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1.
Front Immunol ; 12: 687044, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34630380

RESUMO

Phagosome-lysosome fusion in innate immune cells like macrophages and neutrophils marshal an essential role in eliminating intracellular microorganisms. In microbe-challenged macrophages, phagosome-lysosome fusion occurs 4 to 6 h after the phagocytic uptake of the microbe. However, live pathogenic mycobacteria hinder the transfer of phagosomes to lysosomes, up to 20 h post-phagocytic uptake. This period is required to evade pro-inflammatory response and upregulate the acid-stress tolerant proteins. The exact sequence of events through which mycobacteria retards phagolysosome formation remains an enigma. The macrophage coat protein Coronin1(Cor1) is recruited and retained by mycobacteria on the phagosome membrane to retard its maturation by hindering the access of phagosome maturation factors. Mycobacteria-infected macrophages exhibit an increased cAMP level, and based on receptor stimulus, Cor1 expressing cells show a higher level of cAMP than non-Cor1 expressing cells. Here we have shown that infection of bone marrow-derived macrophages with H37Rv causes a Cor1 dependent rise of intracellular cAMP levels at the vicinity of the phagosomes. This increased cAMP fuels cytoskeletal protein Cofilin1 to depolymerize F-actin around the mycobacteria-containing phagosome. Owing to reduced F-actin levels, the movement of the phagosome toward the lysosomes is hindered, thus contributing to the retarded phagosome maturation process. Additionally, Cor1 mediated upregulation of Cofilin1 also contributes to the prevention of phagosomal acidification, which further aids in the retardation of phagosome maturation. Overall, our study provides first-hand information on Cor1 mediated retardation of phagosome maturation, which can be utilized in developing novel peptidomimetics as part of host-directed therapeutics against tuberculosis.


Assuntos
Cofilina 1/metabolismo , AMP Cíclico/metabolismo , Macrófagos/microbiologia , Proteínas dos Microfilamentos/metabolismo , Infecções por Mycobacterium não Tuberculosas/microbiologia , Mycobacterium bovis/patogenicidade , Mycobacterium smegmatis/patogenicidade , Mycobacterium tuberculosis/patogenicidade , Fagossomos/microbiologia , Tuberculose/microbiologia , Animais , Linhagem Celular , Interações Hospedeiro-Patógeno , Concentração de Íons de Hidrogênio , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Proteínas dos Microfilamentos/genética , Infecções por Mycobacterium não Tuberculosas/imunologia , Infecções por Mycobacterium não Tuberculosas/metabolismo , Mycobacterium bovis/imunologia , Mycobacterium smegmatis/imunologia , Mycobacterium tuberculosis/imunologia , Fagossomos/imunologia , Fagossomos/metabolismo , Sistemas do Segundo Mensageiro , Tuberculose/imunologia , Tuberculose/metabolismo
2.
BMC Vet Res ; 17(1): 148, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33827573

RESUMO

BACKGROUND: Although the pathogenic effect of members of the Mycobacterium tuberculosis complex in susceptible hosts is well known, differences in clinical signs and pathological findings observed in infected animals have been reported, likely due to a combination of host and pathogen-related factors. Here, we investigated whether Mycobacterium bovis strains belonging to different spoligotypes were associated with a higher risk of occurrence of visible/more severe lesions in target organs (lungs and/or lymph nodes) from infected animals. A large collection of 8889 samples belonging to cattle were classified depending on the presence/absence of tuberculosis-like lesions and its degree of severity. All samples were subjected to culture irrespective of the presence of lesions, and isolates retrieved were identified and subjected to spoligotyping. The association between the presence/severity of the lesions and the isolation of strains from a given spoligotype was assessed using non-parametric tests and Bayesian mixed multivariable logistic regression models that accounted for origin (region and herd) effects. RESULTS: Results suggested a difference in severity in lesioned samples depending on the strain's spoligotype. An association between specific spoligotypes and presence of lesions was observed, with a higher risk of finding lesions in animals infected with strains with spoligotypes SB0120, SB0295 and SB1142 compared with SB0121, and in those coming from certain regions in Spain. CONCLUSIONS: Our results suggest that strains belonging to certain spoligotypes may be associated with a higher probability in the occurrence of gross/macroscopic lesions in infected cattle, although these observational findings should be confirmed in further studies that allow accounting for the effect of other possible confounders not considered here, and ultimately through experimental studies.


Assuntos
Técnicas de Tipagem Bacteriana/veterinária , Doenças dos Bovinos/microbiologia , Mycobacterium bovis/classificação , Tuberculose Bovina/patologia , Animais , Bovinos , Doenças dos Bovinos/patologia , Pulmão/microbiologia , Pulmão/patologia , Linfonodos/microbiologia , Mycobacterium bovis/patogenicidade , Tuberculose Bovina/microbiologia
3.
PLoS One ; 16(3): e0248426, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33735292

RESUMO

Industry-led culling of badgers has occurred in England to reduce the incidence of bovine tuberculosis in cattle for a number of years. Badger vaccination is also possible, and a move away from culling was "highly desirable" in a recent report to the UK government. Here we used an established simulation model to examine badger control option in a post-cull environment in England. These options included no control, various intermittent culling, badger vaccination and use of a vaccine combined with fertility control. The initial simulated cull led to a dramatic reduction in the number of infected badgers present, which increased slowly if there was no further badger management. All three approaches led to a further reduction in the number of infected badgers, with little to choose between the strategies. We do note that of the management strategies only vaccination on its own leads to a recovery of the badger population, but also an increase in the number of badgers that need to be vaccinated. We conclude that vaccination post-cull, appears to be particularly effective, compared to vaccination when the host population is at carrying capacity.


Assuntos
Abate de Animais/métodos , Reservatórios de Doenças/veterinária , Mustelidae/microbiologia , Tuberculose Bovina/prevenção & controle , Vacinação/métodos , Abate de Animais/estatística & dados numéricos , Animais , Bovinos , Simulação por Computador , Inglaterra , Incidência , Modelos Estatísticos , Mycobacterium bovis/imunologia , Mycobacterium bovis/isolamento & purificação , Mycobacterium bovis/patogenicidade , Controle da População/métodos , Controle da População/estatística & dados numéricos , Tuberculose Bovina/transmissão , Vacinação/estatística & dados numéricos
4.
Biomed Pharmacother ; 137: 111341, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33561646

RESUMO

Mycobacterium bovis (M. bovis) is a member of mycobacterium tuberculosis complex (MTBC), and a causative agent of chronic respiratory disease in a wide range of hosts. Bacillus Calmette-Guerin (BCG) vaccine is mostly used for the prevention of childhood tuberculosis. Further substantial implications are required for the development and evaluation of new tuberculosis (TB) vaccines as well as improving the role of BCG in TB control strategies. In this study, we prepared PLGA nanoparticles encapsulated with argF antigen (argF-NPs). We hypothesized, that argF nanoparticles mediate immune responses of BCG vaccine in mice models of M. bovis infection. We observed that mice vaccinated with argF-NPs exhibited a significant increase in secretory IFN-γ, CD4+ T cells response and mucosal secretory IgA against M. bovis infection. In addition, a marked increase was observed in the level of secretory IL-1ß, TNF-α and IL-10 both in vitro and in vivo upon argF-NPs vaccination. Furthermore, argF-NPs vaccination resulted in a significant reduction in the inflammatory lesions in the lung's tissues, minimized the losses in total body weight and reduced M. bovis burden in infected mice. Our results indicate that BCG prime-boost strategy might be a promising measure for the prevention against M. bovis infection by induction of CD4+ T cells responses and mucosal antibodies.


Assuntos
Vacina BCG/administração & dosagem , Vacina BCG/imunologia , Mycobacterium bovis , Nanopartículas/administração & dosagem , Ornitina Carbamoiltransferase/imunologia , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/imunologia , Tuberculose Bovina/prevenção & controle , Administração Intranasal , Animais , Formação de Anticorpos/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Bovinos , Linhagem Celular , Modelos Animais de Doenças , Feminino , Imunoglobulina A Secretora/metabolismo , Imunoglobulina G/sangue , Interferon gama/metabolismo , Interleucina-10/sangue , Interleucina-1beta/sangue , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos Endogâmicos BALB C , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/patogenicidade , Nanopartículas/química , Ornitina Carbamoiltransferase/administração & dosagem , Ornitina Carbamoiltransferase/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/química , Proteínas Recombinantes/imunologia , Baço/microbiologia , Baço/patologia , Fator de Necrose Tumoral alfa/sangue
5.
Proc Natl Acad Sci U S A ; 118(3)2021 01 19.
Artigo em Inglês | MEDLINE | ID: mdl-33431676

RESUMO

Pathogen interactions arising during coinfection can exacerbate disease severity, for example when the immune response mounted against one pathogen negatively affects defense of another. It is also possible that host immune responses to a pathogen, shaped by historical evolutionary interactions between host and pathogen, may modify host immune defenses in ways that have repercussions for other pathogens. In this case, negative interactions between two pathogens could emerge even in the absence of concurrent infection. Parasitic worms and tuberculosis (TB) are involved in one of the most geographically extensive of pathogen interactions, and during coinfection worms can exacerbate TB disease outcomes. Here, we show that in a wild mammal natural resistance to worms affects bovine tuberculosis (BTB) severity independently of active worm infection. We found that worm-resistant individuals were more likely to die of BTB than were nonresistant individuals, and their disease progressed more quickly. Anthelmintic treatment moderated, but did not eliminate, the resistance effect, and the effects of resistance and treatment were opposite and additive, with untreated, resistant individuals experiencing the highest mortality. Furthermore, resistance and anthelmintic treatment had nonoverlapping effects on BTB pathology. The effects of resistance manifested in the lungs (the primary site of BTB infection), while the effects of treatment manifested almost entirely in the lymph nodes (the site of disseminated disease), suggesting that resistance and active worm infection affect BTB progression via distinct mechanisms. Our findings reveal that interactions between pathogens can occur as a consequence of processes arising on very different timescales.


Assuntos
Búfalos/imunologia , Resistência à Doença , Hemoncose/microbiologia , Pulmão/imunologia , Linfonodos/imunologia , Tricostrongilose/microbiologia , Tuberculose Bovina/microbiologia , Animais , Antinematódeos/farmacologia , Búfalos/microbiologia , Búfalos/parasitologia , Bovinos , Coinfecção , Progressão da Doença , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Eosinófilos/microbiologia , Eosinófilos/parasitologia , Fezes/parasitologia , Feminino , Fenbendazol/farmacologia , Hemoncose/tratamento farmacológico , Hemoncose/mortalidade , Hemoncose/parasitologia , Haemonchus/efeitos dos fármacos , Haemonchus/genética , Haemonchus/patogenicidade , Imunoglobulina A/sangue , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/parasitologia , Linfonodos/efeitos dos fármacos , Linfonodos/microbiologia , Linfonodos/parasitologia , Mastócitos/efeitos dos fármacos , Mastócitos/imunologia , Mastócitos/microbiologia , Mastócitos/parasitologia , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/patogenicidade , Índice de Gravidade de Doença , Análise de Sobrevida , Tricostrongilose/tratamento farmacológico , Tricostrongilose/mortalidade , Tricostrongilose/parasitologia , Trichostrongylus/efeitos dos fármacos , Trichostrongylus/genética , Trichostrongylus/patogenicidade , Tuberculose Bovina/tratamento farmacológico , Tuberculose Bovina/mortalidade , Tuberculose Bovina/parasitologia
6.
J Infect Dis ; 223(3): 494-507, 2021 02 13.
Artigo em Inglês | MEDLINE | ID: mdl-33206171

RESUMO

BACKGROUND: The role of myeloid-derived suppressor cells (MDSCs) in patients with severe tuberculosis who suffer from uncontrolled pulmonary inflammation caused by hypervirulent mycobacterial infection remains unclear. METHODS: This issue was addressed using C57BL/6 mice infected with highly virulent Mycobacterium bovis strain MP287/03. RESULTS: CD11b+GR1int population increased in the bone marrow, blood and lungs during advanced disease. Pulmonary CD11b+GR1int (Ly6GintLy6Cint) cells showed granularity similar to neutrophils and expressed immature myeloid cell markers. These immature neutrophils harbored intracellular bacilli and were preferentially located in the alveoli. T-cell suppression occurred concomitantly with CD11b+GR1int cell accumulation in the lungs. Furthermore, lung and bone marrow GR1+ cells suppressed both T-cell proliferation and interferon γ production in vitro. Anti-GR1 therapy given when MDSCs infiltrated the lungs prevented expansion and fusion of primary pulmonary lesions and the development of intragranulomatous caseous necrosis, along with increased mouse survival and partial recovery of T-cell function. Lung bacterial load was reduced by anti-GR1 treatment, but mycobacteria released from the depleted cells proliferated extracellularly in the alveoli, forming cords and clumps. CONCLUSIONS: Granulocytic MDSCs massively infiltrate the lungs during infection with hypervirulent mycobacteria, promoting bacterial growth and the development of inflammatory and necrotic lesions, and are promising targets for host-directed therapies.


Assuntos
Granulócitos , Pulmão/metabolismo , Mycobacterium bovis , Células Supressoras Mieloides , Tuberculose , Animais , Antígenos Ly , Medula Óssea , Antígeno CD11b , Proliferação de Células , Modelos Animais de Doenças , Granulócitos/imunologia , Imunomodulação , Pulmão/patologia , Camundongos , Camundongos Endogâmicos C57BL , Mycobacterium bovis/patogenicidade , Células Mieloides , Células Supressoras Mieloides/imunologia , Células Supressoras Mieloides/patologia , Neutrófilos , Tuberculose/patologia
7.
Int Immunopharmacol ; 91: 107215, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33348294

RESUMO

The survivability of Mycobacterium tuberculosis (M.tb) in macrophages in granuloma is a predominant cause for tuberculosis (TB) infection and recurrence. However, the mechanism of mycobacterial clearance in macrophages still needs further study. Here, we explored a novel role of B and T lymphocyte Attenuator (BTLA) in macrophage-mediated host defense against mycobacterial infection. We found that the surface expression of BTLA was increased in CD14+ monocytes from active TB patients. The mRNA levels of BTLA were induced in human and mice monocytes/macrophages during Mycobacterium bovis BCG or M.tb H37Rv infection, as well as spleen and lung of H37Rv-infected mice. Furthermore, silencing of BTLA promoted the intracellular survival of BCG and H37Rv by suppressing the autophagy in macrophages but not effecting phagocytosis, reactive oxygen species (ROS) and apoptosis. Silence of BTLA reduced bacterial-autophagosome and bacterial-lysosome colocalization. Moreover, BTLA inhibited AKT and mTOR signaling substrates S6K and 4EBP1 phosphorylation in BCG and H37Rv infected macrophages, and BTLA-mediated AKT-mTOR signaling and intracellular BCG survival were reversed by PI3K inhibitors in macrophages. Finally, treatment with BTLA agonist ameliorated lung pathology and promoted autophagy and mycobacterial clearance during mycobacterial infection in vivo. These results demonstrate that BTLA promotes host defense against mycobacteria by enhancing autophagy, which may provide potential therapeutic interventions against tuberculosis.


Assuntos
Autofagia , Pulmão/enzimologia , Macrófagos/enzimologia , Mycobacterium bovis/patogenicidade , Mycobacterium tuberculosis/patogenicidade , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores Imunológicos/metabolismo , Serina-Treonina Quinases TOR/metabolismo , Tuberculose Pulmonar/enzimologia , Animais , Antituberculosos/farmacologia , Autofagia/efeitos dos fármacos , Modelos Animais de Doenças , Interações Hospedeiro-Patógeno , Humanos , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Nus , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Células RAW 264.7 , Receptores Imunológicos/agonistas , Receptores Imunológicos/genética , Transdução de Sinais , Células THP-1 , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/microbiologia , Tuberculose Pulmonar/prevenção & controle
8.
Sci Rep ; 10(1): 20856, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33257726

RESUMO

Animal tuberculosis (TB), caused by Mycobacterium bovis, is maintained in Portugal in a multi-host system, with cattle, red deer and wild boar, playing a central role. However, the ecological processes driving transmission are not understood. The main aim of this study was thus to contribute to the reconstruction of the spatiotemporal history of animal TB and to refine knowledge on M. bovis population structure in order to inform novel intervention strategies. A collection of 948 M. bovis isolates obtained during long-term surveillance (2002-2016, 15 years) of cattle (n = 384), red deer (n = 303) and wild boar (n = 261), from the main TB hotspot areas, was characterized by spoligotyping and 8 to 12-loci MIRU-VNTR. Spoligotyping identified 64 profiles and MIRU-VNTR distinguished 2 to 36 subtypes within each spoligotype, enabling differentiation of mixed or clonal populations. Common genotypic profiles within and among livestock and wildlife in the same spatiotemporal context highlighted epidemiological links across hosts and regions, as for example the SB0119-M205 genotype shared by cattle in Beja district or SB0121-M34 shared by the three hosts in Castelo Branco and Beja districts. These genomic data, together with metadata, were integrated in a Bayesian inference framework, identifying five ancestral M. bovis populations. The phylogeographic segregation of M. bovis in specific areas of Portugal where the disease persists locally is postulated. Concurrently, robust statistics indicates an association of the most probable ancient population with cattle and Beja, providing a clue on the origin of animal TB epidemics. This relationship was further confirmed through a multinomial probability model that assessed the influence of host species on spatiotemporal clustering. Two significant clusters were identified, one that persisted between 2004 and 2010, in Beja district, with Barrancos county at the centre, overlapping the central TB core area of the Iberian Peninsula, and highlighting a significant higher risk associated to cattle. The second cluster was predominant in the 2012-2016 period, holding the county Rosmaninhal at the centre, in Castelo Branco district, for which wild boar contributed the most in relative risk. These results provide novel quantitative insights beyond empirical perceptions, that may inform adaptive TB control choices in different regions.


Assuntos
Mycobacterium bovis/genética , Tuberculose Bovina/epidemiologia , Tuberculose Bovina/genética , Animais , Animais Selvagens/microbiologia , Bovinos , Cervos/genética , Cervos/microbiologia , Genótipo , Gado/genética , Mycobacterium bovis/patogenicidade , Filogenia , Portugal/epidemiologia , Sus scrofa/genética , Sus scrofa/microbiologia , Tuberculose/microbiologia
9.
Virulence ; 11(1): 1656-1673, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33356838

RESUMO

Summary: We characterized Mycobacterium bovis BCG isolates found in lung and brain samples from a previously vaccinated patient with IFNγR1 deficiency. The isolates collected displayed distinct genomic and phenotypic features consistent with host adaptation and associated changes in antibiotic susceptibility and virulence traits. Background: We report a case of a patient with partial recessive IFNγR1 deficiency who developed disseminated BCG infection after neonatal vaccination (BCG-vaccine). Distinct M. bovis BCG-vaccine derived clinical strains were recovered from the patient's lungs and brain. Methods: BCG strains were phenotypically (growth, antibiotic susceptibility, lipid) and genetically (whole genome sequencing) characterized. Mycobacteria cell infection models were used to assess apoptosis, necrosis, cytokine release, autophagy, and JAK-STAT signaling. Results: Clinical isolates BCG-brain and BCG-lung showed distinct Rv0667 rpoB mutations conferring high- and low-level rifampin resistance; the latter displayed clofazimine resistance through Rv0678 gene (MarR-like transcriptional regulator) mutations. BCG-brain and BCG-lung showed mutations in fadA2, fadE5, and mymA operon genes, respectively. Lipid profiles revealed reduced levels of PDIM in BCG-brain and BCG-lung and increased TAGs and Mycolic acid components in BCG-lung, compared to parent BCG-vaccine. In vitro infected cells showed that the BCG-lung induced a higher cytokine release, necrosis, and cell-associated bacterial load effect when compared to BCG-brain; conversely, both strains inhibited apoptosis and altered JAK-STAT signaling. Conclusions: During a chronic-disseminated BCG infection, BCG strains can evolve independently at different sites likely due to particular microenvironment features leading to differential antibiotic resistance, virulence traits resulting in dissimilar responses in different host tissues.


Assuntos
Vacina BCG/efeitos adversos , Vacina BCG/imunologia , Mycobacterium bovis/imunologia , Mycobacterium bovis/patogenicidade , Receptores de Interferon/genética , Tuberculose/sangue , Tuberculose/diagnóstico , Animais , Antibacterianos/farmacologia , Vacina BCG/administração & dosagem , Encéfalo/microbiologia , Bovinos , Pré-Escolar , Farmacorresistência Bacteriana , Humanos , Pulmão/microbiologia , Masculino , Mutação , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium bovis/genética , Receptores de Interferon/deficiência , Vacinação , Virulência
10.
Sci Rep ; 10(1): 20369, 2020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33230112

RESUMO

Vaccination of goats against tuberculosis (TB) has been promoted as an ancillary tool for controlling the disease in infected livestock herds. A three-year trial to assess the efficacy of BCG vaccine was carried out in five goat herds. At the beginning of the trial (month 0), all animals were tested for TB using thee different diagnostic tests. Animals negative to all tests were vaccinated with BCG and all replacement goat kids were also systematically vaccinated throughout the trial. All animals were tested by Interferon-gamma release assay (IGRA) using vaccine compatible reagents at months 6, 12, 24, and 36. The risk factors for TB infection were also evaluated. At the end of the study, four out of five farms showed variable reductions of the initial prevalence (93.5%, 28.5%, 23.2%, and 14.3% respectively), and an overall incidence reduction of 50% was observed in BCG vaccinated goats, although adult vaccinated goats showed higher incidences than vaccinated goat kids. The unvaccinated positive animals remaining in herds and adult BCG vaccinated goats significantly enhanced the risk of infection in vaccinated animals. A systematic vaccination of goats with BCG, together with the removal of positive unvaccinated animals, may contribute to reducing the TB prevalence in goat herds.


Assuntos
Vacina BCG/administração & dosagem , Doenças das Cabras/epidemiologia , Cabras/microbiologia , Mycobacterium bovis/imunologia , Tuberculose/epidemiologia , Tuberculose/veterinária , Criação de Animais Domésticos/organização & administração , Animais , Fazendas/organização & administração , Doenças das Cabras/imunologia , Doenças das Cabras/prevenção & controle , Humanos , Imunogenicidade da Vacina , Interferon gama/biossíntese , Mycobacterium/imunologia , Mycobacterium/patogenicidade , Mycobacterium bovis/química , Mycobacterium bovis/patogenicidade , Prevalência , Espanha/epidemiologia , Tuberculose/imunologia , Tuberculose/prevenção & controle , Vacinação/métodos , Potência de Vacina
11.
Front Immunol ; 11: 601534, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33240287

RESUMO

Oxidized cholesterols have emerged as important signaling molecules of immune function, but little is known about the role of these oxysterols during mycobacterial infections. We found that expression of the oxysterol-receptor GPR183 was reduced in blood from patients with tuberculosis (TB) and type 2 diabetes (T2D) compared to TB patients without T2D and was associated with TB disease severity on chest x-ray. GPR183 activation by 7α,25-dihydroxycholesterol (7α,25-OHC) reduced growth of Mycobacterium tuberculosis (Mtb) and Mycobacterium bovis BCG in primary human monocytes, an effect abrogated by the GPR183 antagonist GSK682753. Growth inhibition was associated with reduced IFN-ß and IL-10 expression and enhanced autophagy. Mice lacking GPR183 had significantly increased lung Mtb burden and dysregulated IFNs during early infection. Together, our data demonstrate that GPR183 is an important regulator of intracellular mycobacterial growth and interferons during mycobacterial infection.


Assuntos
Autofagia , Interferons/metabolismo , Leucócitos Mononucleares/microbiologia , Pulmão/microbiologia , Mycobacterium tuberculosis/crescimento & desenvolvimento , Receptores Acoplados a Proteínas G/metabolismo , Tuberculose Pulmonar/microbiologia , Animais , Carga Bacteriana , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/metabolismo , Modelos Animais de Doenças , Feminino , Interações Hospedeiro-Patógeno , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mycobacterium bovis/crescimento & desenvolvimento , Mycobacterium bovis/imunologia , Mycobacterium bovis/patogenicidade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Receptores Acoplados a Proteínas G/genética , Índice de Gravidade de Doença , Transdução de Sinais , Células THP-1 , Tuberculose Pulmonar/imunologia , Tuberculose Pulmonar/metabolismo
12.
Aust J Gen Pract ; 49(10): 651-655, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-33015679

RESUMO

BACKGROUND: The Bacille Calmette-Guérin (BCG) vaccine is primarily used to prevent tuberculosis (TB) infection and disease in settings with high TB incidence. OBJECTIVE: The aim of this review article is to describe the current uses of BCG vaccination in Australia, including the indications and contraindications, efficacy and other off-target effects, and the role of the general practitioner. DISCUSSION: BCG vaccination in Australia is primarily used to prevent TB in neonates and children with a high risk of TB exposure. The BCG vaccine is most effective at preventing severe disseminated TB disease in young children and has variable efficacy in preventing adult disease. The BCG vaccine is usually well tolerated; however, given the small risk of adverse effects, vaccination should be undertaken by a practitioner experienced in its administration. When indicated, the BCG vaccine is available from specialist TB or travel medicine centres.


Assuntos
Vacina BCG/farmacologia , Antituberculosos/farmacologia , Antituberculosos/uso terapêutico , Austrália/epidemiologia , Vacina BCG/uso terapêutico , Pré-Escolar , Guias como Assunto , Humanos , Lactente , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium bovis/patogenicidade , Tuberculose/tratamento farmacológico , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Vacinação/métodos , Vacinação/tendências
13.
Sultan Qaboos Univ Med J ; 20(3): e330-e336, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33110649

RESUMO

Objectives: This study aimed to compare the effectiveness of the bacillus Calmette-Guérin (BCG) vaccine with topical salicylic acid (SA) in the treatment of viral warts. Methods: This non-randomised controlled trial was conducted at the Al-Sader Teaching Hospital, Basrah, Iraq, from January 2016 to April 2017. A total of 201 patients with viral warts were injected with an intradermal purified protein derivative. Subsequently, those with negative tuberculin test results received an intradermal BCG vaccination, while those with positive results underwent conventional treatment with topical SA. Patients were assessed for any signs of improvement at one, two and three months. Results: Overall, 190 patients completed the trial; of these, 133 (70%) received the BCG vaccine and 57 (30%) were treated with topical SA. Complete response to treatment was observed in 9.8% and 5.3% of patients in the BCG and SA groups, respectively (P <0.001). Cure rates were significantly higher for patients with genital (22.2% versus 7.7%; P = 0.002) and common warts (8.5% versus 0%; P = 0.001) treated with the BCG vaccine; however, the reverse was true for flat warts (12.9% versus 25%; P = 0.041). A binary logistic regression analysis indicated that BCG therapy was the only significant independent predictor of positive treatment response (odds ratio: 7.56, 95% confidence interval: 3.72-15.36; P <0.001). Conclusion: The BCG vaccine was more effective than topical SA for treating viral warts, with the best response noted in the treatment of genital warts, followed by flat warts. However, plantar warts demonstrated least response to this treatment.


Assuntos
Vacina BCG/farmacologia , Verrugas/tratamento farmacológico , Adulto , Vacina BCG/uso terapêutico , Feminino , Humanos , Iraque , Masculino , Pessoa de Meia-Idade , Mycobacterium bovis/efeitos dos fármacos , Mycobacterium bovis/patogenicidade , Verrugas/diagnóstico por imagem
14.
Sci Rep ; 10(1): 18495, 2020 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-33116165

RESUMO

Bovine tuberculosis (bTB), a zoonosis mainly caused by Mycobacterium bovis has severe socio-economic consequences and impact on animal health. Host-pathogen interactions during M. bovis infection are poorly understood, especially early events which are difficult to follow in vivo. This study describes the utilisation of an in vitro co-culture model, comprising immortalised bovine alveolar type II (BATII) epithelial cells and bovine pulmonary arterial endothelial cells (BPAECs). When cultured at air-liquid interface, it was possible to follow the migration of live M. bovis Bacille Calmette-Guérin (BCG) and to observe interactions with each cell type, alongside cytokine release. Infection with BCG was shown to exert a detrimental effect primarily upon epithelial cells, with corresponding increases in IL8, TNFα, IL22 and IL17a cytokine release, quantified by ELISA. BCG infection increased expression of CD54, MHC Class I and II molecules in endothelial but not epithelial cells, which exhibited constitutive expression. The effect of peripheral blood mononuclear cell conditioned medium from vaccinated cattle upon apical-basolateral migration of BCG was examined by quantifying recovered BCG from the apical, membrane and basolateral fractions over time. The numbers of recovered BCG in each fraction were unaffected by the presence of PBMC conditioned medium, with no observable differences between vaccinated and naïve animals.


Assuntos
Células Epiteliais Alveolares/microbiologia , Vacina BCG , Células Endoteliais/microbiologia , Pneumopatias/microbiologia , Alvéolos Pulmonares/citologia , Tuberculose Bovina/microbiologia , Animais , Apoptose , Bovinos , Técnicas de Cocultura , Meios de Cultivo Condicionados , Citocinas/metabolismo , Inflamação , Leucócitos Mononucleares/citologia , Mycobacterium bovis/patogenicidade , Necrose , Tuberculose Bovina/metabolismo , Regulação para Cima , Vacinação/veterinária
15.
Bull Exp Biol Med ; 169(4): 467-469, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32910376

RESUMO

Cultured peritoneal macrophages from intact (control) and BCG-infected (experiment) male BALB/c mice were studied 90 days after infection. Polarization of macrophages by M1 (expression of GM-CSF, IFNγ, and CD16/32) and M2 (expression of bFGF and CD36) differentiation pathways was studied with consideration for their the nuclearity class. Mononuclear cells predominated (90% and higher) in macrophage cultures of both groups and presumably, were presented by mainly epithelioid cells. The results indicated polarization of mononuclear and multinuclear macrophages in the M2 direction under conditions of BCG granulomatosis and a higher initial M2 polarization of binuclear macrophages. In control cultures, the ratio of M2 to M1 macrophages was 0.57, in experimental cultures this ratio was 1.6. It seems that long persistence of Mycobacterium tuberculosis in macrophages served as a factor stimulating the plastic processes and transformation of macrophages into epithelioid cells that form the "core" of granulomas and their enlargement upon incorporation of macrophages.


Assuntos
Células Epitelioides/patologia , Regulação da Expressão Gênica/imunologia , Macrófagos Peritoneais/patologia , Mycobacterium bovis/crescimento & desenvolvimento , Tuberculose/patologia , Animais , Antígenos CD36/genética , Antígenos CD36/imunologia , Diferenciação Celular , Transdiferenciação Celular/genética , Transdiferenciação Celular/imunologia , Células Epitelioides/imunologia , Células Epitelioides/microbiologia , Fator 2 de Crescimento de Fibroblastos/genética , Fator 2 de Crescimento de Fibroblastos/imunologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interferon gama/genética , Interferon gama/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/microbiologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Mycobacterium bovis/patogenicidade , Cultura Primária de Células , Receptores de IgG/genética , Receptores de IgG/imunologia , Tuberculose/genética , Tuberculose/imunologia , Tuberculose/microbiologia
16.
Tuberculosis (Edinb) ; 123: 101962, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32741531

RESUMO

Tuberculosis (TB) is a devastating disease in elephants caused by either Mycobacterium tuberculosis or M. bovis. It is an ancient disease, and TB in elephants was first reported over two millennia ago in Sri Lanka. Outbreaks of TB worldwide, in captive and free-ranging elephant populations, have been recorded. Interspecies transmission of TB among elephants and humans has been confirmed in several geographic localities using spoligotyping, MIRU-VNTR analysis, and/or comparative genomics. Active surveillance of TB in wild and captive elephants and their handlers is necessary to prevent TB transmission at the elephant-human interface and to aid in the conservation of Asian and African elephants. In this review, we present an overview of diagnosis, reports of TB outbreaks in the past 25 years, TB in wild elephants, its transmission, and possible prevention and control strategies that can be applied at the elephant-human interface.


Assuntos
Zoonoses Bacterianas , Surtos de Doenças/veterinária , Elefantes/microbiologia , Mycobacterium bovis/patogenicidade , Mycobacterium tuberculosis/patogenicidade , Tuberculose/veterinária , Animais , Espécies em Perigo de Extinção , Genótipo , Humanos , Mycobacterium bovis/genética , Fenótipo , Tuberculose/microbiologia , Tuberculose/prevenção & controle , Tuberculose/transmissão
17.
Microb Pathog ; 147: 104402, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32712114

RESUMO

Bovine tuberculosis caused by Mycobacterium bovis remains a major cause of economic loss in cattle industries worldwide. However, the pathogenic mechanisms remain poorly understood. Post-translation modifications (PTM) such as phosphorylation play a crucial role in pathogenesis. While the change of transcriptome and proteome during the interaction between M. bovis and cattle were studied, there are no reports on the phosphoproteome change. We apply Tandem Mass Tag-based (TMT) quantitative proteomics coupled with immobilized metal-chelated affinity chromatography (IMAC) enrichment to obtain the quantified phosphorylation in vivo of M. bovis infected cattle lung tissue. The phosphorylated proteins are widespread in the nucleus, cytoplasm and plasma membrane. By using a change fold of 1.2, 165 phosphosites from 147 proteins were enriched, with 88 upregulated and 77 downregulated sites respectively. We further constructed the protein-protein interaction (PPI) networks of STAT3, SRRM2 and IRS-1 based on their number of differential phosphorylation sites and KEGG pathways. Similar patterns of gene expression dynamics of selected genes were observed in Mycobacterium tuberculosis infected human sample GEO dataset, implicating crucial roles of these genes in pathogenic Mycobacteria - host interaction. The first phosphorproteome reveals the relationship between bovine tuberculosis and glucose metabolism, and will help further refinement of target proteins for mechanistic study.


Assuntos
Pulmão , Mycobacterium bovis , Proteoma , Tuberculose Bovina , Animais , Bovinos , Pulmão/microbiologia , Pulmão/patologia , Mycobacterium bovis/patogenicidade , Fosforilação
18.
BMC Immunol ; 21(1): 26, 2020 05 12.
Artigo em Inglês | MEDLINE | ID: mdl-32397995

RESUMO

BACKGROUND: Understanding pathogenic mechanisms is imperative for developing novel treatment to the tuberculosis, an important public health burden worldwide. Recent studies demonstrated that host cholesterol levels have implications in the establishment of Mycobacterium tuberculosis (M. tuberculosis, Mtb) infection in host cells, in which the intracellular cholesterol-mediated ATP-binding cassette transporters (ABC-transporters) and cholesterol acyltransferase1 (ACAT1) exhibited abilities to regulate macrophage autophagy induced by Mycobacterium bovis bacillus Calmette-Guérin (BCG). RESULTS: The results showed that a down-regulated expression of the ABC-transporters and ACAT1 in primary bovine alveolar macrophages (AMs) and murine RAW264.7 cells in response to a BCG infection. The inhibited expression of ABC-transporters and ACAT1 was associated with the reduction of intracellular free cholesterol, which in turn induced autophagy in macrophages upon to the Mycobacterial infection. These results strongly suggest an involvement of ABC-transporters and ACAT1 in intracellular cholesterol-mediated autophagy in AMs in response to BCG infection. CONCLUSION: This study thus provides an insight into into a mechanism by which the cholesterol metabolism regulated the autophagy in macrophages in response to mycobacterial infections.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Autofagia/fisiologia , Colesterol/metabolismo , Macrófagos Alveolares/metabolismo , Esterol O-Aciltransferase/metabolismo , Tuberculose Bovina/metabolismo , Animais , Vacina BCG/imunologia , Bovinos , Linhagem Celular , Regulação para Baixo/fisiologia , Macrófagos Alveolares/imunologia , Camundongos , Mycobacterium bovis/imunologia , Mycobacterium bovis/patogenicidade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Células RAW 264.7 , Tuberculose/imunologia , Tuberculose/metabolismo , Tuberculose Bovina/imunologia
19.
Tuberculosis (Edinb) ; 123: 101939, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32452426

RESUMO

Type 2 diabetes mellitus (T2DM) is an important risk factor for development of tuberculosis (TB). Our previous study showed glibenclamide, an anti-diabetic drug used to control blood glucose concentration, reduced interleukin (IL)-8 secretion from primary human monocytes challenged with M. tuberculosis (Mtb). In mice infected with Mtb, IL-1ß is essential for host resistance through the enhancement of cyclooxygenase that limits excessive Type I interferon (IFN) production and fosters Mtb containment. We hypothesize that glibenclamide may also interfere with monocyte mediated immune responses against Mtb and alter the balance between IL-1ß and IFNα-mediated immunity. Purified monocytes from non-diabetic and diabetic individuals were infected with Mtb or M. bovis BCG. We demonstrate that monocytes from diabetes patients who were being treated with glibenclamide showed reduced IL-1ß and IL-8 secretion when exposed to Mtb. Additionally, these responses also occurred when monocytes from non-diabetic individuals were pre-treated with glibenclamide in vitro. Moreover, this pre-treatment enhanced IFNa1 expression but was not involved with prostaglandin E2 (PGE2) expression in response to Mtb infection. Taken together, our data show that glibenclamide might exacerbate susceptibility of diabetes patients to Mtb infection by reducing IL-1ß and IL-8 production by monocytes.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Glibureto/toxicidade , Hipoglicemiantes/toxicidade , Interleucina-1beta/metabolismo , Interleucina-8/metabolismo , Monócitos/efeitos dos fármacos , Mycobacterium bovis/imunologia , Mycobacterium tuberculosis/imunologia , Tuberculose/microbiologia , Adulto , Idoso , Estudos de Casos e Controles , Células Cultivadas , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/imunologia , Dinoprostona/metabolismo , Feminino , Interações Hospedeiro-Patógeno , Humanos , Interferon-alfa/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Monócitos/microbiologia , Mycobacterium bovis/patogenicidade , Mycobacterium tuberculosis/patogenicidade , Medição de Risco , Tuberculose/imunologia
20.
PLoS One ; 15(4): e0230786, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32302313

RESUMO

Mycobacterium tuberculosis is the causative agent of tuberculosis and has evolved an ability to survive in hostile host environments. M. tuberculosis is thought to utilize the rTCA cycle to sustain its latent growth during infection, but the enzymatic characteristics and physiological function for the key citrate lyase of the rTCA cycle, MtbCitE, in the important pathogen remain unclear. In this study, we investigated the function of MtbCitE based on its structural properties and sequence comparisons with other bacterial citrate lyase subunits. We showed that several amino acid residues were important for the citrate cleavage activity of MtbCitE. Strikingly, the citrate cleavage activity of MtbCitE was inhibited by ATP, indicating that energy metabolism might couple with the regulation of MtbCitE activity, which differed from other CitEs. More interestingly, deletion of citE from Mycobacterium bovis BCG decreased the mycobacterial survival rate under hypoxic conditions, whereas complementation with citE restored the phenotype to wild-type levels. Consistently, three key rTCA cycle enzymes were positively regulated under hypoxic conditions in mycobacteria. Therefore, we characterized a unique citrate lyase MtbCitE from M. tuberculosis and found that the CitE protein significantly contributed to mycobacterial survival under hypoxic conditions.


Assuntos
Proteínas de Bactérias/metabolismo , Hipóxia/metabolismo , Complexos Multienzimáticos/metabolismo , Mycobacterium tuberculosis/metabolismo , Mycobacterium tuberculosis/patogenicidade , Oxo-Ácido-Liases/metabolismo , Tuberculose/microbiologia , Sequência de Aminoácidos , Animais , Linhagem Celular , Camundongos , Mycobacterium bovis/metabolismo , Mycobacterium bovis/patogenicidade , Células RAW 264.7 , Taxa de Sobrevida , Virulência/fisiologia
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