immunity ; 38(5): 1050-62, 2013 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-23602766

RESUMEN

Cord factor, also called trehalose-6,6'-dimycolate (TDM), is a potent mycobacterial adjuvant. We herein report that the C-type lectin MCL (also called Clec4d) is a TDM receptor that is likely to arise from gene duplication of Mincle (also called Clec4e). Mincle is known to be an inducible receptor recognizing TDM, whereas MCL was constitutively expressed in myeloid cells. To examine the contribution of MCL in response to TDM adjuvant, we generated MCL-deficient mice. TDM promoted innate immune responses, such as granuloma formation, which was severely impaired in MCL-deficient mice. TDM-induced acquired immune responses, such as experimental autoimmune encephalomyelitis (EAE), was almost completely dependent on MCL, but not Mincle. Furthermore, by generating Clec4e(gfp) reporter mice, we found that MCL was also crucial for driving Mincle induction upon TDM stimulation. These results suggest that MCL is an FcRγ-coupled activating receptor that mediates the adjuvanticity of TDM.


Asunto(s)
Factores Cordón/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Lectinas Tipo C/inmunología , Proteínas de la Membrana/metabolismo , Receptores de IgG/inmunología , Adyuvantes Inmunológicos , Animales , Encefalomielitis Autoinmune Experimental/microbiología , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infecciones por Mycobacterium/inmunología , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/inmunología
16.
Immunity ; 39(3): 537-47, 2013 Sep 19.
Artículo en Inglés | MEDLINE | ID: mdl-24035364

RESUMEN

Autophagy and phagocytosis are conserved cellular functions involved in innate immunity. However, the nature of their interactions remains unclear. We evaluated the role of autophagy in regulating phagocytosis in macrophages from myeloid-specific autophagy-related gene 7-deficient (Atg7⁻/⁻) mice. Atg7⁻/⁻ macrophages exhibited higher bacterial uptake when infected with Mycobacterium tuberculosis (Mtb) or with M. tuberculosis var. bovis BCG (BCG). In addition, BCG-infected Atg7⁻/⁻ mice showed increased bacterial loads and exacerbated lung inflammatory responses. Atg7⁻/⁻ macrophages had increased expression of two class A scavenger receptors: macrophage receptor with collagenous structure (MARCO) and macrophage scavenger receptor 1 (MSR1). The increase in scavenger receptors was caused by increased activity of the nuclear factor (erythroid-derived 2)-like 2 (NFE2L2) transcription factor resulting from accumulated sequestosome 1 (SQSTM1 or p62) in Atg7⁻/⁻ macrophages. These insights increase our understanding of the host-pathogen relationship and suggest that therapeutic strategies should be designed to include modulation of both phagocytosis and autophagy.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Autofagia/inmunología , Proteínas de Choque Térmico/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Factor 2 Relacionado con NF-E2/metabolismo , Fagocitosis/inmunología , Receptores Inmunológicos/biosíntesis , Receptores Depuradores de Clase A/biosíntesis , Animales , Proteína 7 Relacionada con la Autofagia , Carga Bacteriana/inmunología , Células Cultivadas , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/genética , Infecciones por Mycobacterium/inmunología , Mycobacterium bovis/crecimiento & desarrollo , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/inmunología , Neumonía/inmunología , Neumonía/microbiología , Receptores Depuradores/biosíntesis , Receptores Depuradores/inmunología , Proteína Sequestosoma-1 , Regulación hacia Arriba
17.
BMC Pulm Med ; 22(1): 57, 2022 Feb 09.
Artículo en Inglés | MEDLINE | ID: mdl-35139852

RESUMEN

BACKGROUND: Extracellular vesicles (EVs) play a key role in cell communication and the pathogenesis of some diseases. EVs may accelerate cell death during the course of mycobacterial infection and are also considered as a new vaccine design, drug delivery, and biomarker candidates. The current study evaluates the effects of EVs from serum samples of mycobacteria-infected patients on THP-1 monocytes and PBMC cells. METHOD: EVs were purified from the serum, then cultured separately with THP-1 monocytes and PBMCs. The cell death was determined through annexin V-FITC and PI staining. GW4869, an EVs inhibitor, was used to determine if EVs released from serum could increase THP-1 monocytes cell death. RESULTS: The cell death was significantly increased in the presence of 10 µg/ml and 5 µg/ml concentrations of the purified EVs (p < 0.05). Minimal cell death was determined in 2.5 µg/ml and 1.2 µg/ml (p < 0.05). Up to 85% of the cells were viable in the presence of the GW4869 inhibitor (p < 0.05). CONCLUSION: Direct infection of the cells with EVs released from mycobacteria-infected patients samples, the multiplicity of infection with the EVs, and virulent or avirulent mycobacteria may change the status of the cell death. The isolated EVs  from serum samples of patients with mycobacterial  infection accelerated cell death, which means that they might   not be considered as an optimal tool for developing drug delivery and vaccine against tuberculosis.


Asunto(s)
Muerte Celular , Vesículas Extracelulares/metabolismo , Infecciones por Mycobacterium/inmunología , Mycobacterium/fisiología , Adulto , Anciano de 80 o más Años , Femenino , Humanos , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , Mycobacterium/inmunología , Infecciones por Mycobacterium/metabolismo , Infecciones por Mycobacterium/microbiología , Células THP-1 , Virulencia
18.
Int J Mol Sci ; 23(3)2022 Jan 20.
Artículo en Inglés | MEDLINE | ID: mdl-35163035

RESUMEN

Cytokine receptors are critical regulators of the antimycobacterial immune response, playing a key role in initiating and coordinating the recruitment and activation of immune cells during infection. They recognize and bind specific cytokines and are involved in inducing intracellular signal transduction pathways that regulate a diverse range of biological functions, including proliferation, differentiation, metabolism and cell growth. Due to mutations in cytokine receptor genes, defective signaling may contribute to increased susceptibility to mycobacteria, allowing the pathogens to avoid killing and immune surveillance. This paper provides an overview of cytokine receptors important for the innate and adaptive immune responses against mycobacteria and discusses the implications of receptor gene defects for the course of mycobacterial infection.


Asunto(s)
Mutación , Infecciones por Mycobacterium/inmunología , Receptores de Citocinas/metabolismo , Inmunidad Adaptativa , Animales , Citocinas/metabolismo , Humanos , Inmunidad Innata , Infecciones por Mycobacterium/genética , Receptores de Citocinas/genética , Transducción de Señal
19.
BMC Immunol ; 22(1): 62, 2021 09 13.
Artículo en Inglés | MEDLINE | ID: mdl-34517836

RESUMEN

BACKGROUND: Mendelian Susceptibility to Mycobacterial Disease (MSMD) is a primary immunodeficiency (PID) characterised by a predisposition to infection by weakly-pathogenic mycobacteria. In countries with a high prevalence of tuberculosis (TB), individuals with MSMD are also prone to infections by Mycobacterium tuberculosis. Several MSMD-associated genes have been described, all resulting in a disruption of IL-12 and IFN-γ cytokine axis, which is essential for control of mycobacterial infections. An accurate molecular diagnosis, confirmed by phenotypic and functional immune investigations, is essential to ensure that the patient receives optimal treatment and prophylaxis for infections. The aim of this study was to implement a set of functional assays to assess the integrity of the IL-12-IFN-γ cytokine pathways in patients presenting with severe, persistent, unusual and/or recurrent TB, mycobacterial infections or other clinical MSMD-defining infections such as Salmonella. METHODS: Blood was collected for subsequent PBMC isolation from 16 participants with MSMD-like clinical phenotypes. A set of flow cytometry (phenotype and signalling integrity) and ELISA-based (cytokine production) functional assays were implemented to assess the integrity of the IL-12-IFN-γ pathway. RESULTS: The combination of the three assays for the assessment of the integrity of the IL-12-IFN-γ pathway was successful in identifying immune deficits in the IL-12-IFN-γ pathway in all of the participants included in this study. CONCLUSIONS: The data presented here emphasise the importance of investigating PID and TB susceptibility in TB endemic regions such as South Africa as MSMD and other previously described PIDs relating to TB susceptibility may present differently in such regions. It is therefore important to have access to in vitro functional investigations to better understand the immune function of these individuals. Although functional assays alone are unlikely to always provide a clear diagnosis, they do give an overview of the integrity of the IL-12-IFN-γ pathway. It would be beneficial to apply these assays routinely to patients with suspected PID relating to mycobacterial susceptibility. A molecular diagnosis with confirmed functional impairment paves the way for targeted treatment and improved disease management options for these patients.


Asunto(s)
Infecciones por Mycobacterium/inmunología , Mycobacterium tuberculosis/fisiología , Niño , Preescolar , Susceptibilidad a Enfermedades , Femenino , Humanos , Lactante , Interferón gamma/metabolismo , Interleucina-12/metabolismo , Masculino , Análisis de la Aleatorización Mendeliana , Infecciones por Mycobacterium/diagnóstico , Infecciones por Mycobacterium/epidemiología , Fenotipo , Transducción de Señal , Sudáfrica/epidemiología , Adulto Joven
20.
Immunol Cell Biol ; 99(10): 1067-1076, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34555867

RESUMEN

The proinflammatory cytokine tumor necrosis factor (TNF) plays a central role in the host control of mycobacterial infections. Expression and release of TNF are tightly regulated, yet the molecular mechanisms that control the release of TNF by mycobacteria-infected host cells, in particular macrophages, are incompletely understood. Rab GTPases direct the transport of intracellular membrane-enclosed vesicles and are important regulators of macrophage cytokine secretion. Rab6b is known to be predominantly expressed in the brain where it functions in retrograde transport and anterograde vesicle transport for exocytosis. Whether it executes similar functions in the context of immune responses is unknown. Here we show that Rab6b is expressed by primary mouse macrophages, where it localized to the Golgi complex. Infection with Mycobacterium bovis bacille Calmette-Guérin (BCG) resulted in dynamic changes in Rab6b expression in primary mouse macrophages in vitro as well as in organs from infected mice in vivo. We further show that Rab6b facilitated TNF release by M. bovis BCG-infected macrophages, in the absence of discernible impact on Tnf messenger RNA and intracellular TNF protein expression. Our observations identify Rab6b as a positive regulator of M. bovis BCG-induced TNF trafficking and secretion by macrophages and positions Rab6b among the molecular machinery that orchestrates inflammatory cytokine responses by macrophages.


Asunto(s)
Aparato de Golgi/inmunología , Macrófagos/inmunología , Infecciones por Mycobacterium , Factor de Necrosis Tumoral alfa/inmunología , Proteínas de Unión al GTP rab/inmunología , Animales , Ratones , Infecciones por Mycobacterium/inmunología , Mycobacterium bovis
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA