Increased risk of influenza among vaccinated adults who are obese.

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.

The effects of diet-induced obesity on B cell function.

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.

Obesity is associated with impaired immune response to influenza vaccination in humans.

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.

Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice results in selection of identical virulent isolates.

Previous work from our laboratory demonstrated that selenium deficiency in the mouse allows a normally benign (amyocarditic) cloned and sequenced Coxackievirus to cause significant heart damage. Furthermore, Coxsackievirus recovered from the hearts of selenium-deficient mice inoculated into selenium-adequate mice still induced significant heart damage, suggesting that the amyocarditic Coxsackievirus had mutated to a virulent phenotype. Here we report that sequence analysis revealed six nucleotide changes between the virulent virus recovered from the selenium-deficient host and the avirulent input virus. These nucleotide changes are consistent with known differences in base composition between virulent and avirulent strains of Coxsackievirus. To the best of our knowledge, this is the first report of a specific nutritional deficiency driving changes in a viral genome, permitting an avirulent virus to acquire virulence due to genetic mutation.

Requirement of MIP-1 alpha for an inflammatory response to viral infection.

Macrophage inflammatory protein-1 alpha (MIP-1 alpha) is a chemokine that has pro-inflammatory and stem cell inhibitory activities in vitro. Its biologic role in vivo was examined in mice in which the gene encoding MIP-1 alpha had been disrupted. Homozygous MIP-1 alpha mutant (-/-) mice were resistant to Coxsackievirus-induced myocarditis seen in infected wild-type (+/+) mice. Influenza virus-infected -/- mice had reduced pneumonitis and delayed clearance of the virus compared with infected +/+ mice. The -/- mice had no overt hematopoietic abnormalities. These results demonstrate that MIP-1 alpha is an important mediator of virus-induced inflammation in vivo.

Measurement of a superconducting qubit with a microwave photon counter.

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.

Selenium deficiency alters epithelial cell morphology and responses to influenza.

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.

Predicting total dissolved solids release from central Appalachian coal mine spoils.

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.

Tissue factor deficiency increases alveolar hemorrhage and death in influenza A virus-infected mice.

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.

Nutritionally induced oxidative stress: effect on viral disease.

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.

Prenatal undernutrition, postnatal environments, and antibody response to vaccination in adolescence.

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.

The role of oxidative stress in viral infections.

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.

Flavonol glycosides from Eschscholtzia californica.

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.

Interacting nutritional and infectious etiologies of Keshan disease. Insights from coxsackie virus B-induced myocarditis in mice deficient in selenium or vitamin E.

In 1979, Chinese scientists reported that selenium had been linked to Keshan disease, an endemic juvenile cardiomyopathy found in China. However, certain epidemiological features of the disease could not be explained solely on the basis of inadequate selenium nutrition. Fluctuations in the seasonal incidence of the disease suggested involvement of an infectious agent. Indeed, a coxsackievirus B4 isolated from a Keshan disease victim caused more heart muscle damage when inoculated into selenium-deficient mice than when given to selenium-adequate mice. Those results led us to study the relationship of nutritional status to viral virulence. Coxsackievirus B3/0 (CVB3/0), did not cause disease when inoculated into mice fed adequate levels of Se and vitamin E. However, mice fed diets deficient in either Se or vitamin E developed heart lesions when infected with CVB3/0. To determine if the change in viral phenotype was maintained, we passaged virus isolated from Se-deficient hosts, designated as CVB3/0 Se-, back into Se-adequate hosts. The CVB3/0 Se- virus caused disease in Se-adequate mice. To determine if the phenotype change was due to changes in the viral genome, we sequenced viruses isolated from Se-deficient mice and compared them with the input CVB3/0 virus. Six point mutations differed between the parent strain and the recovered CVB3/0 Se- isolates. When the experiment was repeated using vitamin E-deficient mice, the same 6 point mutations were found. This is the first report of a specific host nutritional deficiency altering viral genotype. Keshan disease may be the result of several interacting causes including a dominant nutritional deficiency (selenium), other nutritional factors (vitamin E, polyunsaturated fatty acids), and an infectious agent (virus).

Rapid genomic evolution of a non-virulent coxsackievirus B3 in selenium-deficient mice.

Keshan disease, an endemic cardiomyopathy in China, can be prevented with selenium (Se) supplementation. However, the seasonal and annual nature of the disease suggests that an infectious co-factor is required along with a deficiency in Se. Using a murine model of coxsackievirus B3 (CVB3)-induced myocarditis, Se-deficient mice were shown to be more susceptible to the cardiopathologic effects of the virus. In addition, a normal benign strain of CVB3 becomes virulent in Se-deficient mice. This change in virulence was shown to be due to point mutations in the viral genome. Although the mechanism of the viral mutation is not known, the oxidative stress status of the Se-deficient host may play a role, either by directly affecting the virus and/or affecting host immune defenses.

Impact of institutionalization on the posture of chronic schizophrenic patients.

In this study the impact of institutionalization on the posture of chronic, undifferentiated schizophrenic patients was examined. The postures of a sample group of schizophrenic patients were measured: this group was then divided into those who had been continuously institutionalized and those who had been intermittently institutionalized. Patients who had been hospitalized for a longer, continuous period were found to have significantly poorer posture than those who were institutionalized for a similar period of time, but only intermittently. The authors raise questions about better understanding of posture and movement for more effective therapy programs.

Selenium and host defence towards viruses.

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.

Antioxidants and viral infections: host immune response and viral pathogenicity.

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.