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Obesity is associated with a wide range of complications, including type 2 diabetes mellitus, cardiovascular disease, hypertension and nonalcoholic fatty liver disease. Obesity also increases the incidence and progression of cancers, autoimmunity and infections, as well as lowering vaccine responsiveness. A unifying concept across these differing diseases is dysregulated immunity, particularly inflammation, in response to metabolic overload. Herein, we review emerging mechanisms by which obesity drives inflammation and autoimmunity, as well as impairing tumour immunosurveillance and the response to infections. Among these mechanisms are obesity-associated changes in the hormones that regulate immune cell metabolism and function and drive inflammation. The cargo of extracellular vesicles derived from adipose tissue, which controls cytokine secretion from immune cells, is also dysregulated in obesity, in addition to impairments in fatty acid metabolism related to inflammation. Furthermore, an imbalance exists in obesity in the biosynthesis and levels of polyunsaturated fatty acid-derived oxylipins, which control a range of outcomes related to inflammation, such as immune cell chemotaxis and cytokine production. Finally, there is a need to investigate how obesity influences immunity using innovative model systems that account for the heterogeneous nature of obesity in the human population. In this Review, the emerging cellular and molecular mechanisms by which obesity impairs key aspects of immunity are discussed, including changes in the abundance of key hormones, dysregulation of adipose-tissue-derived extracellular vesicles and dysregulation of polyunsaturated fatty acid metabolism. Key points: Obesity dysregulates immunity through differing mechanisms, which contribute to a range of secondary complications. Obesity influences the level and function of nutritionally regulated hormones that regulate signalling pathways that mediate immune cell metabolism and function and drive inflammation. Expansion of adipose tissue dysregulates the abundance and composition of extracellular vesicles, which carry a wide range of cargo that can affect the activity of immune cells and lipid metabolism. Increased adiposity dysregulates polyunsaturated fatty acid metabolism; notably, the concentration of oxylipins synthesized from polyunsaturated fatty acids, which control a range of outcomes related to inflammation, is imbalanced in obesity. Investigating immunity in obesity requires translation from inbred rodents to humans; one approach is to use Diverse Outbred and Collaborative Cross mouse populations that can model the heterogeneous nature of human obesity. [ABSTRACT FROM AUTHOR]

An epidemic of obesity over the past three decades increases the risk of chronic and infectious diseases for adults and children alike. Within the past few years, obesity has been shown to impair the adaptive immune response to infection through alterations in T cell functioning. Growing evidence suggests that perturbations in T cell metabolism drives this stunted immune response, stemming from nutrient, hormone and adipokine dysregulation in the obese. In this review, recent findings in the fields of obesity and T cell mediated immunity demonstrate a unique relationship between altered mechanisms of T cell metabolic homeostasis and plasticity of adaptive immune responses in the obese setting. [ABSTRACT FROM AUTHOR]

Abstract: Previous studies from our laboratory have shown that dietary α-tocopherol (vitamin E, or VE) is essential for regulating the cytokine and chemokine response in the brain to herpes simplex virus-1 (HSV-1) infection. The timing of T cell infiltration is critical to the resolution of central nervous system HSV-1 infections. Specifically, the appearance of “neuroprotective” CD8+IFN-γ+ T cells is crucial. During CNS infection, CD8+ T cell priming and expansion in the draining lymph node, followed by recruitment and expansion, occurs in the spleen with subsequent accumulation in the brain. Weanling male BALB/cByJ mice were placed on VE-deficient (Def) or -adequate diets for 4 weeks followed by intranasal infection with HSV-1. VE-Def mice had fewer CD8+IFN-γ+ T cells trafficking to the brain despite increased CD8+IFN-γ+ T cells and activated dendritic cells in the periphery. VE-Def mice had increased T regulatory cells (Tregs) in the periphery and brain, and the increase in Tregs decreased CD8+ T cell numbers in the brain. Our results demonstrate that adequate levels of VE are important for trafficking antigen-specific T cells to the brain, and dietary VE levels modulate T regulatory and dendritic cells in the periphery. [Copyright &y& Elsevier]

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 α-tocopherol (α-TOC). In cellular membranes, α-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 lox supplementation does not enhance protection. [ABSTRACT FROM AUTHOR]

Abstract: Several oxidative stressors (dietary selenium deficiency, dietary vitamin E deficiency coupled with fish oil feeding, genetic reduction of glutathione peroxidase activity) allow a normally benign coxsackievirus B3 (CVB3/0) to damage heart muscle in host mice. This study investigated whether dietary iron overload, another oxidant stress, would also permit CVB3/0 to exert a cardiopathologic effect in vitamin E-deficient (−VE) mice. Four groups of mice were fed either a −VE or a +VE diet containing either an adequate or an excessive (30×) amount of iron. After 4 weeks of feeding, the mice were inoculated with CVB3/0 and heart damage was assessed at various times postinfection. Mice fed a diet sufficient in VE with excess iron developed heart damage equivalent to mice fed a diet deficient in vitamin E without excess iron. However, severe heart damage occurred in the group fed a diet deficient in VE with excess iron, which was the most pro-oxidative diet. The highest heart viral titers were found in mice fed the −VE/excessive iron diet. However, the extent of heart damage did not always correlate with the formation of TBARS in liver homogenates. Further research is needed to clarify the role of oxidative stress and iron overload in determining the course of viral infection. [Copyright &y& Elsevier]

The emergence of new infectious diseases and old diseases with new pathogenic properties is a burgeoning worldwide problem. Severe acute respiratory syndrome (SARS) and acquired immune deficiency syndrome (AIDS) are just two of the most widely reported recent emerging infectious diseases. What are the factors that contribute to the rapid evolution of viral species? Various hypotheses have been proposed, all involving opportunities for virus spread (for example, agricultural practices, climate changes, rainforest clearing or air travel). However, the nutritional status of the host, until recently, has not been considered a contributing factor to the emergence of infectious disease. In this review, we show that host nutritional status can influence not only the host response to the pathogen, but can also influence the genetic make-up of the viral genome. This latter finding markedly changes our concept of host–pathogen interactions and creates a new paradigm for the study of such phenomena. [Copyright &y& Elsevier]

The severity of the heart damage caused by a coxsackievirus infection in mice is determined by several factors, including the genotype of the infecting virus as well as the genetic background of the infected host. Earlier work by us showed that the cardiovirulence of a given coxsackievirus genotype could be increased substantially by feeding the host a diet nutritionally deficient in either selenium or vitamin E. Here we report that host genetic background as a determinant of viral infection outcome is superseded by feeding the host a diet nutritionally deficient in both selenium and vitamin E. Mice of the C57Bl/6 strain, normally resistant to coxsackievirus B3-induced myocarditis, become susceptible when fed such a doubly deficient diet. Our results demonstrate the powerful influence of host nutritional status on the course of viral infection compared to other variables traditionally considered to play major roles in determining the extent of virally induced inflammatory heart disease. [Copyright &y& Elsevier]

Examines the influence of selenium (Se) deficiency on viral infection. Relationship between nutrition and viral infection; Discovery of the possibility of the dual etiology of the juvenile cardiomyopathy known as Keshan disease; Susceptibility of individuals living in areas with Se-poor soils to the development of the disease.

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. [ABSTRACT FROM AUTHOR]

Evaluates research on the impact of the nutritional status of the host on the immune response and the viral pathogen during a viral infection. Findings on selenium deficiency and Keshan disease; Impact of vitamin E and selenium deficiency on oxidative stress and viral changes in mice with an avirulent virus; Potential mechanisms for the genomic changes; Analysis of an epidemic of optic/peripheral neuropathy in Cuba.

The COVID-19 pandemic demonstrates that obesity alone, independent of comorbidities, is a significant risk factor for severe outcomes from infection. This susceptibility mirrors a similar pattern with influenza infection; that is, obesity is a unique risk factor for increased morbidity and mortality. Therefore, it is critical to understand how obesity contributes to a reduced ability to respond to respiratory viral infections. Herein, we discuss human and animal studies with influenza infection and vaccination that show obesity impairs immunity. We cover several key mechanisms for the dysfunction. These mechanisms include systemic and cellular level changes that dysregulate immune cell metabolism and function in addition to how obesity promotes deficiencies in metabolites that control the resolution of inflammation and infection. Finally, we discuss major gaps in knowledge, particularly as they pertain to diet and mechanisms, which will drive future efforts to improve outcomes in response to respiratory viral infections in an increasingly obese population. [ABSTRACT FROM AUTHOR]

This document is a comment on a review paper titled "Could Selenium Supplementation Prevent COVID-19? A Comprehensive Review of Available Studies." The authors of the comment are experienced selenium researchers who take issue with the assessments made in the review. They argue that the review is not comprehensive and fails to include important studies that support the association between selenium and COVID-19 outcomes. The authors also address specific criticisms made by the reviewers regarding their own work and highlight the importance of further research into the role of selenium in COVID-19. [Extracted from the article]

Examines the role of oxidative stress in viral infection. Account of related studies; Effect of oxidative stress on the host immune response system and the response to viral infection; Mechanisms involved in the host response to oxidative stress; Role of nutrition in emerging viral diseases.

Studies the effects of Vitamin E deficiency on coxsackievirus B3 infection of mice. Cardiac pathology; Role of host nutritional antioxidant status in determining severity of viral infections; Cardiotoxic effects of coxsackieviruses.

Focuses on viral infections, examining the effects of antioxidants nutrients on viral infections. Information on Keshan disease; Role of nutrition in the emergence of viral diseases; Detailed explanation of the link between nutrition and viral diseases; Information on experiments which were conducted on mice.

Discusses the effects of host deficiency in vitamin E or selenium to the virulence of pathogen. Relationship of nutrition to infectious disease; Etiology of Keshan disease; Effects of selenium deficiency.

Selenium (Se), an essential trace element, and vitamin E, a lipid soluble antioxidant, are important mediators for protection against oxidative stress. Recent work has demonstrated that deficiencies in either Se or vitamin E result in increased viral pathogenicity and altered immune responses. Furthermore, deficiencies in either Se or vitamin E results in specific viral mutations, changing relatively benign viruses into virulent ones. Thus, host nutritional status should be considered a driving force for the emergence of new viral strains or newly pathogenic strains of known viruses. [ABSTRACT FROM AUTHOR]