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BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is characterized by the pathological accumulation of triglycerides in hepatocytes and is associated with insulin resistance, atherogenic dyslipidaemia and cardiometabolic diseases. Thus far, the extent of metabolic dysregulation associated with hepatic triglyceride accumulation has not been fully addressed. In this study, we aimed to identify metabolites associated with hepatic triglyceride content (HTGC) and map these associations using network analysis. METHODS: To gain insight in the spectrum of metabolites associated with hepatic triglyceride accumulation, we performed a comprehensive plasma metabolomics screening of 1363 metabolites in apparently healthy middle aged (age 45-65) individuals (N = 496) in whom HTGC was measured by proton magnetic resonance spectroscopy. An atlas of metabolite-HTGC associations, based on univariate results, was created using correlation-based Gaussian graphical model (GGM) and genome scale metabolic model network analyses. Pathways associated with the clinical prognosis marker fibrosis 4 (FIB-4) index were tested using a closed global test. RESULTS: Our analyses revealed that 118 metabolites were univariately associated with HTGC (p-value <6.59 × 10-5 ), including 106 endogenous, 1 xenobiotic and 11 partially characterized/uncharacterized metabolites. These associations were mapped to several biological pathways including branched amino acids (BCAA), diglycerols, sphingomyelin, glucosyl-ceramide and lactosyl-ceramide. We also identified a novel possible HTGC-related pathway connecting glutamate, metabolonic lactone sulphate and X-15245 using the GGM network. These pathways were confirmed to be associated with the FIB-4 index as well. The full interactive metabolite-HTGC atlas is provided online: https://tofaquih.github.io/AtlasLiver/. CONCLUSIONS: The combined network and pathway analyses indicated extensive associations between BCAA and the lipids pathways with HTGC and the FIB-4 index. Moreover, we report a novel pathway glutamate-metabolonic lactone sulphate-X-15245 with a potential strong association with HTGC. These findings can aid elucidating HTGC metabolomic profiles and provide insight into novel drug targets for fibrosis-related outcomes.
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Ceramidas , Hígado , Persona de Mediana Edad , Humanos , Anciano , Triglicéridos/metabolismo , Hígado/metabolismo , Espectroscopía de Protones por Resonancia Magnética , Fibrosis , Ceramidas/análisis , Ceramidas/metabolismoRESUMEN
Herpes simplex virus (HSV)-1 is a ubiquitous human infection, with increased prevalence in obese populations. Obesity has been linked to increased inflammation, susceptibility to infection, and higher rates of anxiety disorder and cognitive impairment. To determine how obesity alters neuroinflammation and behavior following infection, we infected weanling C57BL/6 or CCR2(RFP/+)/CX3CR1(GFP/+) mice with a very low dose of HSV-1. Following viral latency (14days post infection (d p.i.)), mice were randomly assigned to remain on the low fat (LF) diet or switched to a 45% high fat (HF) diet. Eight weeks post diet shift, latently infected mice on the HF diet (HSV-HF) had greater microglial activation and infiltration of inflammatory CCR2(+) monocytes in the hypothalamus and dentate gyrus, in comparison to both HSV-LF mice and uninfected mice on LF and HF diets. VCAM staining was present in hypothalamus and hippocampus of the HSV-HF mice in the areas of monocyte infiltration. Infiltrating monocytes also produced proinflammatory cytokines demonstrating that, along with activated microglia, monocytes contribute to sustained neuroinflammation in latently infected obese mice. Utilizing a light-dark preference test, we found that HSV-HF mice had increased anxiety-like behavior. In the marble-burying test, HF diet and HSV infection resulted in increased numbers of buried marbles. Together, these mice provide a useful, testable model to study the biobehavioral effects of obesity and latent HSV-1 infection in regards to anxiety and may provide a tool for studying diet intervention programs in the future.
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Ansiedad/inmunología , Conducta Animal/fisiología , Herpes Simple/inmunología , Herpesvirus Humano 1 , Inflamación/inmunología , Monocitos/inmunología , Obesidad/inmunología , Receptores CCR2 , Animales , Dieta con Restricción de Grasas , Dieta Alta en Grasa , Modelos Animales de Enfermedad , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Since the onset of the HIV epidemic, there has been a shift from a deadly diagnosis to the management of a chronic disease. This shift is the result of the development of highly effective drugs that are able to suppress viral replication for years. The availability of these regimens has also shifted the neurocognitive pathology associated with infection from potentially devastating to a much milder phenotype. As the disease outcome has changed significantly with the availability of antiretroviral therapy, there is an opportunity to re-evaluate the currently available models to address the neurocognitive pathology seen in suppressed patients. In the following, we seek to summarize the current literature on humanized mouse models and their utility in understanding how HIV infection leads to changes in the central nervous system (CNS). Also, we identify some of the unanswered questions regarding HIV infection of the CNS as well as the opportunities and limitations of currently existing models to address those questions. Finally, our conclusions indicate that the earlier humanized models used to study HIV infection in the CNS provided an excellent foundation for the type of work currently being performed using novel humanized mouse models. We also indicate the potential of some humanized mouse models that have not been used as of this time for the analysis of HIV infection in the brain.
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Complejo SIDA Demencia , Modelos Animales de Enfermedad , VIH-1 , Animales , Humanos , RatonesRESUMEN
During the 2009 pandemic H1N1 influenza A virus (pH1N1) outbreak, obese individuals were at greater risk for morbidity and mortality from pandemic infection. However, the mechanisms contributing to greater infection severity in obese individuals remain unclear. Although most individuals lacked pre-existing, neutralizing Ab protection to the novel pH1N1 virus, heterologous defenses conferred from exposure to circulating strains or vaccination have been shown to impart protection against pH1N1 infection in humans and mice. Because obese humans and mice have impaired memory T cell and Ab responses following influenza vaccination or infection, we investigated the impact of obesity on heterologous protection from pH1N1 infection using a mouse model of diet-induced obesity. Lean and obese mice were infected with influenza A/Puerto Rico/8/34 (PR8) and 5 wk later challenged with a lethal dose of heterologous pH1N1. Cross-neutralizing Ab protection was absent in this model, but obese mice exhibited a significantly lower level of nonneutralizing, cross-reactive pH1N1 nucleoprotein Abs following the primary PR8 infection. Further, obese mice had elevated viral titers, greater lung inflammation and lung damage, and more cytotoxic memory CD8(+) T cells in the lung airways. Although obese mice had more regulatory T cells (Tregs) in the lung airways than did lean controls during the pH1N1 challenge, Tregs isolated from obese mice were 40% less suppressive than Tregs isolated from lean mice. In sum, excessive inflammatory responses to pH1N1 infection, potentially owing to greater viral burden and impaired Treg function, may be a novel mechanism by which obesity contributes to greater pH1N1 severity.
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Obesidad/complicaciones , Obesidad/inmunología , Infecciones por Orthomyxoviridae/complicaciones , Infecciones por Orthomyxoviridae/inmunología , Animales , Anticuerpos Antivirales/sangre , Reacciones Cruzadas/inmunología , Modelos Animales de Enfermedad , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Subtipo H1N1 del Virus de la Influenza A/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , PandemiasRESUMEN
Short-chain fatty acids (SCFAs) have been extensively studied for potential beneficial roles in glucose homeostasis and risk of diabetes; however, most of this research has focused on butyrate, acetate, and propionate. The effect on metabolism of branched SCFAs (BSCFAs; isobutyrate, isovalerate, and methylbutyrate) is largely unknown. In a cohort of 219 non-Hispanic White participants and 126 African American participants, we examined the association of BSCFA with dysglycemia (prediabetes and diabetes) and oral glucose tolerance test-based measures of glucose and insulin homeostasis, as well as with demographic, anthropometric, lifestyle, and lipid traits, and other SCFAs. We observed a bimodal distribution of BSCFAs, with 25 individuals having high levels (H-BSCFA group) and 320 individuals having lower levels (L-BSCFA group). The prevalence of dysglycemia was lower in the H-BSCFA group compared with the L-BSCFA group (16% vs. 49%; P = 0.0014). This association remained significant after adjustment for age, sex, race, BMI, and levels of other SCFAs. Consistent with the lower rate of dysglycemia, fasting and postprandial glucose levels were lower and the disposition index was higher in the H-BSCFA group. Additional findings in H-BSCFA versus L-BSCFA included lower fasting and postprandial C-peptide levels and lower insulin clearance without differences in insulin levels, insulin sensitivity, insulin secretion, or other variables examined, including diet and physical activity. As one of the first human studies associating higher BSCFA levels with lower odds of dysglycemia and improved glucose homeostasis, this study sets the stage for further investigation of BSCFA as a novel target for prevention or treatment of diabetes.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Microbiota , Estado Prediabético , Humanos , Insulina/metabolismo , Glucemia/metabolismo , Glucosa/metabolismo , Estado Prediabético/metabolismo , Insulina Regular Humana , Ácidos Grasos Volátiles , Homeostasis , Diabetes Mellitus Tipo 2/metabolismoRESUMEN
Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC-driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. SIGNIFICANCE: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742.
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Dieta Alta en Grasa , Ácido Láctico , Obesidad , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-myc , Microambiente Tumoral , Masculino , Animales , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Dieta Alta en Grasa/efectos adversos , Ratones , Humanos , Ácido Láctico/metabolismo , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Obesidad/metabolismo , Obesidad/patología , Línea Celular Tumoral , Ratones Endogámicos C57BL , Macrófagos Asociados a Tumores/metabolismoRESUMEN
The Centers for Disease Control and Prevention has suggested that obesity may be an independent risk factor for increased severity of illness from the H1N1 pandemic strain. Memory T cells generated during primary influenza infection target internal proteins common among influenza viruses, making them effective against encounters with heterologous strains. In male, diet-induced obese C57BL/6 mice, a secondary H1N1 influenza challenge following a primary H3N2 infection led to a 25% mortality rate (with no loss of lean controls), 25% increase in lung pathology, failure to regain weight, and 10- to 100-fold higher lung viral titers. Furthermore, mRNA expression for IFN-gamma was >60% less in lungs of obese mice, along with one third the number of influenza-specific CD8(+) T cells producing IFN-gamma postsecondary infection versus lean controls. Memory CD8(+) T cells from obese mice had a >50% reduction in IFN-gamma production when stimulated with influenza-pulsed dendritic cells from lean mice. Thus, the function of influenza-specific memory T cells is significantly reduced and ineffective in lungs of obese mice. The reality of a worldwide obesity epidemic combined with yearly influenza outbreaks and the current pandemic makes it imperative to understand how influenza virus infection behaves differently in an obese host. Moreover, impairment of memory responses has significant implications for vaccine efficacy in an obese population.
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Grasas de la Dieta/administración & dosificación , Memoria Inmunológica , Obesidad/inmunología , Infecciones por Orthomyxoviridae/inmunología , Infecciones por Orthomyxoviridae/patología , Linfocitos T/inmunología , Linfocitos T/patología , Animales , Citocinas/biosíntesis , Subtipo H1N1 del Virus de la Influenza A/inmunología , Subtipo H3N2 del Virus de la Influenza A/inmunología , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Pulmón/virología , Masculino , Ratones , Ratones Endogámicos C57BL , Obesidad/etiología , Obesidad/mortalidad , Infecciones por Orthomyxoviridae/mortalidad , Distribución Aleatoria , Índice de Severidad de la Enfermedad , Linfocitos T/virologíaRESUMEN
Gut microbiome studies have documented depletion of butyrate-producing taxa in type 2 diabetes. We analyzed associations between butyrate-producing taxa and detailed measures of insulin homeostasis, whose dysfunction underlies diabetes in 224 non-Hispanic Whites and 129 African Americans, all of whom completed an oral glucose tolerance test. Stool microbiome was assessed by whole-metagenome shotgun sequencing with taxonomic profiling. We examined associations among 36 butyrate-producing taxa (n = 7 genera and 29 species) and insulin sensitivity, insulin secretion, disposition index, insulin clearance, and prevalence of dysglycemia (prediabetes plus diabetes, 46% of cohort), adjusting for age, sex, BMI, and race. The genus Coprococcus was associated with higher insulin sensitivity (ß = 0.14; P = 0.002) and disposition index (ß = 0.12; P = 0.012) and a lower rate of dysglycemia (odds ratio [OR] 0.91; 95% CI 0.85-0.97; P = 0.0025). In contrast, Flavonifractor was associated with lower insulin sensitivity (ß = -0.13; P = 0.004) and disposition index (ß = -0.11; P = 0.04) and higher prevalence of dysglycemia (OR 1.22; 95% CI 1.08-1.38; P = 0.0013). Species-level analyses found 10 bacteria associated with beneficial directions of effects and two bacteria with adverse associations on insulin homeostasis and dysglycemia. Although most butyrate producers analyzed appear to be metabolically beneficial, this is not the case for all such bacteria, suggesting that microbiome-directed therapeutic measures to prevent or treat diabetes should be targeted to specific butyrate-producing taxa rather than all butyrate producers.
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Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Microbiota , Humanos , Insulina , Glucemia/análisis , Insulina Regular Humana , Homeostasis , ButiratosRESUMEN
Non-O blood groups are associated with decreased insulin sensitivity and risk of type 2 diabetes. A recent study pinpointed the associations between ABO blood groups and gut microbiome, which may serve as potential mediators for the observed increased disease risks. We aimed to characterize associations between ABO haplotypes and insulin-related traits as well as potential mediating pathways. We assessed insulin homeostasis in African Americans (AAs; n = 109) and non-Hispanic whites (n = 210) from the Microbiome and Insulin Longitudinal Evaluation Study. The ABO haplotype was determined by six SNPs located in the ABO gene. Based on prior knowledge, we included 21 gut bacteria and 13 plasma metabolites for mediation analysis. In the white study cohort (60 ± 9 years, 42% male), compared to the O1 haplotype, A1 was associated with a higher Matsuda insulin sensitivity index, while a lower relative abundance of Bacteroides massiliensis and lactate levels. Lactate was a likely mediator of this association but not Bacteroides massiliensis. In the AAs group (57 ± 8 years, 33% male), we found no association between any haplotype and insulin-related traits. In conclusion, the A1 haplotype may promote healthy insulin sensitivity in non-Hispanic whites and lactate likely play a role in this process but not selected gut bacteria.
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Garrod's concept of 'chemical individuality' has contributed to comprehension of the molecular origins of human diseases. Untargeted high-throughput metabolomic technologies provide an in-depth snapshot of human metabolism at scale. We studied the genetic architecture of the human plasma metabolome using 913 metabolites assayed in 19,994 individuals and identified 2,599 variant-metabolite associations (P < 1.25 × 10-11) within 330 genomic regions, with rare variants (minor allele frequency ≤ 1%) explaining 9.4% of associations. Jointly modeling metabolites in each region, we identified 423 regional, co-regulated, variant-metabolite clusters called genetically influenced metabotypes. We assigned causal genes for 62.4% of these genetically influenced metabotypes, providing new insights into fundamental metabolite physiology and clinical relevance, including metabolite-guided discovery of potential adverse drug effects (DPYD and SRD5A2). We show strong enrichment of inborn errors of metabolism-causing genes, with examples of metabolite associations and clinical phenotypes of non-pathogenic variant carriers matching characteristics of the inborn errors of metabolism. Systematic, phenotypic follow-up of metabolite-specific genetic scores revealed multiple potential etiological relationships.
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Errores Innatos del Metabolismo , Metaboloma , Humanos , Metaboloma/genética , Metabolómica , Plasma/metabolismo , Fenotipo , Errores Innatos del Metabolismo/genética , Proteínas de la Membrana/metabolismo , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/genética , 3-Oxo-5-alfa-Esteroide 4-Deshidrogenasa/metabolismoRESUMEN
Obesity has been associated with increasing the risk for type 2 diabetes and heart disease, but its influence on the immune response to viral infection is understudied. Memory T cells generated during a primary influenza infection are important for protection against subsequent influenza exposures. Previously, we have demonstrated that diet-induced obese (DIO) mice have increased morbidity and mortality following secondary influenza infection compared with lean mice. To determine whether the problem resided in a failure to maintain functional, influenza-specific CD8(+) memory T cells, male DIO and lean mice were infected with influenza X-31. At 84 d postinfection, DIO mice had a 10% reduction in memory T cell numbers. This reduction may have resulted from significantly reduced memory T cell expression of interleukin 2 receptor beta (IL-2R beta, CD122), but not IL-7 receptor alpha (CD127), which are both required for memory cell maintenance. Peripheral leptin resistance in the DIO mice may be a contributing factor to the impairment. Indeed, leptin receptor mRNA expression was significantly reduced in the lungs of obese mice, whereas suppressor of cytokine signaling (Socs)1 and Socs3 mRNA expression were increased. It is imperative to understand how the obese state alters memory T cells, because impairment in maintenance of functional memory responses has important implications for vaccine efficacy in an obese population.
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Linfocitos T CD8-positivos/fisiología , Carbohidratos de la Dieta/efectos adversos , Grasas de la Dieta/efectos adversos , Obesidad/inducido químicamente , Infecciones por Orthomyxoviridae/inmunología , Orthomyxoviridae/inmunología , Animales , Citocinas/genética , Citocinas/metabolismo , Regulación de la Expresión Génica/inmunología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/patología , Infecciones por Orthomyxoviridae/virología , Receptores de Leptina/genética , Receptores de Leptina/metabolismo , Proteínas Supresoras de la Señalización de Citocinas/genética , Proteínas Supresoras de la Señalización de Citocinas/metabolismoRESUMEN
There is a clear link between obesity and metabolic disorders; however, little is known about the effect of obesity on immune function, particularly during an infection. We have previously reported that diet-induced obese mice are more susceptible to morbidity and mortality during influenza infection than lean mice. Obese mice displayed aberrant innate immune responses characterized by minimal induction of interferon (IFN)-alpha/beta, delayed expression of pro-inflammatory cytokines and chemokines, and impaired natural killer cell cytotoxicity. To further examine the abnormal immune response of diet-induced obese mice, we analysed the cellularity of their lungs during influenza virus infection. We found delayed mononuclear cell entry with a marked decrease in dendritic cells (DCs) throughout the infection. Given the critical role of the DC in activating the cell-mediated immune response, we also analysed the functional capacity of DCs from obese mice. We found that, while obesity did not interfere with antigen uptake and migration, it did impair DC antigen presentation. This was probably attributable to an altered cytokine milieu, as interleukin (IL)-2, IL-12, and IL-6 were differentially regulated in the obese mice. Overall, this did not impact the total number of virus-specific CD8(+) T cells that were elicited, but did affect the number and frequency of CD3(+) and CD8(+) T cells in the lung. Thus, obesity interferes with cellular responses during influenza infection, leading to alterations in the T-cell population that ultimately may be detrimental to the host.
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Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Obesidad/inmunología , Infecciones por Orthomyxoviridae/inmunología , Animales , Presentación de Antígeno/inmunología , Células Cultivadas , Dieta/efectos adversos , Inmunidad Innata , Virus de la Influenza A , Interleucina-6/biosíntesis , Pulmón/inmunología , Ganglios Linfáticos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Obesos , Obesidad/complicaciones , Infecciones por Orthomyxoviridae/complicaciones , Ovalbúmina/inmunologíaRESUMEN
Dietary fish oils, rich in (n-3) PUFA, including eicosapentaenoic acid and docosahexaenoic acid, have been shown to have antiinflammatory properties. Although the antiinflammatory properties of fish oil may be beneficial during a chronic inflammatory illness, the same antiinflammatory properties can suppress the inflammatory responses necessary to combat acute viral infection. Given that (n-3) fatty acid-rich fish oil supplementation is on the rise and with the increasing threat of an influenza pandemic, we tested the effect of fish oil feeding for 2 wk on the immune response to influenza virus infection. Male C57BL/6 mice fed either a menhaden fish oil/corn oil diet (4 g fish oil:1 g corn oil, wt:wt at 5 g/100 g diet) or a control corn oil diet were infected with influenza A/PuertoRico/8/34 and analyzed for lung pathology and immune function. Although fish oil-fed mice had lower lung inflammation compared with controls, fish oil feeding also resulted in a 40% higher mortality rate, a 70% higher lung viral load at d 7 post infection, and a prolonged recovery period following infection. Although splenic natural killer (NK) cell activity was suppressed in fish oil-fed mice, lung NK activity was not affected. Additionally, lungs of infected fish oil-fed mice had significantly fewer CD8+ T cells and decreased mRNA expression of macrophage inflammatory protein-1-alpha, tumor necrosis factor-alpha, and interleukin-6. These results suggest that the antiinflammatory properties of fish oil feeding can alter the immune response to influenza infection, resulting in increased morbidity and mortality.
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Antiinflamatorios/efectos adversos , Ácidos Grasos Omega-3/efectos adversos , Aceites de Pescado/efectos adversos , Inmunidad Innata/efectos de los fármacos , Virus de la Influenza A , Pulmón/efectos de los fármacos , Infecciones por Orthomyxoviridae/inmunología , Animales , Aceite de Maíz/farmacología , Citocinas/metabolismo , Suplementos Dietéticos , Ácidos Grasos Omega-3/farmacología , Aceites de Pescado/farmacología , Células Asesinas Naturales/metabolismo , Pulmón/inmunología , Pulmón/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Neutrófilos/metabolismo , ARN Mensajero/metabolismo , Índice de Severidad de la Enfermedad , Bazo/efectos de los fármacos , Bazo/inmunología , Linfocitos T/metabolismo , Carga Viral , Aumento de Peso/efectos de los fármacosRESUMEN
BACKGROUND: Viral infections and exposure to oxidant air pollutants are two of the most important inducers of asthma exacerbation. Our previous studies have demonstrated that exposure to diesel exhaust increases the susceptibility to influenza virus infections both in epithelial cells in vitro and in mice in vivo. Therefore, we examined whether in the setting of allergic asthma, exposure to oxidant air pollutants enhances the susceptibility to respiratory virus infections, which in turn leads to increased virus-induced exacerbation of asthma. Ovalbumin-sensitized (OVA) male C57BL/6 mice were instilled with diesel exhaust particles (DEP) or saline and 24 hours later infected with influenza A/PR/8. Animals were sacrificed 24 hours post-infection and analyzed for markers of lung injury, allergic inflammation, and pro-inflammatory cytokine production. RESULTS: Exposure to DEP or infection with influenza alone had no significant effects on markers of injury or allergic inflammation. However, OVA-sensitized mice that were exposed to DEP and subsequently infected with influenza showed increased levels of eosinophils in lung lavage and tissue. In addition Th2-type cytokines, such as IL-4 and IL-13, and markers of eosinophil chemotaxis, such as CCL11 and CCR3, were increased in OVA-sensitized mice exposed to DEP prior to infection with influenza. These mice also showed increased levels of IL-1alpha, but not IL-10, RANTES, and MCP-1 in lung homogenates. CONCLUSION: These data suggest that in the setting of allergic asthma, exposure to diesel exhaust could enhance virus-induced exacerbation of allergic inflammation.
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Herpes simplex virus encephalitis (HSE) is the most common fatal sporadic encephalitis in humans. HSE is primarily caused by herpes simplex virus (HSV)-1 infection of the brain. HSE results in increased levels of oxidative stress, including the production of reactive oxygen species, free radicals, and neuroinflammation. The most biologically active form of vitamin E (VE) is alpha-tocopherol (alpha-TOC). In cellular membranes, alpha-TOC prevents lipid peroxidation by scavenging free radicals and functioning as an antioxidant. Supplementation with VE has been shown to decrease immunosenescence, improve immune function, and may be neuroprotective. To determine how VE deficiency and VE supplementation would alter the pathogenesis of HSE, we placed weanling male BALB/cByJ mice on VE-deficient (VE-D), VE-adequate (VE-A), or 10x VE-supplemented diets for 4 wk, and then infected the mice intranasally with HSV-1. VE-D mice had more severe symptoms of encephalitis than VE-A mice, including weight loss, keratitis, hunched posture, and morbidity. VE-D mice had increased cytokine and chemokine expression in the brain and increased viral titers. In contrast, VE supplementation failed to decrease cytokine production and had no effect on viral titer. We demonstrated that adequate levels of VE are important in limiting HSE pathology and that 10x supplementation does not enhance protection.
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Dieta , Encefalitis por Herpes Simple/inmunología , Vitamina E/farmacología , Animales , Encéfalo/metabolismo , Encéfalo/virología , Citocinas/metabolismo , Encefalitis por Herpes Simple/metabolismo , Encefalitis por Herpes Simple/virología , Hígado/metabolismo , Masculino , Ratones , ARN Mensajero , Carga Viral , alfa-Tocoferol/metabolismoRESUMEN
Selenium (Se) deficiency is associated with decreased activities of Se-dependent antioxidant enzymes, glutathione peroxidase (GPx) and thioredoxin reductase (TR), and with changes in the cellular redox status. We have previously shown that host Se deficiency is responsible for increased virulence of influenza virus in mice due to changes in the viral genome. The present study examines the antioxidant defense systems in the lung and liver of Se-deficient and Se-adequate mice infected with influenza A/Bangkok/1/79. Results show that neither Se status nor infection changed glutathione (GSH) concentration in the lung. Hepatic GSH concentration was lower in Se-deficient mice, but increased significantly day 5 post infection. No significant differences due to Se status or influenza infection were found in catalase activities. As expected, Se deficiency was associated with significant decreases in GPx and TR activities in both lung and liver. GPx activity increased in the lungs and decreased in the liver of Se-adequate mice in response to infection. Both Se deficiency and influenza infection had profound effects on the activity of superoxide dismutase (SOD). The hepatic SOD activity was higher in Se-deficient than Se-adequate mice before infection. However, following influenza infection, hepatic SOD activity in Se-adequate mice gradually increased. Influenza infection was associated with a significant increase of SOD activity in the lungs of Se-deficient, but not Se-adequate mice. The maximum of SOD activity coincided with the peak of pathogenesis in infected lungs. These data suggest that SOD activation in the lung and liver may be a part of a compensatory response to Se deficiency and/or influenza infection. However, SOD activation that leads to increased production of H(2)O(2) may also contribute to pathogenesis and to influenza virus mutation in lungs of Se-deficient mice.
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Virus de la Influenza A/fisiología , Infecciones por Orthomyxoviridae/metabolismo , Selenio/deficiencia , Superóxido Dismutasa/metabolismo , Animales , Catalasa/metabolismo , Disulfuros/metabolismo , Activación Enzimática , Glutatión/análogos & derivados , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Isoenzimas/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Infecciones por Orthomyxoviridae/genética , Infecciones por Orthomyxoviridae/patología , Selenio/metabolismo , Reductasa de Tiorredoxina-Disulfuro/metabolismoRESUMEN
A devastating consequence of HSV-1 infection is development of HSV-1-induced encephalitis (HSVE). While only a minority of individuals infected with HSV-1 experiences HSVE, clearly defined variables that consistently predict development of the disease remain to be elucidated. The current study examined the effects of a single dose of morphine prior to infection with HSV-1 on the development of HSVE in BALB/cByJ mice. Acute morphine exposure was observed to potentiate the development of HSVE in HSV-1 infected mice. The present data implicate a potential role for the blood-brain barrier in the development of HSVE in morphine-treated mice.
Asunto(s)
Encefalitis/etiología , Encefalitis/virología , Herpesvirus Humano 1/fisiología , Morfina/farmacología , Narcóticos/farmacología , Animales , Ataxia/etiología , Ataxia/virología , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/fisiopatología , Barrera Hematoencefálica/virología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Encéfalo/virología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Herpesvirus Humano 1/patogenicidad , Inmunoglobulina G/metabolismo , Inmunohistoquímica/métodos , Masculino , Manitol/farmacología , Ratones , Ratones Endogámicos BALB C , Parálisis/etiología , Parálisis/virología , ARN Mensajero/biosíntesis , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Índice de Severidad de la Enfermedad , Factores de TiempoRESUMEN
A single injection of morphine significantly increased interferon (IFN)-beta and IFN-alpha mRNA in spleens from herpes simplex virus (HSV)-1 infected male Balb/cByJ mice. However, significant suppression of IFN-gamma and interleukin (IL)-12 production was observed in spleens from morphine-treated mice. Pretreatment with RU486 blocked morphine-induced increases in IFN-beta, and reversed the suppression of IFN-gamma. However, RU486 did not restore IFN-alpha or IL-12. The results suggest that a single exposure to morphine 4 h prior to infection can significantly alter innate immune responses to a viral pathogen, and that these effects are partially mediated by glucocorticoids.
Asunto(s)
Herpesvirus Humano 1/inmunología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Inmunidad Innata/efectos de los fármacos , Morfina/farmacología , Narcóticos/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Análisis de Varianza , Animales , Células Cultivadas , Enfermedades Virales del Sistema Nervioso Central , Corticosterona/sangre , Ensayo de Inmunoadsorción Enzimática/métodos , Regulación de la Expresión Génica/efectos de los fármacos , Herpesvirus Humano 1/patogenicidad , Antagonistas de Hormonas/farmacología , Sistema Hipotálamo-Hipofisario/inmunología , Inmunidad Innata/inmunología , Interferones/clasificación , Interferones/genética , Interferones/metabolismo , Interleucina-12/metabolismo , Masculino , Ratones , Ratones Endogámicos BALB C , Mifepristona/farmacología , Sistema Hipófiso-Suprarrenal/inmunología , Polietilenglicoles/farmacología , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Bazo/citología , Bazo/efectos de los fármacos , Bazo/inmunología , Bazo/virología , Factores de TiempoRESUMEN
BACKGROUND: Diabetics are considered to be at high risk for complications from influenza infection and type 2 diabetes is a significant comorbidity of obesity. Obesity is an independent risk factor for complications from infection with influenza. Annual vaccination is considered the best strategy for protecting against influenza infection and it's complications. Our previous study reported intact antibody responses 30 days post vaccination in an obese population. This study was designed to determine the antibody response to influenza vaccination in type 2 diabetics. METHODS: Subjects enrolled were 18 or older without immunosuppressive diseases or taking immunosuppressive medications. A pre-vaccination blood draw was taken at time of enrollment, the subjects received the influenza vaccine and returned 28-32 days later for a post-vaccination blood draw. Height and weight were also obtained at the first visit and BMI was calculated. Antibody levels to the vaccine were determined by both ELISA and hemagglutination inhibition (HAI) assays. RESULTS: As reported in our previous work, obesity positively correlates with the influenza antibody response (p=0.02), while age was negatively correlated with antibody response (p<0.001). In both year 1 and year 2 of our study there was no significant difference in the percentage of the type 2 diabetic subjects classified as seroprotected or a responder to the influenza vaccine compared to the non-diabetic subjects. CONCLUSIONS: These data are important because they demonstrate that diabetics, considered a high risk group during influenza season, are able to mount an antibody response to influenza vaccination that may protect them from influenza infection.
Asunto(s)
Anticuerpos Antivirales/sangre , Formación de Anticuerpos , Diabetes Mellitus Tipo 2/inmunología , Vacunas contra la Influenza/administración & dosificación , Vacunas contra la Influenza/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ensayo de Inmunoadsorción Enzimática , Femenino , Pruebas de Inhibición de Hemaglutinación , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
Obese individuals are at greater risk for death from influenza virus infection. Paralleling human evidence, obese mice are also more susceptible to influenza infection mortality. However, the underlying mechanisms driving greater influenza severity in the obese remain unclear. Metabolic profiling has been utilized in infectious disease models to enhance prognostic or diagnostic methods, and to gain insight into disease pathogenesis by providing a more global picture of dynamic infection responses. Herein, metabolic profiling was used to develop a deeper understanding of the complex processes contributing to impaired influenza protection in obese mice and to facilitate generation of new explanatory hypotheses. Diet-induced obese and lean mice were infected with influenza A/Puerto Rico/8/34. 1H nuclear magnetic resonance-based metabolic profiling of urine, feces, lung, liver, mesenteric white adipose tissue, bronchoalveolar lavage fluid and serum revealed distinct metabolic signatures in infected obese mice, including perturbations in nucleotide, vitamin, ketone body, amino acid, carbohydrate, choline and lipid metabolic pathways. Further, metabolic data was integrated with immune analyses to obtain a more comprehensive understanding of potential immune-metabolic interactions. Of interest, uncovered metabolic signatures in urine and feces allowed for discrimination of infection status in both lean and obese mice at an early influenza time point, which holds prognostic and diagnostic implications for this methodology. These results confirm that obesity causes distinct metabolic perturbations during influenza infection and provide a basis for generation of new hypotheses and use of this methodology in detection of putative biomarkers and metabolic patterns to predict influenza infection outcome.