RESUMEN

Fast, high-fidelity measurement is a key ingredient for quantum error correction. Conventional approaches to the measurement of superconducting qubits, involving linear amplification of a microwave probe tone followed by heterodyne detection at room temperature, do not scale well to large system sizes. We introduce an approach to measurement based on a microwave photon counter demonstrating raw single-shot measurement fidelity of 92%. Moreover, the intrinsic damping of the photon counter is used to extract the energy released by the measurement process, allowing repeated high-fidelity quantum nondemolition measurements. Our scheme provides access to the classical outcome of projective quantum measurement at the millikelvin stage and could form the basis for a scalable quantum-to-classical interface.

RESUMEN

BACKGROUND: Influenza infects 5-15% of the global population each year, and obesity has been shown to be an independent risk factor for increased influenza-related complications including hospitalization and death. However, the risk of developing influenza or influenza-like illness (ILI) in a vaccinated obese adult population has not been addressed. OBJECTIVE: This study evaluated whether obesity was associated with increased risk of influenza and ILI among vaccinated adults. SUBJECTS AND METHODS: During the 2013-2014 and 2014-2015 influenza seasons, we recruited 1042 subjects to a prospective observational study of trivalent inactivated influenza vaccine (IIV3) in adults. A total of 1022 subjects completed the study. Assessments of relative risk for laboratory confirmed influenza and ILI were determined based on body mass index. Seroconversion and seroprotection rates were determined using prevaccination and 26-35 days post vaccination serum samples. Recruitment criteria for this study were adults 18 years of age and older receiving the seasonal trivalent inactivated influenza vaccine (IIV3) for the years 2013-2014 and 2014-2015. Exclusion criteria were immunosuppressive diseases, use of immunomodulatory or immunosuppressive drugs, acute febrile illness, history of Guillain-Barre syndrome, use of theophylline preparations or use of warfarin. RESULTS: Among obese, 9.8% had either confirmed influenza or influenza-like-illness compared with 5.1% of healthy weight participants. Compared with vaccinated healthy weight, obese participants had double the risk of developing influenza or ILI (relative risk=2.01, 95% CI 1.12, 3.60, P=0.020). Seroconversion or seroprotection rates were not different between healthy weight and obese adults with influenza or ILI. CONCLUSIONS: Despite robust serological responses, vaccinated obese adults are twice as likely to develop influenza and ILI compared with healthy weight adults. This finding challenges the current standard for correlates of protection, suggesting use of antibody titers to determine vaccine effectiveness in an obese population may provide misleading information.

Asunto(s)

Vacunas contra la Influenza , Gripe Humana/inmunología , Obesidad/inmunología , Adulto , Índice de Masa Corporal , Femenino , Investigación sobre Servicios de Salud , Humanos , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/epidemiología , Gripe Humana/prevención & control , Masculino , Persona de Mediana Edad , Obesidad/complicaciones , Obesidad/fisiopatología , Evaluación de Resultado en la Atención de Salud , Estudios Prospectivos , Medición de Riesgo

RESUMEN

Appalachian USA surface coal mines face public and regulatory pressure to reduce total dissolved solids (TDS) in discharge waters, primarily due to effects on sensitive macroinvertebrates. Specific conductance (SC) is an accurate surrogate for TDS and relatively low levels of SC (300-500 µS cm(-1)) have been proposed as regulatory benchmarks for instream water quality. Discharge levels of TDS from regional coal mines are frequently >1000 µS cm(-1). The primary objectives of this study were to (a) determine the effect of rock type and weathering status on SC leaching potentials for a wide range of regional mine spoils; (b) to relate leachate SC from laboratory columns to actual measured discharge SC from field sites; and (c) determine effective rapid lab analyses for SC prediction of overburden materials. We correlated laboratory unsaturated column leaching results for 39 overburden materials with a range of static lab parameters such as total-S, saturated paste SC, and neutralization potential. We also compared column data with available field leaching and valley fill discharge SC data. Leachate SC is strongly related to rock type and pre-disturbance weathering. Fine-textured and non-weathered strata generally produced higher SC and pose greater TDS risk. High-S black shales produced the highest leachate SC. Lab columns generated similar range and overall SC decay response to field observations within 5-10 leaching cycles, while actual reduction in SC in the field occurs over years to decades. Initial peak SC can be reliably predicted (R(2) > 0.850; p < 0.001) by simple lab saturated paste or 1:2 spoil:water SC procedures, but predictions of longer-term SC levels are less reliable and deserve further study. Overall TDS release risk can be accurately predicted by a combination of rock type + S content, weathering extent, and simple rapid SC lab measurements.

Asunto(s)

Minas de Carbón , Monitoreo del Ambiente/métodos , Contaminantes del Agua/análisis , Calidad del Agua , Agua/química , Región de los Apalaches , Contaminantes del Agua/química

RESUMEN

UNLABELLED: Essentials H1N1 Influenza A virus (IAV) infection is a hemostatic challenge for the lung. Tissue factor (TF) on lung epithelial cells maintains lung hemostasis after IAV infection. Reduced TF-dependent activation of coagulation leads to alveolar hemorrhage. Anticoagulation might increase the risk for hemorrhages into the lung during severe IAV infection. SUMMARY: Background Influenza A virus (IAV) infection is a common respiratory tract infection that causes considerable morbidity and mortality worldwide. Objective To investigate the effect of genetic deficiency of tissue factor (TF) in a mouse model of IAV infection. Methods Wild-type mice, low-TF (LTF) mice and mice with the TF gene deleted in different cell types were infected with a mouse-adapted A/Puerto Rico/8/34 H1N1 strain of IAV. TF expression was measured in the lungs, and bronchoalveolar lavage fluid (BALF) was collected to measure extracellular vesicle TF, activation of coagulation, alveolar hemorrhage, and inflammation. Results IAV infection of wild-type mice increased lung TF expression, activation of coagulation and inflammation in BALF, but also led to alveolar hemorrhage. LTF mice and mice with selective deficiency of TF in lung epithelial cells had low basal levels of TF and failed to increase TF expression after infection; these two strains of mice had more alveolar hemorrhage and death than controls. In contrast, deletion of TF in either myeloid cells or endothelial cells and hematopoietic cells did not increase alveolar hemorrhage or death after IAV infection. These results indicate that TF expression in the lung, particularly in epithelial cells, is required to maintain alveolar hemostasis after IAV infection. Conclusion Our study indicates that TF-dependent activation of coagulation is required to limit alveolar hemorrhage and death after IAV infection.

Asunto(s)

Células Epiteliales/virología , Hemorragia/virología , Infecciones por Orthomyxoviridae/patología , Alveolos Pulmonares/metabolismo , Tromboplastina/deficiencia , Animales , Anticoagulantes/uso terapéutico , Coagulación Sanguínea , Líquido del Lavado Bronquioalveolar , Eliminación de Gen , Hemostasis , Inflamación , Subtipo H1N1 del Virus de la Influenza A , Integrasas/metabolismo , Pulmón/patología , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Tromboplastina/metabolismo

RESUMEN

B-1 and B-2 B cell subsets carry out a diverse array of functions that range broadly from responding to innate stimuli, antigen presentation, cytokine secretion and antibody production. In this review, we first cover the functional roles of the major murine B cell subsets. We then highlight emerging evidence, primarily in preclinical rodent studies, to show that select B cell subsets are a therapeutic target in obesity and its associated co-morbidities. High fat diets promote accumulation of select murine B cell phenotypes in visceral adipose tissue. As a consequence, B cells exacerbate inflammation and thereby insulin sensitivity through the production of autoantibodies and via cross-talk with select adipose resident macrophages, CD4(+) and CD8(+) T cells. In contrast, interleukin (IL)-10-secreting regulatory B cells counteract the proinflammatory profile and improve glucose sensitivity. We subsequently review data from rodent studies that show pharmacological supplementation of obesogenic diets with long chain n-3 polyunsaturated fatty acids or specialized pro-resolving lipid mediators synthesized from endogenous n-3 polyunsaturated fatty acids boost B cell activation and antibody production. This may have potential benefits for improving inflammation in addition to combating the increased risk of viral infection that is an associated complication of obesity and type II diabetes. Finally, we propose potential underlying mechanisms throughout the review by which B cell activity could be differentially regulated in response to high fat diets.

Asunto(s)

Linfocitos B/inmunología , Linfocitos B/metabolismo , Dieta , Obesidad/etiología , Tejido Adiposo/inmunología , Tejido Adiposo/patología , Animales , Antígenos de Superficie/metabolismo , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/citología , Diferenciación Celular , Comorbilidad , Ácidos Grasos Insaturados/metabolismo , Humanos , Inmunidad Humoral , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Fenotipo , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo

RESUMEN

BACKGROUND: Obesity is an independent risk factor for morbidity and mortality from pandemic influenza H1N1. Influenza is a significant public health threat, killing an estimated 250,000-500,000 people worldwide each year. More than one in ten of the world's adult population is obese and more than two-thirds of the US adult population is overweight or obese. No studies have compared humoral or cellular immune responses to influenza vaccination in healthy weight, overweight and obese populations despite clear public health importance. OBJECTIVE: The study employed a convenience sample to determine the antibody response to the 2009-2010 inactivated trivalent influenza vaccine (TIV) in healthy weight, overweight and obese participants at 1 and 12 months post vaccination. In addition, activation of CD8⁺ T cells and expression of interferon-γ and granzyme B were measured in influenza-stimulated peripheral blood mononuclear cell (PBMC) cultures. RESULTS: Body mass index (BMI) correlated positively with higher initial fold increase in IgG antibodies detected by enzyme-linked immunosorbent assay to TIV, confirmed by HAI antibody in a subset study. However, 12 months post vaccination, higher BMI was associated with a greater decline in influenza antibody titers. PBMCs challenged ex vivo with vaccine strain virus, demonstrated that obese individuals had decreased CD8⁺ T-cell activation and decreased expression of functional proteins compared with healthy weight individuals. CONCLUSION: These results suggest obesity may impair the ability to mount a protective immune response to influenza virus.

Asunto(s)

Granzimas/metabolismo , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Interferón gamma/metabolismo , Activación de Linfocitos/inmunología , Obesidad/inmunología , Adulto , Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Femenino , Pruebas de Inhibición de Hemaglutinación , Humanos , Vacunas contra la Influenza/efectos adversos , Activación de Linfocitos/efectos de los fármacos , Masculino , Persona de Mediana Edad , Obesidad/complicaciones

RESUMEN

It is unknown whether nutritional deficiencies affect the morphology and function of structural cells, such as epithelial cells, and modify the susceptibility to viral infections. We developed an in vitro system of differentiated human bronchial epithelial cells (BEC) grown either under selenium-adequate (Se+) or selenium-deficient (Se-) conditions, to determine whether selenium deficiency impairs host defense responses at the level of the epithelium. Se- BECs had normal SOD activity, but decreased activity of the selenium-dependent enzyme GPX1. Interestingly, catalase activity was also decreased in Se- BECs. Both Se- and Se+ BECs differentiated into a mucociliary epithelium; however, Se- BEC demonstrated increased mucus production and increased Muc5AC mRNA levels. This effect was also seen in Se+ BEC treated with 3-aminotriazole, an inhibitor of catalase activity, suggesting an association between catalase activity and mucus production. Both Se- and Se+ were infected with influenza A/Bangkok/1/79 and examined 24 h postinfection. Influenza-induced IL-6 production was greater while influenza-induced IP-10 production was lower in Se- BECs. In addition, influenza-induced apoptosis was greater in Se- BEC as compared to the Se+ BECs. These data demonstrate that selenium deficiency has a significant impact on the morphology and influenza-induced host defense responses in human airway epithelial cells.

Asunto(s)

Bronquios/efectos de los fármacos , Virus de la Influenza A/efectos de los fármacos , Gripe Humana/inmunología , Selenio/deficiencia , Adulto , Alantoína/metabolismo , Animales , Bronquios/citología , Bronquios/metabolismo , Catalasa/antagonistas & inhibidores , Catalasa/efectos de los fármacos , Catalasa/metabolismo , Células Cultivadas/efectos de los fármacos , Células Cultivadas/metabolismo , Células Cultivadas/ultraestructura , Quimiocina CXCL10 , Quimiocinas CXC/metabolismo , Pollos , Perros , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Células Epiteliales/ultraestructura , Glutatión/metabolismo , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Humanos , Virus de la Influenza A/inmunología , Virus de la Influenza A/patogenicidad , Gripe Humana/metabolismo , Interleucina-6/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Selenio/administración & dosificación , Tasa de Supervivencia , Virulencia/efectos de los fármacos

RESUMEN

BACKGROUND: Recent evidence suggests that atopic disease may in part be mediated by fetal growth, as well as exposure to infectious disease early in life. Few studies have been able to evaluate these associations simultaneously, or to investigate prospectively the long-term effects of early environments while adequately controlling for potentially confounding variables. OBJECTIVE: To examine how prenatal growth and infectious disease in infancy are related to total IgE production in adolescence. METHODS: Ninety-nine adolescents (aged 14-15 years) were selected from a larger cohort study according to the following criteria: full-term birth, currently healthy, and small-for-gestational age (N=53) or appropriate-for-gestational age (N=46). Plasma total IgE was measured with ELISA, and analysed in relation to anthropometric, nutritional, and environmental quality data collected prospectively beginning in the third trimester prior to birth. RESULTS: Each episode of infectious morbidity recorded at bimonthly intervals in the first 6 months of life was associated with a 0.12 log IU/mL reduction in total IgE in adolescence (P=0.004). Prenatal undernutrition was associated with increased adolescent IgE, but only under conditions of an unsanitary household environment (P=0.002). Each additional kilogram gained per month in the first 6 months of life was associated with an increase in adolescent IgE of 0.74 log IU/mL (P=0.03). Each quartile increase in weekly household income at the time of blood sampling was associated with a 0.10 log IU/mL reduction in total IgE (P=0.02). CONCLUSION: Infectious disease in infancy, as well as interactions between prenatal and postnatal environments, appear to have long-term effects on adolescent total IgE production. Future research should investigate the mechanisms behind these effects, and their implications for symptoms of atopic disease.

Asunto(s)

Enfermedades Transmisibles/inmunología , Retardo del Crecimiento Fetal/inmunología , Inmunoglobulina E/sangre , Efectos Tardíos de la Exposición Prenatal , Adolescente , Lactancia Materna , Diarrea/epidemiología , Diarrea/inmunología , Desarrollo Embrionario y Fetal , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Incidencia , Fenómenos Fisiológicos Nutricionales del Lactante , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Masculino , Embarazo , Estudios Prospectivos , Infecciones del Sistema Respiratorio/epidemiología , Infecciones del Sistema Respiratorio/inmunología , Clase Social

RESUMEN

Malnutrition has long been associated with increased susceptibility to infectious disease. The increase in severity from and susceptibility to infectious disease in malnourished hosts is thought to be the result of an impaired immune response. For example, malnutrition could influence the immune response by inducing a less effective ability to manage the challenge of an infectious disease. Work in our laboratory has demonstrated that not only is the host affected by the nutritional deficiency, but the invading pathogen is as well. Using a deficiency in selenium (Se) as a model system, mice deficient in Se were more susceptible to infection with coxsackievirus, as well as with influenza virus. Se-deficient mice develop myocarditis when infected with a normally benign strain of coxsackievirus. They also develop severe pneumonitis when infected with a mild strain of influenza virus. The immune system was altered in the Se-deficient animals, as was the viral pathogen itself. Sequencing of viral isolates recovered from Se-deficient mice demonstrated mutations in the viral genome of both coxsackievirus and influenza virus. These changes in the viral genome are associated with the increased pathogenesis of the virus. The antioxidant selenoenzyme, glutathione peroxidase-1, was found to be critically important, as glutathione peroxidase knockout mice developed myocarditis, similar to the Se-deficient mice, when infected with the benign strain of myocarditis. This work points to the importance of host nutrition in not only optimizing the host immune response, but also in preventing viral mutations which could increase the viral pathogenicity.

Asunto(s)

Antioxidantes/metabolismo , Trastornos Nutricionales/complicaciones , Selenio/deficiencia , Virosis/inmunología , Virosis/virología , Animales , Infecciones por Coxsackievirus/inmunología , Susceptibilidad a Enfermedades , Enterovirus/genética , Enterovirus/inmunología , Enterovirus/patogenicidad , Genoma Viral , Glutatión Peroxidasa/genética , Glutatión Peroxidasa/metabolismo , Humanos , Ratones , Ratones Noqueados , Mutación , Miocarditis/inmunología , Miocarditis/virología , Orthomyxoviridae/genética , Orthomyxoviridae/inmunología , Orthomyxoviridae/patogenicidad , Virulencia

RESUMEN

BACKGROUND: Recently, researchers have considered the fetal and infant origins of several adult cardiovascular and metabolic diseases, but the implications of early events for immune function and infectious disease are unclear. OBJECTIVE: We investigated the association between prenatal undernutrition and immunocompetence in adolescence and hypothesized that intrauterine growth retardation is associated with a lower likelihood of mounting an adequate antibody response later in life. DESIGN: A subsample of one hundred three 14-15-y-olds was recruited from an ongoing longitudinal study in which data collection began while participants were in utero. A typhoid vaccine was given, and anti-typhoid antibodies were measured 2 wk and 3 mo later as a functional marker of immunocompetence. The likelihood of mounting an adequate antibody response was compared for adolescents who were small for gestational age or appropriate for gestational age at birth while controlling for a range of postnatal exposures. RESULTS: The predicted probability of mounting a positive antibody response for adolescents who were prenatally and currently undernourished was 0.32, compared with probabilities of 0.49-0.70 for adequately nourished adolescents (P = 0.023). Diarrhea in the first year of life (P = 0.009) and fast weight gain during the first 6 mo (P = 0.003) were also associated with a higher probability of response. CONCLUSIONS: These findings extend the concept of fetal and early infant programming of adult diseases to the immune system and suggest that early environments may have long-term implications for immunocompetence and infectious disease risk, particularly in developing countries.

Asunto(s)

Inmunocompetencia , Estado Nutricional , Atención Prenatal , Fiebre Tifoidea/inmunología , Vacunas Tifoides-Paratifoides , Adolescente , Formación de Anticuerpos , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Estudios Longitudinales , Masculino

Asunto(s)

Mutación , Estado Nutricional , Orthomyxoviridae/genética , Selenio/fisiología , Animales , Virus de la Influenza A/genética , Virus de la Influenza A/patogenicidad , Pulmón/patología , Ratones , Orthomyxoviridae/patogenicidad , Infecciones por Orthomyxoviridae/complicaciones , Infecciones por Orthomyxoviridae/patología , Selenio/deficiencia , Proteínas de la Matriz Viral/genética

Asunto(s)

Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/patología , Selenio/deficiencia , Animales , Quimiocinas/biosíntesis , Quimiocinas/genética , Citocinas/biosíntesis , Citocinas/genética , Pulmón/virología , Ganglios Linfáticos/inmunología , Ratones , Modelos Inmunológicos , ARN Mensajero/análisis

RESUMEN

The fetal and early infant origins of a number of adult cardiovascular and metabolic diseases have received considerable attention, but the long-term consequences of early environments for human immune function have not been reported. We investigated the effects of pre- and postnatal environments on thymic hormone production in adolescents participating in an ongoing longitudinal study in the Philippines. Prospective data collected at birth, during y 1 of life, in childhood and in adolescence were used to predict plasma thymopoietin concentration in 14- to 15-y-old adolescents (n = 103). Thymopoietin concentration was compared for small-for-gestational-age and appropriate-for-gestational-age individuals while controlling for a range of postnatal exposures. Prenatal undernutrition was significantly associated with reduced thymopoietin production in interaction with the duration of exclusive breast-feeding (P = 0.006). Growth in length during y 1 of life was positively associated with adolescent thymopoietin production (P = 0.002). These associations remained significant after adjusting for a range of potentially confounding variables. These findings provide support for the importance of fetal and early infant programming of thymic function, and suggest that early environments may have long-term implications for immunocompetence and adult disease risk.

Asunto(s)

Desarrollo Infantil , Enfermedades Fetales/metabolismo , Trastornos Nutricionales/metabolismo , Timopoyetinas/biosíntesis , Timo/metabolismo , Adolescente , Lactancia Materna , Femenino , Humanos , Recién Nacido , Recién Nacido Pequeño para la Edad Gestacional , Estudios Longitudinales , Masculino , Estudios Prospectivos , Valores de Referencia , Factores de Tiempo

RESUMEN

The nutritional status of the host has long been associated with both severity and susceptibility to infectious disease. The accepted model system proposes that inadequate nutrition impairs the functioning of the immune system, thus resulting in increased susceptibility to infection. However, current work suggests that not only can the nutritional status of the host affect the immune response, but it can also affect the viral pathogen. In a mouse model, a benign strain of coxsackievirus B3 became virulent and caused myocarditis in selenium- and vitamin E-deficient mice. This change in pathogenicity was due to mutations in the viral genome, which changed an avirulent virus into a virulent one. Once these mutations occurred, even mice with normal nutriture developed disease from the mutated virus. These results suggest that the oxidative stress status of the host can have a profound influence on a viral pathogen.

Asunto(s)

Estado Nutricional , Virosis/fisiopatología , Animales , Cardiomiopatías/epidemiología , Cardiomiopatías/etiología , Cardiomiopatías/fisiopatología , China/epidemiología , Cuba/epidemiología , Humanos , Ratones , Enfermedades del Sistema Nervioso/epidemiología , Enfermedades del Sistema Nervioso/etiología , Estrés Oxidativo , Virus ARN/genética , Virus ARN/fisiología , Selenio/deficiencia

RESUMEN

It has long been known that the nutritional status of the host can influence both susceptibility to infectious disease and the severity of the disease if contracted. In studies of coxsackievirus infection and selenium deficiency in mice, we found that mice fed a selenium-deficient diet developed myocarditis, but mice fed a diet adequate in selenium did not. Similarly, mice fed a diet deficient in vitamin E developed myocarditis, but mice fed a diet with adequate vitamin E did not. The epidemic of optic and peripheral neuropathy that occurred in Cuba in the early 1990s provides another example of how the nutritional status of the host may affect the impact of a virus. Patients who developed neuropathy had lower blood concentrations of riboflavin, vitamin E, selenium, alpha- and beta-carotenes, and the carotenoid lycopene, which suggests that the disease was associated with an impairment of protective antioxidant pathways. After supplementation of the population with these nutrients, the disease began to subside. The nutritional status of the host can have a profound influence on a virus, so that a normally avirulent virus becomes virulent because of changes in the viral genome. Our studies suggest that outbreaks of disease attributed to a nutritional deficiency may actually result from infection by a virus that has become pathogenic by replicating in a nutritionally deficient host.

Asunto(s)

Infecciones por Coxsackievirus/etiología , Estrés Oxidativo , Enfermedades del Sistema Nervioso Periférico/epidemiología , Selenio/deficiencia , Deficiencia de Vitamina E/complicaciones , Animales , Infecciones por Coxsackievirus/enzimología , Cuba/epidemiología , Brotes de Enfermedades , Glutatión Peroxidasa/efectos de los fármacos , Glutatión Peroxidasa/metabolismo , Humanos , Ratones , Ratones Noqueados , Miocarditis/etiología , Estado Nutricional , Enfermedades del Sistema Nervioso Periférico/etiología , Fenotipo , Ratas

RESUMEN

The immune response to influenza A virus is characterized by an influx of both macrophages and T lymphocytes into the lungs of the infected host, accompanied by induced expression of a number of CC chemokines. CC chemokine receptors CCR5 and CCR2 are both expressed on activated macrophages and T cells. We examined how the absence of these chemokine receptors would affect pulmonary chemokine expression and induced leukocyte recruitment by infecting CCR5-deficient mice and CCR2-deficient mice with a mouse-adapted strain of influenza A virus. CCR5(-/-) mice displayed increased mortality rates associated with acute, severe pneumonitis, whereas CCR2(-/-) mice were protected from the early pathological manifestations of influenza because of defective macrophage recruitment. This delay in macrophage accumulation in CCR2(-/-) mice caused a subsequent delay in T cell migration, which correlated with high pulmonary viral titers at early time points. Infected CCR5(-/-) mice and CCR2(-/-) mice both exhibited increased expression of the gene for MCP-1, the major ligand for CCR2(-/-) and a key regulator of induced macrophage migration. These studies illustrate the very different roles that CCR5 and CCR2 play in the macrophage response to influenza infection and demonstrate how defects in macrophage recruitment affect the normal development of the cell-mediated immune response.

Asunto(s)

Virus de la Influenza A , Infecciones por Orthomyxoviridae , Neumonía/virología , Receptores CCR5/deficiencia , Receptores de Quimiocina/deficiencia , Animales , Quimiocina CCL2/fisiología , Virus de la Influenza A/aislamiento & purificación , Pulmón/patología , Macrófagos/fisiología , Ratones , Infecciones por Orthomyxoviridae/mortalidad , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/fisiopatología , Infecciones por Orthomyxoviridae/virología , Neumonía/mortalidad , Neumonía/patología , Neumonía/fisiopatología , Receptores CCR2 , Análisis de Supervivencia , Linfocitos T/fisiología , Factores de Tiempo

RESUMEN

Previous work in our laboratory demonstrated that a virus could undergo rapid mutation in a host deficient in Se, leading to a normally avirulent virus acquiring virulence due to genome changes. Once these mutations occur, even a host with adequate Se-nutriture is susceptible to the newly virulent virus. What influence does the deficiency in Se have on the immune response of the host? Infection with myocarditic strains of coxsackievirus induces an inflammatory response in the cardiac tissue. It is this immune response that induces the heart damage, rather than direct viral effects on the heart tissue. Chemokines are chemo-attractant molecules that are secreted during an infection in order to attract immune cells to the site of the injury, and have been found to be important for the development of coxsackievirus-induced myocarditis. We found that a deficiency in Se influences the expression of mRNA for the chemokine monocyte chemo-attractant protein-1, which may have implications for the development of myocarditis in the Se-deficient host. Expression of mRNA for interferon-gamma was also greatly decreased in the Se-deficient animal. Thus, a deficiency in Se can have profound effects on the host as well as on the virus itself. How the alteration of the immune response of the Se-deficient animal affects the development of the virulent genotype remains to be answered.

Asunto(s)

Quimiocinas/genética , Infecciones por Coxsackievirus/inmunología , Enterovirus Humano B/inmunología , Micronutrientes/deficiencia , Miocarditis/inmunología , Selenio/deficiencia , Animales , Quimiocinas/inmunología , Infecciones por Coxsackievirus/virología , Enterovirus Humano B/patogenicidad , Genotipo , Interferón gamma , Ratones , Micronutrientes/inmunología , Mutación , Miocarditis/virología , ARN Mensajero , Selenio/inmunología , Virulencia

RESUMEN

Oxidative stress is implicated as a pathogenic factor in a number of viral infections. Our work has shown that nutritionally induced oxidative stress exacerbates the pathogenesis of coxsackievirus B3 (CVB3) infection in mice. Of particular note, mice fed on a diet deficient in antioxidants developed myocarditis when infected with a normally benign strain of CVB3. This change in virulence was found to be due to changes in the viral genome. Immune functions of the oxidatively stressed mice were also altered. Another example of the effect of oxidative stress on a viral pathogen took place in Cuba in the 1990s. An epidemic of optic and peripheral neuropathy in the population occurred that was associated with a lack of dietary antioxidants and with smoking (a pro-oxidant). A coxsackie-like virus was isolated from the cerebrospinal fluid from 84% of patients cultured. Thus, oxidative stress can have profound effects, not only on the host, but on the pathogen as well.

Asunto(s)

Infecciones por Coxsackievirus , Enterovirus , Estrés Oxidativo , Animales , Infecciones por Coxsackievirus/etiología , Infecciones por Coxsackievirus/metabolismo , Ratones

RESUMEN

The association between viral disease and nutrition has long been thought to be due to effects on the host immune system. This theory suggests that when a host is malnourished, the immune system is compromised, and thus increased susceptibility to viral infection will occur. However, the virus itself may also be affected by the nutritional status of the host. We have demonstrated that a normally-benign strain of coxsackievirus B3 (CVB3/0) becomes virulent in either Se-deficient or vitamin E-deficient mice. Although the deficient animals are immunosuppressed, the virus itself is also altered. Six nucleotide changes were found in the virus that replicated in the deficient mice, and once these mutations occurred, even mice with normal nutrition became susceptible to disease. Thus, the nutritional status of the host was able to transform an avirulent virus into a virulent one due to genomic changes in the virus. We believe that a common mechanism of oxidative stress is the underlying cause of the genetic changes. Both vitamin E and Se act as antioxidants, and benign virus inoculated into GSH peroxidase (EC 1.11.1.9)-knockout mice will also convert to virulence due to genomic changes. Our work points to the importance of host nutrition during a viral disease, not only from the perspective of the host, but from the perspective of the viral pathogen as well.

Asunto(s)

Inmunidad Innata , Selenio/fisiología , Virosis/inmunología , Animales , Cardiomiopatías/virología , Infecciones por Coxsackievirus/inmunología , Enterovirus Humano B/genética , Glutatión Peroxidasa/genética , Humanos , Ratones , Ratones Noqueados , Enfermedades del Sistema Nervioso/virología , Estrés Oxidativo , Selenio/deficiencia

RESUMEN

The aqueous EtOH extract of aerial parts of Eschscholtzia californica Cham. yielded six flavonol 3-O-glycosides including two new compounds: quercetin 3-O-[alpha-rhamnopyranosyl-(1-4)-alpha-rhamnopyranosyl-(1-6)-beta- glucopyranoside] and isorhamnetin 3-O-[alpha-rhamnopyranosyl-(1-4)-alpha-rhamnopyranosyl-(1-6)-beta- glucopyranoside]. Their structures were established on the basis of spectroscopic studies.

Asunto(s)

Flavonoides/química , Glicósidos/aislamiento & purificación , Papaver/química , Plantas Medicinales , Flavonoles , Glicósidos/química , Espectroscopía de Resonancia Magnética , Espectrometría de Masas/métodos , Estructura Molecular , Espectrofotometría Ultravioleta