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1.
Food Microbiol ; 85: 103280, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-31500706

RESUMEN

Listeria monocytogenes causes severe diseases in humans, including febrile gastroenteritis and systemic infections that has a high mortality despite antibiotic treatment. This pathogen may cause massive outbreaks associated to the consumption of contaminated food products, which highlight its importance in public health. In the last decade, L. monocytogenes has emerged as a foodborne pathogen of major importance in Chile. A previous work showed that in Chile during 2008 and 2009, L. monocytogenes serotypes 1/2a, 1/2b and 4b were the most frequently identified in food and clinical strains. Here we report the molecular characterization of L. monocytogenes strains isolated from 2008 to 2017 in the country. Our results indicate that serotypes 1/2a, 1/2b and 4b continue to be the most commonly found in food products. In addition, we identify persistent and widespread PFGE subtypes. This study reports ten years of epidemiological surveillance ofL. monocytogenes in Chile.


Asunto(s)
Monitoreo Epidemiológico , Microbiología de Alimentos , Enfermedades Transmitidas por los Alimentos/epidemiología , Listeria monocytogenes/genética , Listeriosis/epidemiología , Chile/epidemiología , Recuento de Colonia Microbiana , ADN Bacteriano/genética , Brotes de Enfermedades , Enfermedades Transmitidas por los Alimentos/microbiología , Gastroenteritis/epidemiología , Gastroenteritis/microbiología , Variación Genética , Humanos , Listeria monocytogenes/patogenicidad , Productos de la Carne/microbiología , Epidemiología Molecular , Salud Pública , Serogrupo , Serotipificación , Factores de Virulencia/genética
2.
J Infect Dis ; 219(3): 420-428, 2019 01 09.
Artículo en Inglés | MEDLINE | ID: mdl-30010905

RESUMEN

Background: Initiation of antiretroviral therapy (ART) in human immunodeficiency virus (HIV)-infected individuals with cryptococcal meningitis places them at risk for Cryptococcus-associated immune reconstitution inflammatory syndrome (C-IRIS). The relationship between antibody immunity and C-IRIS risk has not been investigated. Methods: We compared plasma levels of immunoglobulins, C. neoformans glucuronoxylomannan (GXM) capsule-specific and laminarin (Lam)-binding IgM and IgG, and percentages of peripheral blood total and memory B cells between 27 HIV-infected patients with CM who developed C-IRIS and 63 who did not, and evaluated associations of these parameters with risk of C-IRIS. Results: Prior to initiation of ART, plasma IgM, Lam-binding IgM (Lam-IgM), Lam-IgG, and GXM-IgM levels were significantly lower in patients who developed C-IRIS than those who did not. Multivariate analysis revealed significant inverse associations between C-IRIS and IgM (P = .0003), Lam-IgM (P = .0005), Lam-IgG (P = .002), and GXM-IgM (P = .002) independent of age, sex, HIV viral load, CD4+ T-cell count, and cerebrospinal fluid fungal burden. There were no associations between C-IRIS and total or memory B cells. Discussion: Antibody profiles that include plasma IgM, Lam-IgM, Lam-IgG, and/or GXM-IgM may have value in furthering our understanding of C-IRIS pathogenesis and hold promise as candidate biomarkers of C-IRIS risk.


Asunto(s)
Formación de Anticuerpos/inmunología , Criptococosis/inmunología , Síndrome Inflamatorio de Reconstitución Inmune/inmunología , Inmunoglobulinas/sangre , Meningitis Criptocócica/inmunología , Plasma/inmunología , Antirretrovirales , Linfocitos B , Cryptococcus neoformans/inmunología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina M/sangre , Análisis Multivariante , Polisacáridos/inmunología
3.
Front Immunol ; 10: 2993, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31998297

RESUMEN

Macrophage activation is intimately linked to metabolic reprogramming. Inflammatory (M1) macrophages are able to sustain inflammatory responses and to kill pathogens, mostly by relying on aerobic glycolysis and fatty acid biosynthesis. Glycolysis is a fast way of producing ATP, and fatty acids serve as precursors for the synthesis of inflammatory mediators. On the opposite side, anti-inflammatory (M2) macrophages mediate the resolution of inflammation and tissue repair, switching their metabolism to fatty acid oxidation and oxidative phosphorylation. Over the years, this classical view has been challenged by recent discoveries pointing to a more complex metabolic network during macrophage activation. Lipid metabolism plays a critical role in the activation of both M1 and M2 macrophages. Recent evidence shows that fatty acid oxidation is also essential for inflammasome activation in M1 macrophages, and glycolysis is now known to fuel fatty acid oxidation in M2 macrophages. Ultimately, targeting lipid metabolism in macrophages can improve the outcome of metabolic diseases. Here, we review the main aspects of macrophage immunometabolism from the perspective of the metabolism of lipids. Building a reliable metabolic network during macrophage activation will bring us closer to targeting macrophages for improving human health.

5.
Cell Chem Biol ; 25(5): 571-584.e8, 2018 05 17.
Artículo en Inglés | MEDLINE | ID: mdl-29576533

RESUMEN

Glycosylceramides that activate CD1d-restricted invariant natural killer T (iNKT) cells have potential therapeutic applications for augmenting immune responses against cancer and infections. Previous studies using mouse models identified sphinganine variants of α-galactosylceramide as promising iNKT cell activators that stimulate cytokine responses with a strongly proinflammatory bias. However, the activities of sphinganine variants in mice have generally not translated well to studies of human iNKT cell responses. Here, we show that strongly proinflammatory and anti-tumor iNKT cell responses were achieved in mice by a variant of α-galactosylceramide that combines a sphinganine base with a hydrocinnamoyl ester on C6″ of the sugar. Importantly, the activities observed with this variant were largely preserved for human iNKT cell responses. Structural and in silico modeling studies provided a mechanistic basis for these findings and suggested basic principles for capturing useful properties of sphinganine analogs of synthetic iNKT cell activators in the design of immunotherapeutic agents.


Asunto(s)
Antineoplásicos Inmunológicos/química , Antineoplásicos Inmunológicos/farmacología , Galactosilceramidas/química , Galactosilceramidas/farmacología , Activación de Linfocitos/efectos de los fármacos , Células T Asesinas Naturales/efectos de los fármacos , Neoplasias/terapia , Adolescente , Adulto , Anciano , Animales , Antígenos CD1d/inmunología , Línea Celular Tumoral , Células Cultivadas , Femenino , Humanos , Inmunoterapia , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Células T Asesinas Naturales/inmunología , Neoplasias/inmunología
6.
Front Immunol ; 9: 26, 2018.
Artículo en Inglés | MEDLINE | ID: mdl-29403503

RESUMEN

Vaccines have significantly reduced the detrimental effects of numerous human infectious diseases worldwide, helped to reduce drastically child mortality rates and even achieved eradication of major pathogens, such as smallpox. These achievements have been possible due to a dedicated effort for vaccine research and development, as well as an effective transfer of these vaccines to public health care systems globally. Either public or private institutions have committed to developing and manufacturing vaccines for local or international population supply. However, current vaccine manufacturers worldwide might not be able to guarantee sufficient vaccine supplies for all nations when epidemics or pandemics events could take place. Currently, different countries produce their own vaccine supplies under Good Manufacturing Practices, which include the USA, Canada, China, India, some nations in Europe and South America, such as Germany, the Netherlands, Italy, France, Argentina, and Brazil, respectively. Here, we discuss some of the vaccine programs and manufacturing capacities, comparing the current models of vaccine management between industrialized and developing countries. Because local vaccine production undoubtedly provides significant benefits for the respective population, the manufacture capacity of these prophylactic products should be included in every country as a matter of national safety.


Asunto(s)
Control de Enfermedades Transmisibles/métodos , Programas de Inmunización , Vacunas , Enfermedades Transmisibles/epidemiología , Humanos , Instalaciones Industriales y de Fabricación , Investigación , Vacunas/síntesis química , Vacunas/provisión & distribución , Vacunas/uso terapéutico
7.
Open Forum Infect Dis ; 5(1): ofx255, 2018 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-29354657

RESUMEN

The importance of antibody immunity in protection against Cryptococcus neoformans remains unresolved. We measured serum C neoformans-specific and total antibody levels and peripheral blood B cell subsets of 12 previously healthy patients with cryptococcosis (cases) and 21 controls. Before and after adjustment for age, sex, and race, cryptococcal capsular polysaccharide immunoglobulin G was higher in cases than controls, whereas total B and memory B cell levels were lower. These associations parallel previous findings in patients with human immunodeficiency virus-associated cryptococcosis and suggest that B cell subset perturbations may also associate with disease in previously normal individuals with cryptococcosis.

8.
Int Rev Immunol ; 36(6): 315-337, 2017 11 02.
Artículo en Inglés | MEDLINE | ID: mdl-28933579

RESUMEN

Modulation of the immune system has been widely targeted for the treatment of several immune-related diseases, such as autoimmune disorders and cancer, due to its crucial role in these pathologies. Current available therapies focus mainly on symptomatic treatment and are often associated with undesirable secondary effects. For several years, remission of disease and subsequently recovery of immune homeostasis has been a major goal for immunotherapy. Most current immunotherapeutic strategies are aimed to inhibit or potentiate directly the adaptive immune response by modulating antibody production and B cell memory, as well as the effector potential and memory of T cells. Although these immunomodulatory approaches have shown some success in the clinic with promising therapeutic potential, they have some limitations related to their effectiveness in disease models and clinical trials, as well as elevated costs. In the recent years, a renewed interest has emerged on targeting innate immune cells for immunotherapy, due to their high plasticity and ability to exert a potent and extremely rapid response, which can influence the outcome of the adaptive immune response. In this review, we discuss the immunomodulatory potential of several innate immune cells, as well as they use for immunotherapy, especially in autoimmunity and cancer.


Asunto(s)
Enfermedades Autoinmunes/terapia , Células Dendríticas/inmunología , Inmunidad Innata , Inmunoterapia Adoptiva/métodos , Células T Asesinas Naturales/inmunología , Neoplasias/terapia , Animales , Enfermedades Autoinmunes/inmunología , Plasticidad de la Célula , Humanos , Inmunidad , Células T Asesinas Naturales/trasplante , Neoplasias/inmunología
9.
Nanomedicine ; 13(7): 2267-2270, 2017 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-28712918

RESUMEN

Systemic therapies are preferred for treating dermal dermatophytosis due to inadequate penetration of topical agents. However, systemic antifungals are associated with off-target effects and limited tissue penetration, and antimicrobial resistance is a growing concern. To address this, we investigated topical nitric oxide-releasing nanoparticles (NO-np), which have been used against superficial fungal infections and bacterial abscesses. In addition to enhanced penetration and permeation conferred by nanoparticles, nitric oxide, a broad-spectrum multi-mechanistic antimicrobial agent, offers decreased likelihood of resistance development. In the current study, NO-np inhibited Trichophyton rubrum in vitro, as well as in a murine model of dermal dermatophytosis. In mice, NO-np reduced fungal burden after three days, with complete clearance after seven. Furthermore, NO-np decreased tissue IL-2, 6, 10 and TNFα, indicating earlier attenuation of the host inflammatory response and decreased tissue morbidity. Thus, topical NO-np represent an attractive alternative to systemic therapy against dermal T. rubrum infection.


Asunto(s)
Antifúngicos/uso terapéutico , Nanopartículas/uso terapéutico , Óxido Nítrico/uso terapéutico , Tiña/tratamiento farmacológico , Trichophyton/efectos de los fármacos , Administración Cutánea , Animales , Antifúngicos/administración & dosificación , Modelos Animales de Enfermedad , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/microbiología , Ratones , Ratones Endogámicos BALB C , Nanopartículas/administración & dosificación , Óxido Nítrico/administración & dosificación , Tiña/complicaciones , Tiña/microbiología
11.
Nat Microbiol ; 1(9): 16133, 2016 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-27562263

RESUMEN

Suppression of major histocompatibility complex (MHC) class II antigen presentation is believed to be among the major mechanisms used by Mycobacterium tuberculosis to escape protective host immune responses. Through a genome-wide screen for the genetic loci of M. tuberculosis that inhibit MHC class II-restricted antigen presentation by mycobacteria-infected dendritic cells, we identified the PE_PGRS47 protein as one of the responsible factors. Targeted disruption of the PE_PGRS47 (Rv2741) gene led to attenuated growth of M. tuberculosis in vitro and in vivo, and a PE_PGRS47 mutant showed enhanced MHC class II-restricted antigen presentation during in vivo infection of mice. Analysis of the effects of deletion or over-expression of PE_PGRS47 implicated this protein in the inhibition of autophagy in infected host phagocytes. Our findings identify PE_PGRS47 as a functionally relevant, non-redundant bacterial factor in the modulation of innate and adaptive immunity by M. tuberculosis, suggesting strategies for improving antigen presentation and the generation of protective immunity during vaccination or infection.


Asunto(s)
Presentación de Antígeno , Autofagia , Proteínas Bacterianas/metabolismo , Antígenos de Histocompatibilidad Clase II/inmunología , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Inmunidad Adaptativa , Animales , Proteínas Bacterianas/genética , Línea Celular , Células Dendríticas/inmunología , Femenino , Eliminación de Gen , Expresión Génica , Interacciones Huésped-Patógeno , Humanos , Macrófagos/inmunología , Ratones Endogámicos C57BL , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/metabolismo , Tuberculosis/microbiología
12.
Clin Transl Immunology ; 5(4): e69, 2016 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-27195112

RESUMEN

Certain types of glycolipids have been found to have remarkable immunomodulatory properties as a result of their ability to activate specific T lymphocyte populations with an extremely wide range of immune effector properties. The most extensively studied glycolipid reactive T cells are known as invariant natural killer T (iNKT) cells. The antigen receptors of these cells specifically recognize certain glycolipids, most notably glycosphingolipids with α-anomeric monosaccharides, presented by the major histocompatibility complex class I-like molecule CD1d. Once activated, iNKT cells can secrete a very diverse array of pro- and anti-inflammatory cytokines to modulate innate and adaptive immune responses. Thus, glycolipid-mediated activation of iNKT cells has been explored for immunotherapy in a variety of disease states, including cancer and a range of infections. In this review, we discuss the design of synthetic glycolipid activators for iNKT cells, their impact on adaptive immune responses and their use to modulate iNKT cell responses to improve immunity against infections and cancer. Current challenges in translating results from preclinical animal studies to humans are also discussed.

13.
J Infect Dis ; 214(3): 426-37, 2016 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-27234419

RESUMEN

BACKGROUND: Bacillus Calmette-Guerin (BCG) vaccine is widely used for the prevention of tuberculosis, despite limited efficacy. Most immunological studies of BCG or Mycobacterium tuberculosis strains grow bacteria in the presence of detergent, which also strips the mycobacterial capsule. The impact of the capsule on vaccine efficacy has not been explored. METHODS: We tested the influence of detergent in cultures of BCG and M. tuberculosis strains on the outcome of vaccination experiments on mice and transcriptional responses on M. tuberculosis RESULTS: Vaccination of mice with encapsulated BCG promoted a more potent immune response relative to vaccination with unencapsulated BCG, including higher polysaccharide-specific capsule antibody titers, higher interferon γ and interleukin 17 splenic responses, and more multifunctional CD4(+) T cells. These differences correlated with variability in the bacterial burden in lung and spleen of mice infected with encapsulated or unencapsulated M. tuberculosis The combination of vaccination and challenge with encapsulated strains resulted in the greatest protection efficacy. The transcriptome of encapsulated M. tuberculosis was similar to that of starvation, hypoxia, stationary phase, or nonreplicating persistence. CONCLUSIONS: The presence of detergent in growth media and a capsule on BCG were associated with differences in the outcome of vaccination, implying that these are important variables in immunological studies.


Asunto(s)
Vacuna BCG/inmunología , Cápsulas Bacterianas/inmunología , Cápsulas Bacterianas/metabolismo , Medios de Cultivo/química , Mycobacterium bovis/inmunología , Mycobacterium bovis/metabolismo , Adyuvantes Inmunológicos , Animales , Anticuerpos Antibacterianos/sangre , Linfocitos T CD4-Positivos/inmunología , Femenino , Perfilación de la Expresión Génica , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones Endogámicos C57BL , Mycobacterium bovis/crecimiento & desarrollo , Mycobacterium tuberculosis/genética , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/metabolismo
14.
Immunology ; 149(1): 1-12, 2016 09.
Artículo en Inglés | MEDLINE | ID: mdl-26938875

RESUMEN

Haem-oxygenase-1 (HO-1) is an enzyme responsible for the degradation of haem that can suppress inflammation, through the production of carbon monoxide (CO). It has been shown in several experimental models that genetic and pharmacological induction of HO-1, as well as non-toxic administration of CO, can reduce inflammatory diseases, such as endotoxic shock, type 1 diabetes and graft rejection. Recently, it was shown that the HO-1/CO system can alter the function of antigen-presenting cells (APCs) and reduce T-cell priming, which can be beneficial during immune-driven inflammatory diseases. The molecular mechanisms by which the HO-1 and CO reduce both APC- and T-cell-driven immunity are just beginning to be elucidated. In this article we discuss recent findings related to the immune regulatory capacity of HO-1 and CO at the level of recognition of pathogen-associated molecular patterns and T-cell priming by APCs. Finally, we propose a possible regulatory role for HO-1 and CO over the recently described mitochondria-dependent immunity. These concepts could contribute to the design of new therapeutic tools for inflammation-based diseases.


Asunto(s)
Presentación de Antígeno , Hemo-Oxigenasa 1/metabolismo , Enfermedades del Sistema Inmune/tratamiento farmacológico , Tolerancia Inmunológica , Inflamación/metabolismo , Linfocitos T/inmunología , Animales , Monóxido de Carbono/metabolismo , Diseño de Drogas , Humanos , Inmunomodulación , Activación de Linfocitos
15.
Iatreia ; 29(1): 51-64, ene.-mar. 2016. ilus, tab
Artículo en Español | LILACS, COLNAL | ID: lil-776278

RESUMEN

Aunque se ha logrado un conocimiento amplio acerca de las células T asesinas naturales (iNKT), aún no existe consenso sobre sus mecanismos de activación. Dichas células reconocen diferentes antígenos glicolipídicos presentados por medio de la molécula CD1d, los cuales pueden ser endógenos, exógenos derivados de organismos como bacterias y sintéticos desarrollados para aplicaciones clínicas. Existe mucho interés en entender cómo estas distintas variantes glicolipídicas inducen diferentes tipos de polarización, pero ha sido muy difícil llegar a un consenso, debido a que la respuesta depende de varios factores como la naturaleza, la internalización y el procesamiento de los glicolípidos. Además, la activación de las células iNKT la determinan el tipo y estado de activación de la célula presentadora de antígeno, las moléculas coestimuladoras, los mecanismos de transactivación y la localización de los complejos CD1d-glicolípido en distintas microrregiones de la membrana plasmática, como las balsas lipídicas. Esta revisión explora la evidencia sobre los factores que afectan la activación de las células iNKT con el fin de entender su potencial inmunomodulador.


A great amount of knowledge on natural killer T cells (iNKTs) is now available, but a consensus about their activation mechanisms has not been reached. These cells recognize different glycolipid antigens through the CD1d molecule. Such antigens may be endogenous, derived from bacteria (foreign) and synthetic, the latter have been developed for clinical applications. There exists much interest in understanding how these different glycolipid compounds induce different types of polarization, but it has been difficult to reach a consensus due to the fact that responses depend on different factors such as: the nature of the molecule, the internalization process and the presentation of the glycolipids. Moreover, activation of iNKT cells is determined by the type and state of the antigen presenting cell, the co-stimulatory molecules, the transactivation mechanisms and the location of the glycolipid-CD1d complexes on the plasma membrane, such as the lipid rafts. This review explores the evidence about the factors that affect activation of iNKT cells in order to understand their immune-modulatory potential.


Ainda que se conseguiu um conhecimento amplo a respeito das células T assassinas naturais (iNKT), ainda não existe consenso sobre seus mecanismos de ativação. Ditas células reconhecem diferentes antígenos glicolipídicos apresentados por meio da molécula CD1d, os quais pode ser: endógenos, exógenos derivados de organismos como bactérias e sintéticos desenvolvidos para aplicações clínicas. Existe muito interesse em entender como estas diferentes variantes glicolipídicas induzem diferentes tipos de polarização, mas foi muito difícil chegar a um consenso, devido a que a resposta depende de vários fatores como a natureza, a internalização e o processamento dos glicolípidos. Ademais, a ativação das células iNKT a determinam o tipo e estado de ativação da célula apresentadora de antígeno, as moléculas co-estimuladoras, os mecanismos de transativação e a localização dos complexos CD1d-glicolípido em diferentes microrregiões da membrana plasmática, como as balsas lipídicas. Esta revisão explora a evidência sobre os fatores que afetam a ativação das células iNKT com o fim de entender seu potencial imunomodulador.


Asunto(s)
Humanos , Antígenos CD1d , Células T Asesinas Naturales , Linfocitos T , Antígenos
16.
Iatreia ; 29(1): 51-64, ene.-mar. 2016. tab, ilus
Artículo en Español | LILACS | ID: lil-785513

RESUMEN

Aunque se ha logrado un conocimiento amplio acerca de las células T asesinas naturales (iNKT), aún no existe consenso sobre sus mecanismos de activación. Dichas células reconocen diferentes antígenos glicolipídicos presentados por medio de la molécula CD1d, los cuales pueden ser endógenos, exógenos derivados de organismos como bacterias y sintéticos desarrollados para aplicaciones clínicas. Existe mucho interés en entender cómo estas distintas variantes glicolipídicas inducen diferentes tipos de polarización, pero ha sido muy difícil llegar a un consenso, debido a que la respuesta depende de varios factores como la naturaleza, la internalización y el procesamiento de los glicolípidos. Además, la activación de las células iNKT la determinan el tipo y estado de activación de la célula presentadora de antígeno, las moléculas coestimuladoras, los mecanismos de transactivación y la localización de los complejos CD1d-glicolípido en distintas microrregiones de la membrana plasmática, como las balsas lipídicas. Esta revisión explora la evidencia sobre los factores que afectan la activación delas células iNKT con el fin de entender su potencial inmunomodulador...


A great amount of knowledge on natural killer T cells (iNKTs) is now available, but a consensus about their activation mechanisms has not been reached. These cells recognize different glycolipidantigens through the CD1d molecule. Such antigens may be endogenous, derived from bacteria (foreign) and synthetic, the latter have been developed for clinical applications. There exists much interest in understanding how these different glycolipid compounds induce different types of polarization, but it has been difficult to reach a consensus due to the fact that responses depend on different factorssuch as: the nature of the molecule, the internalization process and the presentation of the glycolipids. Moreover, activation of iNKT cells is determined by the type and state of the antigen presenting cell, the co-stimulatory molecules, the transactivation mechanisms and the location of the glycolipid-CD1d complexes on the plasma membrane, such as the lipid rafts. This review explores the evidence about the factorsthat affect activation of iNKT cells in order to understand their immune-modulatory potential...


Ainda que se conseguiu um conhecimento amplo a respeito das células T assassinas naturais (iNKT), ainda não existe consenso sobre seus mecanismos de ativação. Ditas células reconhecem diferentes antígenosglicolipídicos apresentados por meio da molécula CD1d, os quais pode ser: endógenos, exógenos derivados de organismos como bactérias e sintéticosdesenvolvidos para aplicações clínicas. Existe muito interesse em entender como estas diferentes variantes glicolipídicas induzem diferentes tipos de polarização, mas foi muito difícil chegar a um consenso, devido a que a resposta depende de vários fatores como a natureza, a internalização e o processamento dos glicolípidos. Ademais, a ativação das células iNKT a determinam o tipo e estado de ativação da célula apresentadora de antígeno, as moléculas co-estimuladoras, os mecanismos de transativação e a localização dos complexos CD1d-glicolípido em diferentes microrregiões da membrana plasmática, como as balsas lipídicas. Esta revisão explora a evidência sobre os fatores que afetam a ativação das células iNKT com o fim de entender seu potencial imunomodulador...


Asunto(s)
Humanos , Células T Asesinas Naturales , Linfocitos T
17.
Expert Rev Vaccines ; 14(11): 1493-507, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-26366616

RESUMEN

The development of more effective vaccines against Mycobacterium tuberculosis (Mtb) remains a major goal in the effort to reduce the enormous global burden of disease caused by this pathogen. Whole-cell vaccines based on live mycobacteria with attenuated virulence represent an appealing approach, providing broad antigen exposure and intrinsic adjuvant properties to prime durable immune responses. However, designing vaccine strains with an optimal balance between attenuation and immunogenicity has proven to be extremely challenging. Recent basic and clinical research efforts have broadened our understanding of Mtb pathogenesis and created numerous new vaccine candidates that have been designed to overcome different aspects of immune evasion by Mtb. In this review, we provide an overview of the current efforts to create improved vaccines against tuberculosis based on modifications of live attenuated mycobacteria. In addition, we discuss the use of such vaccine strains as vectors for stimulating protective immunity against other infectious diseases and cancers.


Asunto(s)
Descubrimiento de Drogas/métodos , Mycobacterium tuberculosis/inmunología , Vacunas contra la Tuberculosis/inmunología , Vacunas contra la Tuberculosis/aislamiento & purificación , Descubrimiento de Drogas/tendencias , Humanos , Tuberculosis/prevención & control , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/aislamiento & purificación
18.
mBio ; 5(5): e01921-14, 2014 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-25271291

RESUMEN

UNLABELLED: Pathogenic and nonpathogenic species of bacteria and fungi release membrane vesicles (MV), containing proteins, polysaccharides, and lipids, into the extracellular milieu. Previously, we demonstrated that several mycobacterial species, including bacillus Calmette-Guerin (BCG) and Mycobacterium tuberculosis, release MV containing lipids and proteins that subvert host immune response in a Toll-like receptor 2 (TLR2)-dependent manner (R. Prados-Rosales et al., J. Clin. Invest. 121:1471-1483, 2011, doi:10.1172/JCI44261). In this work, we analyzed the vaccine potential of MV in a mouse model and compared the effects of immunization with MV to those of standard BCG vaccination. Immunization with MV from BCG or M. tuberculosis elicited a mixed humoral and cellular response directed to both membrane and cell wall components, such as lipoproteins. However, only vaccination with M. tuberculosis MV was able to protect as well as live BCG immunization. M. tuberculosis MV boosted BCG vaccine efficacy. In summary, MV are highly immunogenic without adjuvants and elicit immune responses comparable to those achieved with BCG in protection against M. tuberculosis. IMPORTANCE: This work offers a new vaccine approach against tuberculosis using mycobacterial MV. Mycobacterium MV are a naturally released product combining immunogenic antigens in the context of a lipid structure. The fact that MV do not need adjuvants and elicit protection comparable to that elicited by the BCG vaccine encourages vaccine approaches that combine protein antigens and lipids. Consequently, mycobacterium MV establish a new type of vaccine formulation.


Asunto(s)
Proteínas de la Membrana/inmunología , Mycobacterium tuberculosis/inmunología , Vacunas contra la Tuberculosis/inmunología , Tuberculosis/prevención & control , Adyuvantes Inmunológicos/administración & dosificación , Animales , Anticuerpos Antibacterianos/sangre , Vacuna BCG/inmunología , Ensayo de Inmunoadsorción Enzimática , Femenino , Inmunidad Humoral , Inmunidad Innata , Lipoproteínas/inmunología , Ratones , Ratones Endogámicos C57BL , Mycobacterium bovis/inmunología , Receptor Toll-Like 2/inmunología
19.
PLoS One ; 9(9): e108383, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-25255287

RESUMEN

Recombinant Mycobacterium bovis bacillus Calmette-Guèrin (rBCG) has been explored as a vector for vaccines against HIV because of its ability to induce long lasting humoral and cell mediated immune responses. To maximize the potential for rBCG vaccines to induce effective immunity against HIV, various strategies are being employed to improve its ability to prime CD8+ T cells, which play an important role in the control of HIV infections. In this study we adopted a previously described approach of incorporating glycolipids that activate CD1d-restricted natural killer T (NKT) cells to enhance priming of CD8+ T cells by rBCG strains expressing an SIV Gag antigen (rBCG-SIV gag). We found that the incorporation of the synthetic NKT activating glycolipid α-galactosylceramide (α-GC) into rBCG-SIV gag significantly enhanced CD8+ T cell responses against an immunodominant Gag epitope, compared to responses primed by unmodified rBCG-SIV gag. The abilities of structural analogues of α-GC to enhance CD8+ T cell responses to rBCG were compared in both wild type and partially humanized mice that express human CD1d molecules in place of mouse CD1d. These studies identified an α-GC analogue known as 7DW8-5, which has previously been used successfully as an adjuvant in non-human primates, as a promising compound for enhancing immunogenicity of antigens delivered by rBCG.vectors. Our findings support the incorporation of synthetic glycolipid activators of NKT cells as a novel approach to enhance the immunogenicity of rBCG-vectored antigens for induction of CD8+ T cell responses. The glycolipid adjuvant 7DW8-5 may be a promising candidate for advancing to non-human primate and human clinical studies for the development of HIV vaccines based on rBCG vectors.


Asunto(s)
Antígenos Virales/inmunología , Vacuna BCG/inmunología , Glucolípidos/inmunología , Mycobacterium bovis/inmunología , Células T Asesinas Naturales/inmunología , Animales , Vacuna BCG/administración & dosificación , Vacuna BCG/genética , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Anergia Clonal/inmunología , Modelos Animales de Enfermedad , Femenino , Galactosilceramidas/inmunología , Productos del Gen gag/genética , Productos del Gen gag/inmunología , Humanos , Memoria Inmunológica , Activación de Linfocitos/inmunología , Ratones , Ratones Transgénicos , Virus de la Inmunodeficiencia de los Simios/genética , Virus de la Inmunodeficiencia de los Simios/inmunología
20.
Immunotherapy ; 6(3): 309-20, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24762075

RESUMEN

NKT cells are a subpopulation of T lymphocytes with phenotypic properties of both T and NK cells and a wide range of immune effector properties. In particular, one subset of these cells, known as invariant NKT cells (iNKT cells), has attracted substantial attention because of their ability to be specifically activated by glycolipid antigens presented by a cell surface protein called CD1d. The development of synthetic α-galactosylceramides as a family of powerful glycolipid agonists for iNKT cells has led to approaches for augmenting a wide variety of immune responses, including those involved in vaccination against infections and cancers. Here, we review basic, preclinical and clinical observations supporting approaches to improving immune responses through the use of iNKT cell-activating glycolipids. Results from preclinical animal studies and preliminary clinical studies in humans identify many promising applications for this approach in the development of vaccines and novel immunotherapies.


Asunto(s)
Adyuvantes Inmunológicos , Antígenos/inmunología , Glucolípidos/inmunología , Células T Asesinas Naturales/inmunología , Animales , Antígenos Bacterianos/inmunología , Antígenos CD1d/inmunología , Antígenos de Neoplasias/inmunología , Infecciones Bacterianas/prevención & control , Infecciones Bacterianas/terapia , Vacunas Bacterianas/inmunología , Vacunas contra el Cáncer/inmunología , Citocinas/metabolismo , Células Dendríticas/inmunología , Galactosilceramidas/inmunología , Glucolípidos/agonistas , Humanos , Memoria Inmunológica , Inmunoterapia Activa , Ligandos , Activación de Linfocitos , Ratones , Células T Asesinas Naturales/metabolismo , Neoplasias/terapia , Primates , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Vacunación
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