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 to 500,000 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 one and 11 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 cultures. Results BMI correlated positively with higher initial fold increase in IgG antibodies detected by ELISA to TIV, confirmed by HAI antibody in a subset study. However, eleven months post vaccination, higher BMI was associated with a greater decline in influenza antibody titers. PBMC’s 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.
In mammals, a family of five acyl-CoA synthetases (ACSLs), each the product of a separate gene, activates long chain fatty acids to form acyl-CoAs. Because the ACSL isoforms have overlapping preferences for fatty acid chain length and saturation and are expressed in many of the same tissues, the individual function of each isoform has remained uncertain. Thus, we constructed a mouse model with a liver-specific knock-out of ACSL1, a major ACSL isoform in liver. Eliminating ACSL1 in liver resulted in a 50% decrease in total hepatic ACSL activity and a 25-35% decrease in long chain acyl-CoA content. Although the content of triacylglycerol was unchanged in Acsl1 L؊/؊ liver after mice were fed either low or high fat diets, in isolated primary hepatocytes the absence of ACSL1 diminished the incorporation of [ 14 C]oleate into triacylglycerol. Further, small but consistent increases were observed in the percentage of 16:0 in phosphatidylcholine and phosphatidylethanolamine and of 18:1 in phosphatidylethanolamine and lysophosphatidylcholine, whereas concomitant decreases were seen in 18:0 in phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, and lysophosphatidylcholine. In addition, decreases in long chain acylcarnitine content and diminished production of acid-soluble metabolites from [ 14 C]oleate suggested that hepatic ACSL1 is important for mitochondrial -oxidation of long chain fatty acids. Because the Acsl1 L؊/؊ mice were not protected from developing either high fat diet-induced hepatic steatosis or insulin resistance, our study suggests that lowering the content of hepatic acyl-CoA without a concomitant decrease in triacylglycerol and other lipid intermediates is insufficient to protect against hepatic insulin resistance. Acyl-CoA synthetase (ACSL)3 activates long chain fatty acid (FA) to acyl-CoA, thereby enhancing vectorial FA transport across the plasma membrane (1) and providing substrates for most downstream pathways that metabolize FA. ACSL1 is one of five ACSL isoforms, each encoded by a separate gene. Its mRNA expression is highest in adipose tissue, liver, and heart (2); and because Acsl1 mRNA and total ACSL1 activity increase 160-fold (3) and 100-fold (4), respectively, in differentiating 3T3-L1 adipocytes, ACSL1 has been thought to be important in activating FA destined for triacylglycerol (TAG) synthesis. In support of this idea, overexpressing ACSL1 in mouse heart increases cardiac myocyte TAG accumulation 12-fold and induces apoptotic pathways, cardiac hypertrophy, left ventricular dysfunction, and heart failure (5). However, Acsl1 mRNA expression is up-regulated in liver and adipose tissue by activators of peroxisome proliferator-activated factor ␣ (PPAR␣) (6, 7) via a PPAR response element in the promoter region of Acsl1 (8), suggesting a possible function related to the -oxidation of fatty acids. Moreover, overexpression of ACSL1 in rat primary hepatocytes increases oleate incorporation into diacylglycerol (DAG) but does not increase TAG mass (9). Thus, the exact role of ACSL1 ...
Objective Obese adults have a greater risk of morbidity and mortality from infection with pandemic H1N1 influenza A virus (pH1N1). The objective of the present study was to elucidate the specific mechanisms by which obesity and overweight impact the cellular immune response to pH1N1. Design and Methods We stimulated peripheral blood mononuclear cells from healthy weight, overweight, and obese individuals ex vivo with live pH1N1 and then measured markers of activation and function using flow cytometry and cytokine secretion using cytometric bead array assays. Results Our data indicate that CD4+ and CD8+ T cells from overweight and obese individuals expressed lower levels of CD69, CD28, CD40 ligand, and interleukin-12 receptor, as well as, produced lower levels of interferon-γ and granzyme B, compared to healthy weight individuals, suggesting deficiencies in activation and function. Dendritic cells from the three groups expressed similar levels of major histocompatibility complex-II, CD40, CD80, and CD86, as well as, produced similar levels of interleukin-12. Conclusions The defects in CD4+ and CD8+ T cells may contribute to the increased morbidity and mortality from pH1N1 in obese individuals. These data also provide evidence that both overweight and obesity cause impairments in immune function.
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.
Recent reports suggest that obesity may be an independent risk factor for influenza A virus (IAV) H1N1 infection. Obese mice are also more susceptible to IAV infection. While many studies focus on the host immune response to IAV infection, few focus specifically on the response of lung epithelial cells, one of the primary targets for IAV infection. In an obese state, lung epithelial cells are exposed to serum containing high amounts of lipids, including fatty acids (FAs). A459 lung epithelial cells were used to test the hypothesis that lipid‐induced modifications would alter cellular responses to IAV infection. Cells were incubated for 24 hours with media containing a combination of the FAs palmitate, palmitoleate, stearate, and oleate, complexed to albumin, or control media without FAs, followed by infection with IAV. Cells incubated with FAs were found to have higher influenza viral titers compared with control cells. Concomitant with the higher titers, FA‐treated cells expressed higher levels of mRNA for the antiviral cytokines interferon (IFN)‐α and IFN‐β, and the proinflammatory cytokine interleukin‐6, likely in response to the higher viral load. These data suggest that lung epithelial cells in obese individuals may be more susceptible to viral infection due to exposure to FA‐rich serum and provide a novel mechanism for increased susceptibility to influenza infection due to obesity.
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