Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 143
Filtrar
Más filtros

País/Región como asunto
Intervalo de año de publicación
2.
Mol Cell ; 82(13): 2385-2400.e9, 2022 07 07.
Artículo en Inglés | MEDLINE | ID: mdl-35594856

RESUMEN

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.


Asunto(s)
COVID-19 , Proteasas 3C de Coronavirus , Células Epiteliales , Inflamasomas , Proteínas NLR , SARS-CoV-2 , COVID-19/genética , COVID-19/metabolismo , COVID-19/virología , Caspasa 3/metabolismo , Proteasas 3C de Coronavirus/genética , Proteasas 3C de Coronavirus/metabolismo , Células Epiteliales/metabolismo , Humanos , Inflamasomas/genética , Inflamasomas/metabolismo , Pulmón/metabolismo , Pulmón/virología , Proteínas NLR/genética , Proteínas NLR/metabolismo , Péptido Hidrolasas/genética , Péptido Hidrolasas/metabolismo , Proteínas de Unión a Fosfato/genética , Proteínas de Unión a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Piroptosis , SARS-CoV-2/enzimología , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad
3.
PLoS Biol ; 22(4): e3002259, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38683873

RESUMEN

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.


Asunto(s)
Antituberculosos , Modelos Animales de Enfermedad , Macrófagos , Mycobacterium tuberculosis , Oxadiazoles , Tuberculosis , Zinc , Animales , Oxadiazoles/farmacología , Humanos , Antituberculosos/farmacología , Antituberculosos/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Zinc/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Tuberculosis/tratamiento farmacológico , Ratones Endogámicos C57BL , Femenino , Sinergismo Farmacológico
4.
Mol Cell ; 73(6): 1282-1291.e8, 2019 03 21.
Artículo en Inglés | MEDLINE | ID: mdl-30792174

RESUMEN

Toxin-antitoxin (TA) systems regulate fundamental cellular processes in bacteria and represent potential therapeutic targets. We report a new RES-Xre TA system in multiple human pathogens, including Mycobacterium tuberculosis. The toxin, MbcT, is bactericidal unless neutralized by its antitoxin MbcA. To investigate the mechanism, we solved the 1.8 Å-resolution crystal structure of the MbcTA complex. We found that MbcT resembles secreted NAD+-dependent bacterial exotoxins, such as diphtheria toxin. Indeed, MbcT catalyzes NAD+ degradation in vitro and in vivo. Unexpectedly, the reaction is stimulated by inorganic phosphate, and our data reveal that MbcT is a NAD+ phosphorylase. In the absence of MbcA, MbcT triggers rapid M. tuberculosis cell death, which reduces mycobacterial survival in macrophages and prolongs the survival of infected mice. Our study expands the molecular activities employed by bacterial TA modules and uncovers a new class of enzymes that could be exploited to treat tuberculosis and other infectious diseases.


Asunto(s)
Antitoxinas/metabolismo , Proteínas Bacterianas/metabolismo , Toxinas Bacterianas/metabolismo , Macrófagos/microbiología , Mycobacterium tuberculosis/enzimología , Fosforilasas/metabolismo , Sistemas Toxina-Antitoxina , Tuberculosis/microbiología , Animales , Antibióticos Antituberculosos/farmacología , Antitoxinas/química , Antitoxinas/genética , Carga Bacteriana , Proteínas Bacterianas/química , Proteínas Bacterianas/genética , Toxinas Bacterianas/química , Toxinas Bacterianas/genética , Células Cultivadas , Modelos Animales de Enfermedad , Femenino , Interacciones Huésped-Patógeno , Humanos , Cinética , Macrófagos/efectos de los fármacos , Ratones Endogámicos C57BL , Ratones SCID , Ratones Transgénicos , Viabilidad Microbiana , Modelos Moleculares , Mycobacterium smegmatis/enzimología , Mycobacterium smegmatis/genética , Mycobacterium smegmatis/patogenicidad , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/patogenicidad , NAD/metabolismo , Fosforilasas/química , Fosforilasas/genética , Conformación Proteica , Sistemas Toxina-Antitoxina/genética , Tuberculosis/tratamiento farmacológico
5.
Mol Microbiol ; 120(4): 502-507, 2023 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-37303242

RESUMEN

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.

6.
Mol Microbiol ; 117(3): 682-692, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-34605588

RESUMEN

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.


Asunto(s)
Mycobacterium abscessus , Mycobacterium tuberculosis , Tuberculosis , Humanos , Macrófagos/microbiología , Micobacterias no Tuberculosas , Organoides , Tuberculosis/microbiología
7.
J Immunol ; 207(7): 1857-1870, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34479945

RESUMEN

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.


Asunto(s)
Lactobacillus/fisiología , Pulmón/inmunología , Mycobacterium tuberculosis/fisiología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Tuberculosis Pulmonar/inmunología , Animales , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Pulmón/microbiología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Neumonía
8.
PLoS Pathog ; 16(10): e1008929, 2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-33002063

RESUMEN

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 ß-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.


Asunto(s)
Células Espumosas/microbiología , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Metabolismo de los Lípidos , Macrófagos/microbiología , Mycobacterium tuberculosis/patogenicidad , Animales , Gotas Lipídicas/metabolismo , Activación de Macrófagos/fisiología , Macrófagos/metabolismo , Masculino , Ratones Endogámicos BALB C , Mycobacterium tuberculosis/fisiología , Tuberculosis/microbiología
9.
Immunity ; 38(5): 1038-49, 2013 May 23.
Artículo en Inglés | MEDLINE | ID: mdl-23684988

RESUMEN

Macrophages act as the primary effector cells during Leishmania infection through production of reactive oxygen species (ROS) and interleukin-1ß (IL-1ß). However, how macrophage-killing mechanisms are activated during Leishmania-macrophage interactions is poorly understood. Here, we report that the macrophage response against Leishmania infantum in vivo is characterized by an M2b-like phenotype and C-type lectin receptors (CLRs) signature composed of Dectin-1, mannose receptor (MR), and the DC-SIGN homolog SIGNR3 expression. Dectin-1 and MR were crucial for the microbicidal response as indicated by the fact that they activated Syk-p47phox and arachidonic acid (AA)-NADPH oxidase signaling pathways, respectively, needed for ROS production and also triggered Syk-coupled signaling for caspase-1-induced IL-1ß secretion. In contrast, SIGNR3 has divergent functions during Leishmania infantum pathogenesis; this CLR favored parasite resilience through inhibition of the LTB4-IL-1ß axis. These pathways also operated during infection of primary human macrophages. Therefore, our study promotes CLRs as potential targets for treatment, diagnosis, and prevention of visceral leishmaniasis.


Asunto(s)
Antígenos CD/metabolismo , Lectinas Tipo C/metabolismo , Leishmania infantum/inmunología , Macrófagos/inmunología , Lectinas de Unión a Manosa/metabolismo , Receptores de Superficie Celular/metabolismo , Animales , Ácido Araquidónico/metabolismo , Caspasa 1/metabolismo , Células Cultivadas , Humanos , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Lectinas Tipo C/inmunología , Leishmaniasis Visceral/inmunología , Leishmaniasis Visceral/parasitología , Leucotrieno B4/antagonistas & inhibidores , Receptor de Manosa , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , NADPH Oxidasas/metabolismo , Proteínas Tirosina Quinasas/metabolismo , Interferencia de ARN , ARN Interferente Pequeño , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal , Quinasa Syk
10.
Int J Mol Sci ; 23(21)2022 Nov 07.
Artículo en Inglés | MEDLINE | ID: mdl-36362409

RESUMEN

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.


Asunto(s)
Tratamiento Farmacológico de COVID-19 , SARS-CoV-2 , Animales , Ratones , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antivirales/farmacología , Antivirales/uso terapéutico , Ceramidas , Modelos Animales de Enfermedad , Fluoxetina/farmacología , Fluoxetina/uso terapéutico
11.
Curr Top Microbiol Immunol ; 429: 19-62, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32060645

RESUMEN

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.


Asunto(s)
Lectinas Tipo C , Receptores de Reconocimiento de Patrones , Inmunidad Innata , Lectinas Tipo C/genética , Lectinas Tipo C/metabolismo , Moléculas de Patrón Molecular Asociado a Patógenos , Receptores de Reconocimiento de Patrones/genética , Transducción de Señal
12.
Artículo en Inglés | MEDLINE | ID: mdl-32253217

RESUMEN

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.


Asunto(s)
Infecciones por Mycobacterium no Tuberculosas , Mycobacterium abscessus , Animales , Antibacterianos/farmacología , Diarilquinolinas , Imipenem/farmacología , Ratones , Pruebas de Sensibilidad Microbiana , Infecciones por Mycobacterium no Tuberculosas/tratamiento farmacológico
13.
Proc Natl Acad Sci U S A ; 114(42): 11205-11210, 2017 10 17.
Artículo en Inglés | MEDLINE | ID: mdl-28973928

RESUMEN

Mycobacterium tuberculosis is a major human pathogen that is able to survive inside host cells and resist immune clearance. Most particularly, it inhibits several arms of the innate immune response, including phagosome maturation or cytokine production. To better understand the molecular mechanisms by which M. tuberculosis circumvents host immune defenses, we used a transposon mutant library generated in a virulent clinical isolate of M. tuberculosis of the W/Beijing family to infect human macrophages, utilizing a cell line derivative of THP-1 cells expressing a reporter system for activation of the transcription factor NF-κB, a key regulator of innate immunity. We identified several M. tuberculosis mutants inducing a NF-κB activation stronger than that of the wild-type strain. One of these mutants was found to be deficient for the synthesis of cell envelope glycolipids, namely sulfoglycolipids, suggesting that the latter can interfere with innate immune responses. Using natural and synthetic molecular variants, we determined that sulfoglycolipids inhibit NF-κB activation and subsequent cytokine production or costimulatory molecule expression by acting as competitive antagonists of Toll-like receptor 2, thereby inhibiting the recognition of M. tuberculosis by this receptor. Our study reveals that producing glycolipid antagonists of pattern recognition receptors is a strategy used by M. tuberculosis to undermine innate immune defense. Sulfoglycolipids are major and specific lipids of M. tuberculosis, considered for decades as virulence factors of the bacilli. Our study uncovers a mechanism by which they may contribute to M. tuberculosis virulence.


Asunto(s)
Glucolípidos/metabolismo , Inmunidad Innata , Mycobacterium tuberculosis/metabolismo , Receptor Toll-Like 2/antagonistas & inhibidores , Glucolípidos/farmacología , Humanos , Macrófagos/metabolismo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/inmunología , FN-kappa B/metabolismo
14.
Proc Natl Acad Sci U S A ; 114(4): E540-E549, 2017 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-28069953

RESUMEN

Immune response against pathogens is a tightly regulated process that must ensure microbial control while preserving integrity of the infected organs. Tuberculosis (TB) is a paramount example of a chronic infection in which antimicrobial immunity is protective in the vast majority of infected individuals but can become detrimental if not finely tuned. Here, we report that C-type lectin dendritic cell (DC) immunoreceptor (DCIR), a key component in DC homeostasis, is required to modulate lung inflammation and bacterial burden in TB. DCIR is abundantly expressed in pulmonary lesions in Mycobacterium tuberculosis-infected nonhuman primates during both latent and active disease. In mice, we found that DCIR deficiency impairs STAT1-mediated type I IFN signaling in DCs, leading to increased production of IL-12 and increased differentiation of T lymphocytes toward Th1 during infection. As a consequence, DCIR-deficient mice control M. tuberculosis better than WT animals but also develop more inflammation characterized by an increased production of TNF and inducible NOS (iNOS) in the lungs. Altogether, our results reveal a pathway by which a C-type lectin modulates the equilibrium between infection-driven inflammation and pathogen's control through sustaining type I IFN signaling in DCs.


Asunto(s)
Células Dendríticas/inmunología , Interferón Tipo I/inmunología , Lectinas Tipo C/inmunología , Tuberculosis/inmunología , Animales , Femenino , Lectinas Tipo C/genética , Macaca mulatta , Ratones Endogámicos C57BL , Ratones Noqueados , Fosforilación , Factor de Transcripción STAT1/inmunología , Transducción de Señal
15.
EMBO J ; 34(7): 829-31, 2015 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-25736375

RESUMEN

Beneficial microbes hold great promise for the treatment of a wide range of immune and inflammatory disorders. In this issue of The EMBO Journal, Lightfoot and colleagues report how the food-grade bacterium Lactobacillus acidophilus helps the immune system to limit experimental colitis in mice through interaction between SIGNR3 and surface layer protein A (SlpA) in L. acidophilus. These results pave the way for future development of novel therapies for inflammatory diseases, including inflammatory bowel disease.


Asunto(s)
Antígenos CD/inmunología , Proteínas Bacterianas/inmunología , Enfermedades Inflamatorias del Intestino/inmunología , Mucosa Intestinal/inmunología , Lactobacillus acidophilus/inmunología , Lectinas Tipo C/inmunología , Animales
16.
PLoS Pathog ; 13(11): e1006752, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-29176894

RESUMEN

The unique ability of the tuberculosis (TB) bacillus, Mycobacterium tuberculosis, to persist for long periods of time in lung hypoxic lesions chiefly contributes to the global burden of latent TB. We and others previously reported that the M. tuberculosis ancestor underwent massive episodes of horizontal gene transfer (HGT), mostly from environmental species. Here, we sought to explore whether such ancient HGT played a part in M. tuberculosis evolution towards pathogenicity. We were interested by a HGT-acquired M. tuberculosis-specific gene set, namely moaA1-D1, which is involved in the biosynthesis of the molybdenum cofactor. Horizontal acquisition of this gene set was striking because homologues of these moa genes are present all across the Mycobacterium genus, including in M. tuberculosis. Here, we discovered that, unlike their paralogues, the moaA1-D1 genes are strongly induced under hypoxia. In vitro, a M. tuberculosis moaA1-D1-null mutant has an impaired ability to respire nitrate, to enter dormancy and to survive in oxygen-limiting conditions. Conversely, heterologous expression of moaA1-D1 in the phylogenetically closest non-TB mycobacterium, Mycobacterium kansasii, which lacks these genes, improves its capacity to respire nitrate and grants it with a marked ability to survive oxygen depletion. In vivo, the M. tuberculosis moaA1-D1-null mutant shows impaired survival in hypoxic granulomas in C3HeB/FeJ mice, but not in normoxic lesions in C57BL/6 animals. Collectively, our results identify a novel pathway required for M. tuberculosis resistance to host-imposed stress, namely hypoxia, and provide evidence that ancient HGT bolstered M. tuberculosis evolution from an environmental species towards a pervasive human-adapted pathogen.


Asunto(s)
Coenzimas/biosíntesis , Transferencia de Gen Horizontal , Metaloproteínas/biosíntesis , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Oxígeno/metabolismo , Tuberculosis/microbiología , Animales , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , Femenino , Regulación Bacteriana de la Expresión Génica , Humanos , Hipoxia/metabolismo , Hipoxia/microbiología , Ratones , Ratones Endogámicos C57BL , Cofactores de Molibdeno , Mycobacterium/genética , Mycobacterium/metabolismo , Nitratos/metabolismo , Pteridinas , Tuberculosis/metabolismo
17.
Cell Microbiol ; 20(12): e12966, 2018 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-30329198

RESUMEN

The pulmonary microbial community, described only a few years ago, forms a discreet part of the human host microbiota. The airway microbiota has been found to be substantially altered in the context of numerous respiratory disorders; nonetheless, its role in health and disease is as yet only poorly understood. Another important parameter to consider is the gut-lung axis, where distal (gut) immune modulation during respiratory disease is mediated by the gut microbiota. The use of specific microbiota strains, termed "probiotics," with beneficial effects on the host immunity and/or against pathogens, has proven successful in the treatment of intestinal disorders and is also showing promise in the context of airway diseases. In this review, we highlight the beneficial role of the body's commensal bacteria during airway infectious diseases, including recent evidence highlighting their local (lung) or distal (gut) contribution in this process.


Asunto(s)
Pulmón/microbiología , Microbiota/fisiología , Infecciones del Sistema Respiratorio/microbiología , Animales , Disbiosis/microbiología , Microbioma Gastrointestinal , Interacciones Huésped-Patógeno/fisiología , Humanos , Probióticos/uso terapéutico
18.
Am J Respir Crit Care Med ; 197(6): 801-813, 2018 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-29161093

RESUMEN

RATIONALE: In addition to their well-known function as antibody-producing cells, B lymphocytes can markedly influence the course of infectious or noninfectious diseases via antibody-independent mechanisms. In tuberculosis (TB), B cells accumulate in lungs, yet their functional contribution to the host response remains poorly understood. OBJECTIVES: To document the role of B cells in TB in an unbiased manner. METHODS: We generated the transcriptome of B cells isolated from Mycobacterium tuberculosis (Mtb)-infected mice and validated the identified key pathways using in vitro and in vivo assays. The obtained data were substantiated using B cells from pleural effusion of patients with TB. MEASUREMENTS AND MAIN RESULTS: B cells isolated from Mtb-infected mice displayed a STAT1 (signal transducer and activator of transcription 1)-centered signature, suggesting a role for IFNs in B-cell response to infection. B cells stimulated in vitro with Mtb produced type I IFN, via a mechanism involving the innate sensor STING (stimulator of interferon genes), and antagonized by MyD88 (myeloid differentiation primary response 88) signaling. In vivo, B cells expressed type I IFN in the lungs of Mtb-infected mice and, of clinical relevance, in pleural fluid from patients with TB. Type I IFN expression by B cells induced an altered polarization of macrophages toward a regulatory/antiinflammatory profile in vitro. In vivo, increased provision of type I IFN by B cells in a murine model of B cell-restricted Myd88 deficiency correlated with an enhanced accumulation of regulatory/antiinflammatory macrophages in Mtb-infected lungs. CONCLUSIONS: Type I IFN produced by Mtb-stimulated B cells favors macrophage polarization toward a regulatory/antiinflammatory phenotype during Mtb infection.


Asunto(s)
Linfocitos B/metabolismo , Interferón Tipo I/metabolismo , Macrófagos/metabolismo , Tuberculosis/metabolismo , Animales , Modelos Animales de Enfermedad , Humanos , Pulmón/metabolismo , Pulmón/microbiología , Ratones , Ratones Endogámicos C57BL , Mycobacterium tuberculosis , Transducción de Señal , Bazo/metabolismo , Bazo/microbiología
19.
Mem Inst Oswaldo Cruz ; 114: e190102, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31411311

RESUMEN

BACKGROUND: Once in the pulmonary alveoli, Mycobacterium tuberculosis (Mtb) enters into contact with alveolar macrophages and dendritic cells (DCs). DCs represent the link between the innate and adaptive immune system owing to their capacity to be both a sentinel and an orchestrator of the antigen-specific immune responses against Mtb. The effect that the virulence of Mtb has on the interaction between the bacilli and human DCs has not been fully explored. OBJECTIVE: To evaluate the effect of Mtb virulence on human monocyte-derived DCs. METHODS: We exposed human monocyte-derived DCs to Mtb clinical strains (isolated from an epidemiological Mtb diversity study in Mexico) bearing different degrees of virulence and evaluated the capacity of DCs to internalise the bacilli, control intracellular growth, engage cell death pathways, express markers for activation and antigen presentation, and expand to stimulate autologous CD4+ T cells proliferation. FINDINGS: In the case of the hypervirulent Mtb strain (Phenotype 1, strain 9005186, lineage 3), we report that DCs internalise and neutralise intracellular growth of the bacilli, undergo low rates of apoptosis, and contribute poorly to T-cell expansion, as compared to the H37Rv reference strain. In the case of the hypovirulent Mtb strain (Phenotype 4, strain 9985449, lineage 4), although DCs internalise and preclude proliferation of the bacilli, the DCs also display a high level of apoptosis, massive levels of apoptosis that prevent them from maintaining autologous CD4+ T cells in a co-culture system, as compared to H37Rv. MAIN CONCLUSIONS: Our findings suggest that variability in virulence among Mtb clinical strains affects the capacity of DCs to respond to pathogenic challenge and mount an immune response against it, highlighting important parallels to studies previously done in mouse models.


Asunto(s)
Células Dendríticas/virología , Activación de Linfocitos , Mycobacterium tuberculosis/patogenicidad , Linfocitos T Reguladores/parasitología , Animales , Humanos , Ratones , Transducción de Señal , Virulencia
20.
Immunol Rev ; 264(1): 249-63, 2015 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-25703564

RESUMEN

Mycobacterium tuberculosis is a facultative intracellular pathogen that thrives inside host macrophages. A key trait of M. tuberculosis is to exploit and manipulate metal cation trafficking inside infected macrophages to ensure survival and replication inside the phagosome. Here, we describe the recent fascinating discoveries that the mammalian immune system responds to infections with M. tuberculosis by overloading the phagosome with copper and zinc, two metals which are essential nutrients in small quantities but are toxic in excess. M. tuberculosis has developed multi-faceted resistance mechanisms to protect itself from metal toxicity including control of uptake, sequestration inside the cell, oxidation, and efflux. The host response to infections combines this metal poisoning strategy with nutritional immunity mechanisms that deprive M. tuberculosis from metals such as iron and manganese to prevent bacterial replication. Both immune mechanisms rely on the translocation of metal transporter proteins to the phagosomal membrane during the maturation process of the phagosome. This review summarizes these recent findings and discusses how metal-targeted approaches might complement existing TB chemotherapeutic regimens with novel anti-infective therapies.


Asunto(s)
Interacciones Huésped-Patógeno , Macrófagos/inmunología , Macrófagos/metabolismo , Metales/metabolismo , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Tuberculosis/metabolismo , Animales , Antituberculosos/uso terapéutico , Antituberculosos/toxicidad , Cobre/metabolismo , Humanos , Inmunidad Innata , Hierro/metabolismo , Macrófagos/microbiología , Metales/uso terapéutico , Metales/toxicidad , Mycobacterium tuberculosis/efectos de los fármacos , Mycobacterium tuberculosis/patogenicidad , Fagosomas/metabolismo , Fagosomas/microbiología , Tuberculosis/tratamiento farmacológico , Tuberculosis/microbiología , Virulencia , Zinc/metabolismo
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA