Emerging mechanisms of obesity-associated immune dysfunction.

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.

Obesity Is Associated with an Impaired Baseline Repertoire of Anti-Influenza Virus Antibodies.

Obesity is a risk factor for severe disease and mortality for both influenza and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. While previous studies show that individuals with obesity generate antibody responses following influenza vaccination, infection rates within the obese group were twice as high as those in the healthy-weight group. The repertoire of antibodies raised against influenza viruses following previous vaccinations and/or natural exposures is referred to here as baseline immune history (BIH).

Obesity Dysregulates the Immune Response to Influenza Infection and Vaccination Through Metabolic and Inflammatory Mechanisms.

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.

Inflammation and Metabolism of Influenza-Stimulated Peripheral Blood Mononuclear Cells From Adults With Obesity Following Bariatric Surgery.

Background: Obesity dysregulates immunity to influenza infection. Therefore, there is a critical need to investigate how obesity impairs immunity and to establish therapeutic approaches that mitigate the impact of increased adiposity. One mechanism by which obesity may alter immune responses is through changes in cellular metabolism.

Myeloid Protease-Activated Receptor-2 Contributes to Influenza A Virus Pathology in Mice.

Background: Innate immune responses to influenza A virus (IAV) infection are initiated in part by toll-like receptor 3 (TLR3). TLR3-dependent signaling induces an antiviral immune response and an NFκB-dependent inflammatory response. Protease-activated receptor 2 (PAR2) inhibits the antiviral response and enhances the inflammatory response.

Metabolic and functional impairment of CD8 T cells from the lungs of influenza-infected obese mice.

Obesity is an independent risk factor for morbidity and mortality in response to influenza infection. However, the underlying mechanisms by which obesity impairs immunity are unclear. Herein, we investigated the effects of diet-induced obesity on pulmonary CD8 T cell metabolism, cytokine production, and transcriptome as a potential mechanism of impairment during influenza virus infection in mice.

Obesity is associated with an altered baseline and post-vaccination influenza antibody repertoire.

As highlighted by the ongoing COVID-19 pandemic, vaccination is critical for infectious disease prevention and control. Obesity is associated with increased morbidity and mortality from respiratory virus infections. While obese individuals respond to influenza vaccination, what is considered a seroprotective response may not fully protect the global obese population.

PAR1 regulation of CXCL1 expression and neutrophil recruitment to the lung in mice infected with influenza A virus.

Background: Protease-activated receptor 1 (PAR1) is expressed in various immune cells and in the lung. We showed that PAR1 plays a role in Coxsackievirus B3 infection by enhancing toll-like receptor 3-dependent interferon- expression in cardiac fibroblasts.

Objectives: We investigated the role of PAR1 in a mouse model of influenza A virus (IAV) infection.

Targeting T-cell oxidative metabolism to improve influenza survival in a mouse model of obesity.

Background: Obesity is associated with impaired primary and secondary immune responses to influenza infection, with T cells playing a critical role. T-cell function is highly influenced by the cellular metabolic state; however, it remains unknown how altered systemic metabolism in obesity alters T-cell metabolism and function to influence immune response. Our objective was to identify the altered cellular metabolic state of T cells from obese mice so that we may target T-cell metabolism to improve immune response to infection.

Individuals with obesity and COVID-19: A global perspective on the epidemiology and biological relationships.

The linkage of individuals with obesity and COVID-19 is controversial and lacks systematic reviews. After a systematic search of the Chinese and English language literature on COVID-19, 75 studies were used to conduct a series of meta-analyses on the relationship of individuals with obesity-COVID-19 over the full spectrum from risk to mortality. A systematic review of the mechanistic pathways for COVID-19 and individuals with obesity is presented.

Obesity Expands a Distinct Population of T Cells in Adipose Tissue and Increases Vulnerability to Infection.

Obesity in humans is associated with poorer health outcomes after infections compared with non-obese individuals. Here, we examined the effects of white adipose tissue and obesity on T cell responses to viral infection in mice. We show that lymphocytic choriomeningitis virus (LCMV) grows to high titer in adipose tissue.

Myeloid -Deficient Murine Model Revealed Macrophage Activation and Metabolic Phenotype Are Fueled by GLUT1.

Macrophages (MΦs) are heterogeneous and metabolically flexible, with metabolism strongly affecting immune activation. A classic response to proinflammatory activation is increased flux through glycolysis with a downregulation of oxidative metabolism, whereas alternative activation is primarily oxidative, which begs the question of whether targeting glucose metabolism is a viable approach to control MΦ activation. We created a murine model of myeloid-specific glucose transporter GLUT1 () deletion.

Obesity-Induced Changes in T-Cell Metabolism Are Associated With Impaired Memory T-Cell Response to Influenza and Are Not Reversed With Weight Loss.

Background: Obesity is an independent risk factor for increased influenza mortality and is associated with impaired memory T-cell response, resulting in increased risk of infection. In this study, we investigated if weight loss would restore memory T-cell response to influenza.

Methods: Male C57BL/6J mice were fed either low-fat or high-fat diet to induce obesity.

Mechanisms by Which Dietary Fatty Acids Regulate Mitochondrial Structure-Function in Health and Disease.

Mitochondria are the energy-producing organelles within a cell. Furthermore, mitochondria have a role in maintaining cellular homeostasis and proper calcium concentrations, building critical components of hormones and other signaling molecules, and controlling apoptosis. Structurally, mitochondria are unique because they have 2 membranes that allow for compartmentalization.

Obesity Impairs the Adaptive Immune Response to Influenza Virus.

Influenza, a highly contagious respiratory tract infection, affects millions of adults and children each year. Several high-risk populations include children, the elderly, the immunocompromised, and recently the obese. Given the dramatic rise in obesity over the past few decades, this increased risk for influenza infection poses a serious public health threat because nearly 500 million adults and children worldwide are classified as obese.

Obesity altered T cell metabolism and the response to infection.

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.

Swine Influenza Virus (H1N2) Characterization and Transmission in Ferrets, Chile.

Phylogenetic analysis of the influenza hemagglutinin gene (HA) has suggested that commercial pigs in Chile harbor unique human seasonal H1-like influenza viruses, but further information, including characterization of these viruses, was unavailable. We isolated influenza virus (H1N2) from a swine in a backyard production farm in Central Chile and demonstrated that the HA gene was identical to that in a previous report. Its HA and neuraminidase genes were most similar to human H1 and N2 viruses from the early 1990s and internal segments were similar to influenza A(H1N1)pdm09 virus.

Anticoagulation increases alveolar hemorrhage in mice infected with influenza A.

Influenza A virus infection is a common respiratory tract infection. Alveolar hemorrhage has been reported in patients with influenza pneumonia and in mice infected with influenza A. In this study, we investigated the effect of two anticoagulants on alveolar hemorrhage after influenza A virus (IAV) infection of wild-type mice.

Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation.

Objective: A novel approach to regulate obesity-associated adipose inflammation may be through metabolic reprogramming of macrophages (MΦs). Broadly speaking, MΦs dependent on glucose are pro-inflammatory, classically activated MΦs (CAM), which contribute to adipose inflammation and insulin resistance. In contrast, MΦs that primarily metabolize fatty acids are alternatively activated MΦs (AAM) and maintain tissue insulin sensitivity.

Obesity Increases Mortality and Modulates the Lung Metabolome during Pandemic H1N1 Influenza Virus Infection in Mice.

Obese individuals are at greater risk for hospitalization and death from infection with the 2009 pandemic H1N1 influenza virus (pH1N1). In this study, diet-induced and genetic-induced obese mouse models were used to uncover potential mechanisms by which obesity increases pH1N1 severity. High-fat diet-induced and genetic-induced obese mice exhibited greater pH1N1 mortality, lung inflammatory responses, and excess lung damage despite similar levels of viral burden compared with lean control mice.

Respiratory transmission of an avian H3N8 influenza virus isolated from a harbour seal.

The ongoing human H7N9 influenza infections highlight the threat of emerging avian influenza viruses. In 2011, an avian H3N8 influenza virus isolated from moribund New England harbour seals was shown to have naturally acquired mutations known to increase the transmissibility of highly pathogenic H5N1 influenza viruses. To elucidate the potential human health threat, here we evaluate a panel of avian H3N8 viruses and find that the harbour seal virus displays increased affinity for mammalian receptors, transmits via respiratory droplets in ferrets and replicates in human lung cells.

1H NMR-based profiling reveals differential immune-metabolic networks during influenza virus infection in obese mice.

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.