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1.
Proc Natl Acad Sci U S A ; 117(34): 20848-20859, 2020 08 25.
Artículo en Inglés | MEDLINE | ID: mdl-32778586

RESUMEN

Tuberculosis (TB) claims 1.5 million lives per year. This situation is largely due to the low efficacy of the only licensed TB vaccine, Bacillus Calmette-Guérin (BCG) against pulmonary TB. The metabolic disease type 2 diabetes (T2D) is a risk factor for TB and the mechanisms underlying increased TB susceptibility in T2D are not well understood. Furthermore, it is unknown if new TB vaccines will provide protection in the context of T2D. Here we used a diet-induced murine model of T2D to investigate the underlying mechanisms of TB/T2D comorbidity and to evaluate the protective capacity of two experimental TB vaccines in comparison to conventional BCG. Our data reveal a distinct immune dysfunction that is associated with diminished recognition of mycobacterial antigens in T2D. More importantly, we provide compelling evidence that mucosal delivery of recombinant BCG strains expressing the Mycobacterium tuberculosis (Mtb) ESX-1 secretion system (BCG::RD1 and BCG::RD1 ESAT-6 ∆92-95) are safe and confer superior immunity against aerosol Mtb infection in the context of T2D. Our findings suggest that the remarkable anti-TB immunity by these recombinant BCG strains is achieved via augmenting the numbers and functional capacity of antigen presenting cells in the lungs of diabetic mice.


Asunto(s)
Antígenos Bacterianos/farmacología , Proteínas Bacterianas/farmacología , Diabetes Mellitus Tipo 2/metabolismo , Animales , Antígenos Bacterianos/inmunología , Antígenos Bacterianos/metabolismo , Vacuna BCG , Proteínas Bacterianas/inmunología , Proteínas Bacterianas/metabolismo , Diabetes Mellitus Experimental , Modelos Animales de Enfermedad , Pulmón/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Membrana Mucosa/inmunología , Mycobacterium bovis/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Vacunas contra la Tuberculosis/inmunología , Vacunación
2.
Int J Mol Sci ; 23(18)2022 Sep 13.
Artículo en Inglés | MEDLINE | ID: mdl-36142559

RESUMEN

Whole-blood-derived transcriptional profiling is widely used in biomarker discovery, immunological research, and therapeutic development. Traditional molecular and high-throughput transcriptomic platforms, including molecular assays with quantitative PCR (qPCR) and RNA-sequencing (RNA-seq), are dependent upon high-quality and intact RNA. However, collecting high-quality RNA from field studies in remote tropical locations can be challenging due to resource restrictions and logistics of post-collection processing. The current study tested the relative performance of the two most widely used whole-blood RNA collection systems, PAXgene® and Tempus™, in optimal laboratory conditions as well as suboptimal conditions in tropical field sites, including the effects of extended storage times and high storage temperatures. We found that Tempus™ tubes maintained a slightly higher RNA quantity and integrity relative to PAXgene® tubes at suboptimal tropical conditions. Both PAXgene® and Tempus™ tubes gave similar RNA purity (A260/A280). Additionally, Tempus™ tubes preferentially maintained the stability of mRNA transcripts for two reference genes tested, Succinate dehydrogenase complex, subunit A (SDHA) and TATA-box-binding protein (TBP), even when RNA quality decreased with storage length and temperature. Both tube types preserved the rRNA transcript 18S ribosomal RNA (18S) equally. Our results suggest that Tempus™ blood RNA collection tubes are preferable to PAXgene® for whole-blood collection in suboptimal tropical conditions for RNA-based studies in resource-limited settings.


Asunto(s)
ARN , Succinato Deshidrogenasa , Biomarcadores , Recolección de Muestras de Sangre/métodos , Perfilación de la Expresión Génica/métodos , ARN/genética , ARN Mensajero/genética , ARN Ribosómico 18S/genética , Succinato Deshidrogenasa/genética , Proteína de Unión a TATA-Box/genética , Temperatura
3.
Artículo en Inglés | MEDLINE | ID: mdl-33046495

RESUMEN

Comorbid type 2 diabetes poses a great challenge to the global control of tuberculosis. Here, we assessed the efficacy of metformin (MET), an antidiabetic drug, in mice infected with a very low dose of Mycobacterium tuberculosis In contrast to diabetic mice, infected nondiabetic mice that received the same therapeutic concentration of MET presented with significantly higher disease burden. This warrants further studies to investigate the disparate efficacy of MET against tuberculosis in diabetic and nondiabetic individuals.


Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Metformina , Mycobacterium tuberculosis , Tuberculosis , Animales , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Metformina/farmacología , Metformina/uso terapéutico , Ratones , Tuberculosis/tratamiento farmacológico
4.
J Infect Dis ; 218(2): 324-335, 2018 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-29236994

RESUMEN

Acute rheumatic fever and rheumatic heart disease (ARF/RHD) have long been described as autoimmune sequelae of Streptococcus pyogenes or group A streptococcal (GAS) infection. Both antibody and T-cell responses against immunodominant GAS virulence factors, including M protein, cross-react with host tissue proteins, triggering an inflammatory response leading to permanent heart damage. However, in some ARF/RHD-endemic regions, throat carriage of GAS is low. Because Streptococcus dysgalactiae subspecies equisimilis organisms, also known as ß-hemolytic group C streptococci and group G streptococci (GGS), also express M protein, we postulated that streptococci other than GAS may have the potential to initiate or exacerbate ARF/RHD. Using a model initially developed to investigate the uniquely human disease of ARF/RHD, we have discovered that GGS causes interleukin 17A/interferon γ-induced myocarditis and valvulitis, hallmarks of ARF/RHD. Remarkably the histological, immunological, and functional changes in the hearts of rats exposed to GGS are identical to those exposed to GAS. Furthermore, antibody cross-reactivity to cardiac myosin was comparable in both GGS- and GAS-exposed animals, providing additional evidence that GGS can induce and/or exacerbate ARF/RHD.


Asunto(s)
Enfermedades Autoinmunes/etiología , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Cardiopatía Reumática/etiología , Infecciones Estreptocócicas/patología , Streptococcus/inmunología , Animales , Antígenos Bacterianos/inmunología , Enfermedades Autoinmunes/microbiología , Enfermedades Autoinmunes/fisiopatología , Proteínas de la Membrana Bacteriana Externa/inmunología , Proteínas Portadoras/inmunología , Modelos Animales de Enfermedad , Femenino , Enfermedades de las Válvulas Cardíacas/etiología , Enfermedades de las Válvulas Cardíacas/microbiología , Enfermedades de las Válvulas Cardíacas/fisiopatología , Miocarditis/etiología , Miocarditis/microbiología , Miocarditis/fisiopatología , Ratas Endogámicas Lew , Cardiopatía Reumática/microbiología , Cardiopatía Reumática/fisiopatología , Streptococcus/patogenicidad
5.
Arterioscler Thromb Vasc Biol ; 37(3): 553-566, 2017 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-28062506

RESUMEN

OBJECTIVE: Sclerostin (SOST) has been identified as an important regulator of bone formation; however, it has not been previously implicated in arterial disease. The aim of this study was to assess the role of SOST in aortic aneurysm (AA) and atherosclerosis using human samples, a mouse model, and in vitro investigations. APPROACH AND RESULTS: SOST protein was downregulated in human and mouse AA samples compared with controls. Transgenic introduction of human SOST in apolipoprotein E-deficient (ApoE-/-) mice (SOSTTg .ApoE-/-) and administration of recombinant mouse Sost inhibited angiotensin II-induced AA and atherosclerosis. Serum concentrations of several proinflammatory cytokines were significantly reduced in SOSTTg .ApoE-/- mice. Compared with controls, the aortas of mice receiving recombinant mouse Sost and SOSTTg .ApoE-/- mice showed reduced matrix degradation, reduced elastin breaks, and preserved collagen. Decreased inflammatory cell infiltration and a reduction in the expression of wingless-type mouse mammary virus integration site/ß-catenin responsive genes, including matrix metalloproteinase-9, osteoprotegerin, and osteopontin, were observed in the aortas of SOSTTg .ApoE-/- mice. SOST expression was downregulated and the wingless-type mouse mammary virus integration site/ß-catenin pathway was activated in human AA samples. The cytosine-phosphate-guanine islands in the SOST gene promoter showed significantly higher methylation in human AA samples compared with controls. Incubation of vascular smooth muscle cells with the demethylating agent 5-azacytidine resulted in upregulation of SOST, suggesting that SOST is epigenetically regulated. CONCLUSIONS: This study identifies that SOST is expressed in the aorta and downregulated in human AA possibly because of epigenetic silencing. Upregulating SOST inhibits AA and atherosclerosis development, with potential important implications for treating these vascular diseases.


Asunto(s)
Angiotensina II , Aneurisma de la Aorta/prevención & control , Aterosclerosis/prevención & control , Proteínas Morfogenéticas Óseas/metabolismo , Glicoproteínas/administración & dosificación , Músculo Liso Vascular/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacos , Vía de Señalización Wnt/efectos de los fármacos , Proteínas Adaptadoras Transductoras de Señales , Anciano , Anciano de 80 o más Años , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/metabolismo , Aorta Abdominal/patología , Aorta Torácica/efectos de los fármacos , Aorta Torácica/metabolismo , Aorta Torácica/patología , Aneurisma de la Aorta/inducido químicamente , Aneurisma de la Aorta/genética , Aneurisma de la Aorta/metabolismo , Apolipoproteínas E/deficiencia , Apolipoproteínas E/genética , Aterosclerosis/inducido químicamente , Aterosclerosis/genética , Aterosclerosis/metabolismo , Proteínas Morfogenéticas Óseas/genética , Células Cultivadas , Citocinas/metabolismo , Epigénesis Genética/efectos de los fármacos , Matriz Extracelular/metabolismo , Femenino , Marcadores Genéticos/genética , Predisposición Genética a la Enfermedad , Humanos , Péptidos y Proteínas de Señalización Intercelular , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patología , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , Fenotipo , Remodelación Vascular/efectos de los fármacos
6.
Emerg Infect Dis ; 23(5)2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28418830

RESUMEN

Neurologic melioidosis is a serious, potentially fatal form of Burkholderia pseudomallei infection. Recently, we reported that a subset of clinical isolates of B. pseudomallei from Australia have heightened virulence and potential for dissemination to the central nervous system. In this study, we demonstrate that this subset has a B. mallei-like sequence variation of the actin-based motility gene, bimA. Compared with B. pseudomallei isolates having typical bimA alleles, isolates that contain the B. mallei-like variation demonstrate increased persistence in phagocytic cells and increased virulence with rapid systemic dissemination and replication within multiple tissues, including the brain and spinal cord, in an experimental model. These findings highlight the implications of bimA variation on disease progression of B. pseudomallei infection and have considerable clinical and public health implications with respect to the degree of neurotropic threat posed to human health.


Asunto(s)
Burkholderia pseudomallei/genética , Infecciones Bacterianas del Sistema Nervioso Central/microbiología , Variación Genética , Melioidosis/microbiología , Proteínas de Microfilamentos/genética , Animales , Australia , Burkholderia mallei/genética , Burkholderia pseudomallei/aislamiento & purificación , Infecciones Bacterianas del Sistema Nervioso Central/mortalidad , Infecciones Bacterianas del Sistema Nervioso Central/patología , Enfermedades Transmisibles Emergentes/microbiología , Enfermedades Transmisibles Emergentes/mortalidad , Enfermedades Transmisibles Emergentes/patología , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Muermo/microbiología , Humanos , Melioidosis/mortalidad , Melioidosis/patología , Ratones , Mucosa Nasal/microbiología , Fagocitos/inmunología , Fagocitos/microbiología , Virulencia/genética
7.
Arterioscler Thromb Vasc Biol ; 36(5): 898-907, 2016 05.
Artículo en Inglés | MEDLINE | ID: mdl-26966276

RESUMEN

OBJECTIVE: Abdominal aortic aneurysm (AAA) is an important cause of mortality in older adults. Activity of the local kallikrein-kinin system may be important in cardiovascular disease. The effect of kinin B2 receptor (B2R) agonist and antagonist peptides on experimental AAA was investigated. APPROACH AND RESULTS: AAA was induced in apolipoprotein E-deficient mice via infusion of angiotensin II (1.0 µg/kg per minute SC). B2R agonists or antagonists were given via injection (2 mg/kg IP) every other day. The B2R agonist (B9772) promoted aortic rupture in response to angiotensin II associated with an increase in neutrophil infiltration of the aorta in comparison to controls. Mice receiving a B2R/kinin B1 receptor antagonist (B9430) were relatively protected from aortic rupture. Neutrophil depletion abrogated the ability of the B2R agonist to promote aortic rupture. Progression of angiotensin II-induced aortic dilatation was inhibited in mice receiving a B2R antagonist (B9330). Secretion of metalloproteinase-2 and -9, osteoprotegerin, and osteopontin by human AAA explant was reduced in the presence of the B2R antagonist (B9330). B2R agonist and antagonist peptides enhanced and inhibited, respectively, angiotensin II-induced neutrophil activation and aortic smooth muscle cell inflammatory phenotype. The B2R antagonist (B9330; 5 µg) delivered directly to the aortic wall 1 week post-AAA induction with calcium phosphate in a rat model reduced aneurysm growth associated with downregulation of aortic metalloproteinase-9. CONCLUSIONS: B2R signaling promotes aortic rupture within a mouse model associated with the ability to stimulate inflammatory phenotypes of neutrophils and vascular smooth muscle cells. B2R antagonism could be a potential therapy for AAA.


Asunto(s)
Angiotensina II , Aorta Abdominal/metabolismo , Aneurisma de la Aorta Abdominal/metabolismo , Rotura de la Aorta/metabolismo , Apolipoproteínas E/deficiencia , Receptor de Bradiquinina B2/metabolismo , Animales , Aorta Abdominal/efectos de los fármacos , Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/genética , Aneurisma de la Aorta Abdominal/patología , Aneurisma de la Aorta Abdominal/prevención & control , Rotura de la Aorta/genética , Rotura de la Aorta/patología , Rotura de la Aorta/prevención & control , Apolipoproteínas E/genética , Bradiquinina/análogos & derivados , Bradiquinina/farmacología , Antagonistas del Receptor de Bradiquinina B2/farmacología , Fosfatos de Calcio , Dilatación Patológica , Modelos Animales de Enfermedad , Predisposición Genética a la Enfermedad , Humanos , Masculino , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Noqueados , Activación Neutrófila/efectos de los fármacos , Osteopontina/metabolismo , Osteoprotegerina/metabolismo , Fenotipo , Ratas Sprague-Dawley , Receptor de Bradiquinina B2/agonistas , Transducción de Señal , Factores de Tiempo , Técnicas de Cultivo de Tejidos
9.
Infect Immun ; 82(10): 4233-40, 2014 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-25069976

RESUMEN

Burkholderia pseudomallei, the etiological agent for melioidosis, is an important cause of community-acquired sepsis in northern Australia and northeast Thailand. Due to the rapid dissemination of disease in acute melioidosis, we hypothesized that dendritic cells (DC) could act as a vehicle for dissemination of B. pseudomallei. Therefore, this study investigated the effect of B. pseudomallei infection on DC migration capacity and whether migration of DC enabled transportation of B. pseudomallei from the site of infection. B. pseudomallei stimulated significantly increased migration of bone marrow-derived DC (BMDC), both in vitro and in vivo, compared to uninfected BMDC. Furthermore, migration of BMDC enabled significantly increased in vitro trafficking of B. pseudomallei and in vivo dissemination of B. pseudomallei to secondary lymphoid organs and lungs of C57BL/6 mice. DC within the footpad infection site of C57BL/6 mice also internalized B. pseudomallei and facilitated dissemination. Although DC have previously been shown to kill intracellular B. pseudomallei in vitro, the findings of this study demonstrate that B. pseudomallei-infected DC facilitate the systemic spread of this pathogen.


Asunto(s)
Burkholderia pseudomallei/inmunología , Burkholderia pseudomallei/fisiología , Movimiento Celular , Células Dendríticas/inmunología , Células Dendríticas/microbiología , Melioidosis/inmunología , Melioidosis/microbiología , Animales , Modelos Animales de Enfermedad , Endocitosis , Pulmón/microbiología , Tejido Linfoide/microbiología , Melioidosis/patología , Ratones , Ratones Endogámicos C57BL
10.
Blood ; 119(11): 2545-51, 2012 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-22271449

RESUMEN

In vivo imaging has revolutionized understanding of the spatiotemporal complexity that subserves the generation of successful effector and regulatory immune responses. Until now, invasive surgery has been required for microscopic access to lymph nodes (LNs), making repeated imaging of the same animal impractical and potentially affecting lymphocyte behavior. To allow longitudinal in vivo imaging, we conceived the novel approach of transplanting LNs into the mouse ear pinna. Transplanted LNs maintain the structural and cellular organization of conventional secondary lymphoid organs. They participate in lymphocyte recirculation and exhibit the capacity to receive and respond to local antigenic challenge. The same LN could be repeatedly imaged through time without the requirement for surgical exposure, and the dynamic behavior of the cells within the transplanted LN could be characterized. Crucially, the use of blood vessels as fiducial markers also allowed precise re-registration of the same regions for longitudinal imaging. Thus, we provide the first demonstration of a method for repeated, noninvasive, in vivo imaging of lymphocyte behavior.


Asunto(s)
Diagnóstico por Imagen , Sistema Inmunológico/patología , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Enfermedades Linfáticas/patología , Animales , Presentación de Antígeno/inmunología , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Proteínas Fluorescentes Verdes/metabolismo , Estudios Longitudinales , Enfermedades Linfáticas/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Fotones , Receptores de Antígenos de Linfocitos T/fisiología , Linfocitos T/inmunología
11.
Clin Sci (Lond) ; 126(7): 517-27, 2014 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-24107226

RESUMEN

AAA (abdominal aortic aneurysm) is an important cause of sudden death in older adults, but there is no current effective drug therapy for this disease. The UCNs (urocortins1-3) and their receptors: CRFR (corticotrophin-releasing factor receptor)-1 and -2 have been implicated in various CVDs (cardiovascular diseases). We assessed the relative expression of UCN1-3 in AAA by qRT-PCR (quantitative reverse transcription-PCR) and ELISA, and examined in vitro how UCN2 affects human aortic VSMC (vascular smooth muscle cell) Akt phosphorylation, pro-inflammatory cytokine IL (interleukin)-6 secretion, proliferation, cell cycle and apoptosis. UCN2 and CRFR2 expression were significantly up-regulated in biopsies from the AAA body. AAA body biopsies released high amounts of UCN2 in vitro. Median plasma UCN2 concentrations were 2.20 ng/ml (interquartile range 1.14-4.55 ng/ml, n=67) in AAA patients and 1.11 ng/ml (interquartile range 0.76-2.55 ng/ml, n=67) in patients with non-aneurysmal PAD (peripheral artery disease) (P=0.001). Patients with UCN2 in the highest quartile had a 4.12-fold (95% confidence interval, 1.37-12.40) greater prevalence of AAA independent of other risk factors, P=0.012. In vitro, UCN2 significantly inhibited VSMC Akt phosphorylation and proliferation in a dose-dependent manner. UCN2 induced VSMC G1 cell-cycle arrest and increased IL-6 secretion over 24 h. The CRFR2 antagonist astressin-2B significantly abrogated the effects of UCN2 on VSMCs. In conclusion, UCN2 is significantly associated with AAA and inhibits VSMC proliferation by inducing a G1 cell cycle arrest suggesting a plausible regulatory role in AAA pathogenesis.


Asunto(s)
Aneurisma de la Aorta Abdominal/fisiopatología , Hormona Liberadora de Corticotropina/fisiología , Músculo Liso Vascular/patología , Receptores de Hormona Liberadora de Corticotropina/fisiología , Urocortinas/fisiología , Proliferación Celular , Células Cultivadas , Hormona Liberadora de Corticotropina/sangre , Humanos , Interleucina-8/metabolismo , Músculo Liso Vascular/enzimología , Músculo Liso Vascular/metabolismo , Fosforilación , Proteínas Proto-Oncogénicas c-akt/metabolismo , Urocortinas/sangre
12.
J Immunol ; 184(11): 6378-85, 2010 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-20421640

RESUMEN

Activation of auto-reactive T cells by activated dendritic cells (DCs) presenting self-Ag is widely assumed to be the precipitating event in the development of autoimmune disease. However, despite such widely held preconceptions, supporting data are scarce and subjective, particularly in experimental arthropathy. We have adapted a novel murine model of breach of self-tolerance allowing evaluation of the contribution of endogenous DCs to the development of autoimmune responses and disease. For the first time, we reveal the critical role played by conventional DCs, and the timing and location of this process. We further demonstrate the importance of this finding by clinically relevant, therapeutic manipulation of conventional DC function, resulting in decreased autoimmune phenotype and disease severity.


Asunto(s)
Artritis Experimental/inmunología , Autoinmunidad/inmunología , Células Dendríticas/inmunología , Autotolerancia/inmunología , Animales , Presentación de Antígeno/inmunología , Artritis Reumatoide/inmunología , Linfocitos B/inmunología , Separación Celular , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Linfocitos T/inmunología
13.
J Exp Med ; 201(11): 1815-23, 2005 Jun 06.
Artículo en Inglés | MEDLINE | ID: mdl-15928201

RESUMEN

The behavior of antigen-specific CD4+ T lymphocytes during initial exposure to antigen probably influences their decision to become primed or tolerized, but this has not been examined directly in vivo. We have therefore tracked such cells in real time, in situ during the induction of oral priming versus oral tolerance. There were marked contrasts with respect to rate and type of movement and clustering between naive T cells and those exposed to antigen in immunogenic or tolerogenic forms. However, the major difference when comparing tolerized and primed T cells was that the latter formed larger and longer-lived clusters within mucosal and peripheral lymph nodes. This is the first comparison of the behavior of antigen-specific CD4+ T cells in situ in mucosal and systemic lymphoid tissues during the induction of priming versus tolerance in a physiologically relevant model in vivo.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Movimiento Celular/inmunología , Inmunidad Mucosa , Administración Oral , Animales , Antígenos/administración & dosificación , Linfocitos T CD4-Positivos/citología , Memoria Inmunológica , Ganglios Linfáticos/citología , Ganglios Linfáticos/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Membrana Mucosa/citología , Membrana Mucosa/inmunología , Ovalbúmina
14.
Microbes Infect ; 23(4-5): 104793, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33571673

RESUMEN

Co-occurrence of bacterial infections with type 2 diabetes (T2D) is a global problem. Melioidosis caused by Burkholderia pseudomallei is 10 times more likely to occur in patients with T2D, than in normoglycemic individuals. Using an experimental model of T2D, we observed that greater susceptibility in T2D was due to differences in proportions of infiltrating leucocytes and reduced levels of MCP-1, IFN-γ and IL-12 at sites of infection within 24 h post-infection. However, by 72 h the levels of inflammatory cytokines and bacteria were markedly higher in visceral tissue and blood in T2D mice. In T2D, dysregulated early immune responses are responsible for the greater predisposition to B. pseudomallei infection.


Asunto(s)
Alimentación Animal/toxicidad , Burkholderia pseudomallei/inmunología , Diabetes Mellitus Tipo 2/etiología , Diabetes Mellitus Tipo 2/inmunología , Melioidosis/inmunología , Animales , Diabetes Mellitus Experimental , Modelos Animales de Enfermedad , Índice Glucémico , Ratones
15.
J Leukoc Biol ; 107(2): 263-271, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31617241

RESUMEN

The role of group A streptococcal and Streptococcus dysgalactiae subspecies equisimilis M-protein specific Abs and T-cells in endothelial cell activation was investigated using cultured rat aortic endothelial cells, and in a rat model of autoimmune valvulitis. Heat inactivated serum and mononuclear cells from streptococcal M-protein immunized rats independently induced upregulation of the endothelial cell adhesion molecules, vascular cell adhesion molecule (VCAM)-1 and intercellular adhesion molecule (ICAM)-1 in cultured cells. We also observed T-cell migration across endothelial cell monolayers incubated with serum from M-protein-immunized rats. Furthermore, we observed VCAM-1 and ICAM-1 expression in the myocardium of rats injected with M-protein compared to control animals. These observations support the contention that initial interactions between streptococcal M-protein specific Abs and/or T-cells with the heart endothelium lead to endothelial cell activation followed by transmigration of M-protein specific T-cells into heart tissue leading to an inflammatory process that leads to carditis in rheumatic fever and rheumatic heart disease.


Asunto(s)
Anticuerpos Antibacterianos/inmunología , Antígenos Bacterianos/inmunología , Enfermedades Autoinmunes/etiología , Proteínas de la Membrana Bacteriana Externa/inmunología , Proteínas Portadoras/inmunología , Endotelio Vascular/inmunología , Miocarditis/etiología , Cardiopatía Reumática/etiología , Linfocitos T/inmunología , Animales , Antígenos Bacterianos/metabolismo , Enfermedades Autoinmunes/patología , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Portadoras/metabolismo , Movimiento Celular , Endotelio Vascular/metabolismo , Femenino , Molécula 1 de Adhesión Intercelular/metabolismo , Miocarditis/patología , Ratas , Ratas Endogámicas Lew , Cardiopatía Reumática/patología , Streptococcus/inmunología , Linfocitos T/metabolismo , Molécula 1 de Adhesión Celular Vascular/metabolismo
16.
Sci Adv ; 6(10): eaaz1767, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-32181361

RESUMEN

Tuberculosis (TB) is the deadliest infectious disease worldwide. Bacille-Calmette-Guérin (BCG), the only licensed TB vaccine, affords variable protection against TB but remains the gold standard. BCG improvement is focused around three strategies: recombinant BCG strains, heterologous routes of administration, and booster vaccination. It is currently unknown whether combining these strategies is beneficial. The preclinical evaluation for new TB vaccines is heavily skewed toward immunogenicity and efficacy; however, safety and efficacy are the dominant considerations in human use. To facilitate stage gating of TB vaccines, we developed a simple empirical model to systematically rank vaccination strategies by integrating multiple measurements of safety, immunogenicity, and efficacy. We assessed 24 vaccination regimens, composed of three BCG strains and eight combinations of delivery. The model presented here highlights that mucosal booster vaccination may cause adverse outcomes and provides a much needed strategy to evaluate and rank data obtained from TB vaccine studies using different routes, strains, or animal models.


Asunto(s)
Vacuna BCG/administración & dosificación , Inmunización Secundaria/métodos , Inmunogenicidad Vacunal , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Pulmonar/prevención & control , Vacunación/métodos , Animales , Femenino , Humanos , Esquemas de Inmunización , Inyecciones Espinales , Inyecciones Subcutáneas , Ratones , Ratones Endogámicos C57BL , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/patogenicidad , Seguridad del Paciente , Proyectos de Investigación , Resultado del Tratamiento , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patología , Vacunas Sintéticas
17.
Immunology ; 128(4): 463-71, 2009 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19930039

RESUMEN

Despite the recent advances in our understanding of the dynamics of the cellular interactions associated with the induction of immune responses, comparatively little is known about the in vivo behaviour of antigen-experienced T cells upon secondary antigen exposure in either priming or tolerance. Such information would provide an insight into the functional mechanisms employed by memory T cells of distinct phenotypes and provide invaluable knowledge of how a specific tolerogenic or immunogenic state is maintained. Using real-time imaging to follow the in vivo motility of naïve, primed and tolerized CD4(+) T cells and their interactions with dendritic cells (DCs), we demonstrate that each of these distinct functional phenotypes is associated with specific patterns of behaviour. We show that antigen-experienced CD4(+) T cells, whether primed or tolerized, display inherently slower migration, making many short contacts with DCs in the absence of antigen. Following secondary exposure to antigen, primed T cells increase their intensity or area of interaction with DCs whereas contacts between DCs and tolerized T cells are reduced. Importantly, this was not associated with alterations in the contact time between DCs and T cells, suggesting that T cells that have previously encountered antigen are more effective at surveying DCs. Thus, our studies are the first to demonstrate that naïve, primed and tolerized T cells show distinct behaviours before and after secondary antigen-encounter, providing a novel mechanism for the increased immune surveillance associated with memory T cells. These findings have important consequences for many immunotherapeutics, which aim to manipulate secondary immune responses.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Células Dendríticas/inmunología , Tolerancia Inmunológica/inmunología , Animales , Células Cultivadas , Quimiotaxis de Leucocito/inmunología , Citocinas/biosíntesis , Memoria Inmunológica/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Modelos Animales , Ovalbúmina/inmunología
18.
PLoS Pathog ; 3(10): 1380-7, 2007 Oct 12.
Artículo en Inglés | MEDLINE | ID: mdl-17937497

RESUMEN

Interactions between antigen-presenting dendritic cells (DCs) and T cells are essential for the induction of an immune response. However, during malaria infection, DC function is compromised and immune responses against parasite and heterologous antigens are reduced. Here, we demonstrate that malaria infection or the parasite pigment hemozoin inhibits T cell and DC interactions both in vitro and in vivo, while signal 1 intensity remains unaltered. This altered cellular behaviour is associated with the suppression of DC costimulatory activity and functional T cell responses, potentially explaining why immunity is reduced during malaria infection.


Asunto(s)
Presentación de Antígeno/inmunología , Células Dendríticas/inmunología , Malaria/inmunología , Plasmodium chabaudi/inmunología , Señales de Clasificación de Proteína/fisiología , Linfocitos T/inmunología , Animales , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/inmunología , Células Dendríticas/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Hemoproteínas/metabolismo , Hemoproteínas/farmacología , Interacciones Huésped-Parásitos , Activación de Linfocitos/inmunología , Malaria/sangre , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Transgénicos , Fagocitosis , Pigmentos Biológicos/metabolismo , Pigmentos Biológicos/farmacología , Señales de Clasificación de Proteína/efectos de los fármacos , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo
19.
Tuberculosis (Edinb) ; 115: 113-120, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30948165

RESUMEN

Diabetes is one of the major co-morbidities contributing to the high global burden of tuberculosis (TB). The increased susceptibility of individuals with type 2 diabetes (T2D) to TB is multifactorial and may influence the efficacy of vaccines. This study was undertaken to determine the early immune responses that occur following infection with Mycobacterium bovis Bacille Calmette-Guérin (BCG) in a diet-induced murine model of T2D. The phagocytic capabilities of alveolar (AM) and resident peritoneal macrophages (RPM) were assessed using ex vivo assays. Compared to macrophages from non-diabetic mice, macrophages from diabetic animals showed decreased BCG uptake and killing and inflammatory cytokine production (TNF-α, MCP-1, IL-6, IL-1ß). In vivo susceptibility to BCG was determined following intravenous infection and diabetic mice showed a trend towards increased mortality, higher bacterial burden in the lung, liver and spleen and increased inflammatory lesions compared to controls. Differences between tissue cytokines were observed as early as one day post-infection and by days 14 and 35, lung and liver TNF-α and IFN-γ levels were decreased in diabetic mice compared to controls. These results suggest that early dysregulated immune responses may influence the susceptibility of T2D mice to BCG infection.


Asunto(s)
Citocinas/metabolismo , Diabetes Mellitus Tipo 2/inmunología , Mycobacterium bovis/inmunología , Tuberculosis/inmunología , Animales , Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/patología , Modelos Animales de Enfermedad , Susceptibilidad a Enfermedades , Inmunidad Celular/inmunología , Hígado/química , Pulmón/química , Macrófagos/inmunología , Macrófagos/microbiología , Masculino , Ratones Endogámicos C57BL , Fagocitosis/inmunología , Tuberculosis/patología
20.
Tuberculosis (Edinb) ; 102: 47-54, 2017 01.
Artículo en Inglés | MEDLINE | ID: mdl-28061952

RESUMEN

Type 2 diabetes (T2D) is one of the major risk factors for tuberculosis (TB). In this study, a diet induced murine model of T2D (DIMT2D) was developed and characterized in the context of metabolic, biochemical and histopathological features following diet intervention. Mycobacterial susceptibility was investigated using Mycobacterium fortuitum as a surrogate. Phagocytic capability of alveolar macrophages and resident peritoneal macrophages were determined by in vitro assays using mycolic acid coated beads and M. fortuitum. Results demonstrated that bacillary loads were significantly higher in liver, spleen, and lungs of diabetic mice compared to controls. Higher inflammatory lesions and impaired cytokine kinetics (TNF-α, MCP-1, IL-12, IFN-γ) were also observed in diabetic mice. Macrophages isolated from diabetic mice had lower uptake of mycolic acid coated beads, reduced bacterial internalization and killing and altered cytokine responses (TNF-α, IL-6, MCP-1). This model will be useful to further investigate different facets of host-pathogen interactions in TB-T2D.


Asunto(s)
Diabetes Mellitus Experimental/inmunología , Diabetes Mellitus Tipo 2/inmunología , Macrófagos Alveolares/inmunología , Macrófagos Peritoneales/inmunología , Infecciones por Mycobacterium no Tuberculosas/inmunología , Mycobacterium fortuitum/aislamiento & purificación , Infecciones Oportunistas/inmunología , Animales , Carga Bacteriana , Células Cultivadas , Citocinas/biosíntesis , Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patología , Diabetes Mellitus Tipo 2/complicaciones , Diabetes Mellitus Tipo 2/patología , Dieta/efectos adversos , Susceptibilidad a Enfermedades , Interacciones Huésped-Patógeno , Hígado/microbiología , Pulmón/microbiología , Masculino , Ratones Endogámicos C57BL , Infecciones por Mycobacterium no Tuberculosas/complicaciones , Infecciones por Mycobacterium no Tuberculosas/microbiología , Infecciones por Mycobacterium no Tuberculosas/patología , Infecciones Oportunistas/complicaciones , Infecciones Oportunistas/microbiología , Fagocitosis/inmunología , Bazo/microbiología
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