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1.
Immunity ; 44(2): 368-79, 2016 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-26885859

RESUMEN

Humans that are heterozygous for the common S180L polymorphism in the Toll-like receptor (TLR) adaptor Mal (encoded by TIRAP) are protected from a number of infectious diseases, including tuberculosis (TB), whereas those homozygous for the allele are at increased risk. The reason for this difference in susceptibility is not clear. We report that Mal has a TLR-independent role in interferon-gamma (IFN-γ) receptor signaling. Mal-dependent IFN-γ receptor (IFNGR) signaling led to mitogen-activated protein kinase (MAPK) p38 phosphorylation and autophagy. IFN-γ signaling via Mal was required for phagosome maturation and killing of intracellular Mycobacterium tuberculosis (Mtb). The S180L polymorphism, and its murine equivalent S200L, reduced the affinity of Mal for the IFNGR, thereby compromising IFNGR signaling in macrophages and impairing responses to TB. Our findings highlight a role for Mal outside the TLR system and imply that genetic variation in TIRAP may be linked to other IFN-γ-related diseases including autoimmunity and cancer.


Asunto(s)
Interferón gamma/metabolismo , Macrófagos/fisiología , Glicoproteínas de Membrana/metabolismo , Mycobacterium tuberculosis/inmunología , Receptores de Interleucina-1/metabolismo , Tuberculosis Pulmonar/inmunología , Animales , Autofagia/genética , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Células HEK293 , Humanos , Inmunidad Innata/genética , Sistema de Señalización de MAP Quinasas/genética , Macrófagos/microbiología , Glicoproteínas de Membrana/genética , Ratones , Ratones Noqueados , Polimorfismo Genético , Unión Proteica/genética , ARN Interferente Pequeño/genética , Receptores de Interferón/metabolismo , Receptores de Interleucina-1/genética , Tuberculosis Pulmonar/genética , Receptor de Interferón gamma
2.
PLoS Pathog ; 17(3): e1009410, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33720986

RESUMEN

The Mycobacterium tuberculosis complex (MTBC) is a group of related pathogens that cause tuberculosis (TB) in mammals. MTBC species are distinguished by their ability to sustain in distinct host populations. While Mycobacterium bovis (Mbv) sustains transmission cycles in cattle and wild animals and causes zoonotic TB, M. tuberculosis (Mtb) affects human populations and seldom causes disease in cattle. The host and pathogen determinants underlying host tropism between MTBC species are still unknown. Macrophages are the main host cell that encounters mycobacteria upon initial infection, and we hypothesised that early interactions between the macrophage and mycobacteria influence species-specific disease outcome. To identify factors that contribute to host tropism, we analysed blood-derived primary human and bovine macrophages (hMϕ or bMϕ, respectively) infected with Mbv and Mtb. We show that Mbv and Mtb reside in different cellular compartments and differentially replicate in hMϕ whereas both Mbv and Mtb efficiently replicate in bMϕ. Specifically, we show that out of the four infection combinations, only the infection of bMϕ with Mbv promoted the formation of multinucleated giant cells (MNGCs), a hallmark of tuberculous granulomas. Mechanistically, we demonstrate that both MPB70 from Mbv and extracellular vesicles released by Mbv-infected bMϕ promote macrophage multinucleation. Importantly, we extended our in vitro studies to show that granulomas from Mbv-infected but not Mtb-infected cattle contained higher numbers of MNGCs. Our findings implicate MNGC formation in the contrasting pathology between Mtb and Mbv for the bovine host and identify MPB70 from Mbv and extracellular vesicles from bMϕ as mediators of this process.


Asunto(s)
Interacciones Huésped-Patógeno/fisiología , Macrófagos/microbiología , Mycobacterium bovis , Mycobacterium tuberculosis , Tuberculosis/microbiología , Tropismo Viral/fisiología , Animales , Bovinos , Células Gigantes , Humanos
3.
NAR Genom Bioinform ; 3(3): lqab070, 2021 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-34396095

RESUMEN

Current evolutionary scenarios posit the emergence of Mycobacterium tuberculosis from an environmental saprophyte through a cumulative process of genome adaptation. Mycobacterium riyadhense, a related bacillus, is being increasingly isolated from human clinical cases with tuberculosis-like symptoms in various parts of the world. To elucidate the evolutionary relationship between M. riyadhense and other mycobacterial species, including members of the M. tuberculosis complex (MTBC), eight clinical isolates of M. riyadhense were sequenced and analyzed. We show, among other features, that M. riyadhense shares a large number of conserved orthologs with M. tuberculosis and shows the expansion of toxin/antitoxin pairs, PE/PPE family proteins compared with other non-tuberculous mycobacteria. We observed M. riyadhense lacks wecE gene which may result in the absence of lipooligosaccharides (LOS) IV. Comparative transcriptomic analysis of infected macrophages reveals genes encoding inducers of Type I IFN responses, such as cytosolic DNA sensors, were relatively less expressed by macrophages infected with M. riyadhense or M. kansasii, compared to BCG or M. tuberculosis. Overall, our work sheds new light on the evolution of M. riyadhense, its relationship to the MTBC, and its potential as a system for the study of mycobacterial virulence and pathogenesis.

4.
Cell Rep ; 30(1): 124-136.e4, 2020 01 07.
Artículo en Inglés | MEDLINE | ID: mdl-31914380

RESUMEN

Increased glycolytic metabolism recently emerged as an essential process driving host defense against Mycobacterium tuberculosis (Mtb), but little is known about how this process is regulated during infection. Here, we observe repression of host glycolysis in Mtb-infected macrophages, which is dependent on sustained upregulation of anti-inflammatory microRNA-21 (miR-21) by proliferating mycobacteria. The dampening of glycolysis by miR-21 is mediated through targeting of phosphofructokinase muscle (PFK-M) isoform at the committed step of glycolysis, which facilitates bacterial growth by limiting pro-inflammatory mediators, chiefly interleukin-1ß (IL-1ß). Unlike other glycolytic genes, PFK-M expression and activity is repressed during Mtb infection through miR-21-mediated regulation, while other less-active isoenzymes dominate. Notably, interferon-γ (IFN-γ), which drives Mtb host defense, inhibits miR-21 expression, forcing an isoenzyme switch in the PFK complex, augmenting PFK-M expression and macrophage glycolysis. These findings place the targeting of PFK-M by miR-21 as a key node controlling macrophage immunometabolic function.


Asunto(s)
Glucólisis , Interacciones Huésped-Patógeno , Interleucina-1beta/metabolismo , MicroARNs/metabolismo , Mycobacterium tuberculosis/fisiología , Fosfofructoquinasa-1/metabolismo , Animales , Antiinflamatorios/metabolismo , Secuencia de Bases , Proliferación Celular , Células HEK293 , Humanos , Interferón gamma/metabolismo , Activación de Macrófagos , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/microbiología , Ratones , MicroARNs/genética , Fosfofructoquinasa-1/genética , Células RAW 264.7 , Tuberculosis/microbiología
5.
Microb Genom ; 4(3)2018 03.
Artículo en Inglés | MEDLINE | ID: mdl-29557774

RESUMEN

Members of the Mycobacterium tuberculosis complex (MTBC) are the causative agents of tuberculosis in a range of mammals, including humans. A key feature of MTBC pathogens is their high degree of genetic identity yet distinct host tropism. Notably, while Mycobacterium bovis is highly virulent and pathogenic for cattle, the human pathogen M. tuberculosis is attenuated in cattle. Previous research also suggests that host preference amongst MTBC members has a basis in host innate immune responses. To explore MTBC host tropism, we present in-depth profiling of the MTBC reference strains M. bovis AF2122/97 and M. tuberculosis H37Rv at both the global transcriptional and the translational level via RNA-sequencing and SWATH MS. Furthermore, a bovine alveolar macrophage infection time course model was used to investigate the shared and divergent host transcriptomic response to infection with M. tuberculosis H37Rv or M. bovis AF2122/97. Significant differential expression of virulence-associated pathways between the two bacilli was revealed, including the ESX-1 secretion system. A divergent transcriptional response was observed between M. tuberculosis H37Rv and M. bovis AF2122/97 infection of bovine alveolar macrophages, in particular cytosolic DNA-sensing pathways at 48 h post-infection, and highlights a distinct engagement of M. bovis with the bovine innate immune system. The work presented here therefore provides a basis for the identification of host innate immune mechanisms subverted by virulent host-adapted mycobacteria to promote their survival during the early stages of infection.


Asunto(s)
Inmunidad Innata , Macrófagos Alveolares , Mycobacterium bovis , Mycobacterium tuberculosis , Transcriptoma , Tuberculosis Bovina , Tuberculosis Pulmonar , Animales , Bovinos , Humanos , Macrófagos Alveolares/metabolismo , Macrófagos Alveolares/microbiología , Mycobacterium bovis/genética , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/inmunología , Proteómica , Tuberculosis Bovina/genética , Tuberculosis Bovina/inmunología , Tuberculosis Pulmonar/genética , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología
6.
Sci Rep ; 8(1): 894, 2018 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-29343690

RESUMEN

The Mycobacterium tuberculosis complex (MTBC) is the collective term given to the group of bacteria that cause tuberculosis (TB) in mammals. It has been reported that M. tuberculosis H37Rv, a standard reference MTBC strain, is attenuated in cattle compared to Mycobacterium bovis. However, as M. tuberculosis H37Rv was isolated in the early 1930s, and genetic variants are known to exist, we sought to revisit this question of attenuation of M. tuberculosis for cattle by performing a bovine experimental infection with a recent M. tuberculosis isolate. Here we report infection of cattle using M. bovis AF2122/97, M. tuberculosis H37Rv, and M. tuberculosis BTB1558, the latter isolated in 2008 during a TB surveillance project in Ethiopian cattle. We show that both M. tuberculosis strains caused reduced gross pathology and histopathology in cattle compared to M. bovis. Using M. tuberculosis H37Rv and M. bovis AF2122/97 as the extremes in terms of infection outcome, we used RNA-Seq analysis to explore differences in the peripheral response to infection as a route to identify biomarkers of progressive disease in contrast to a more quiescent, latent infection. Our work shows the attenuation of M. tuberculosis strains for cattle, and emphasizes the potential of the bovine model as a 'One Health' approach to inform human TB biomarker development and post-exposure vaccine development.


Asunto(s)
Bacillus/inmunología , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis Bovina/inmunología , Tuberculosis/inmunología , Animales , Biomarcadores/metabolismo , Bovinos , Femenino , Humanos , Tuberculosis/metabolismo , Tuberculosis/microbiología , Tuberculosis Bovina/metabolismo , Tuberculosis Bovina/microbiología
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