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1.
Front Immunol ; 12: 770066, 2021.
Article in English | MEDLINE | ID: covidwho-1518490

ABSTRACT

Acute inflammation is a critical host defense response during viral infection. When dysregulated, inflammation drives immunopathology and tissue damage. Excessive, damaging inflammation is a hallmark of both pandemic influenza A virus (IAV) infections and Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2) infections. Chronic, low-grade inflammation is also a feature of obesity. In recent years, obesity has been recognized as a growing pandemic with significant mortality and associated costs. Obesity is also an independent risk factor for increased disease severity and death during both IAV and SARS-CoV-2 infection. This review focuses on the effect of obesity on the inflammatory response in the context of viral respiratory infections and how this leads to increased viral pathology. Here, we will review the fundamentals of inflammation, how it is initiated in IAV and SARS-CoV-2 infection and its link to disease severity. We will examine how obesity drives chronic inflammation and trained immunity and how these impact the immune response to IAV and SARS-CoV-2. Finally, we review both medical and non-medical interventions for obesity, how they impact on the inflammatory response and how they could be used to prevent disease severity in obese patients. As projections of global obesity numbers show no sign of slowing down, future pandemic preparedness will require us to consider the metabolic health of the population. Furthermore, if weight-loss alone is insufficient to reduce the risk of increased respiratory virus-related mortality, closer attention must be paid to a patient's history of health, and new therapeutic options identified.


Subject(s)
COVID-19/immunology , Inflammation/immunology , Influenza A virus , Influenza, Human/immunology , Obesity/immunology , SARS-CoV-2 , Animals , Humans , Severity of Illness Index
2.
Front Immunol ; 12: 732913, 2021.
Article in English | MEDLINE | ID: covidwho-1504188

ABSTRACT

Obesity prevails worldwide to an increasing effect. For example, up to 42% of American adults are considered obese. Obese individuals are prone to a variety of complications of metabolic disorders including diabetes mellitus, hypertension, cardiovascular disease, and chronic kidney disease. Recent meta-analyses of clinical studies in patient cohorts in the ongoing coronavirus-disease 2019 (COVID-19) pandemic indicate that the presence of obesity and relevant disorders is linked to a more severe prognosis of COVID-19. Given the significance of obesity in COVID-19 progression, we provide a review of host metabolic and immune responses in the immunometabolic dysregulation exaggerated by obesity and the viral infection that develops into a severe course of COVID-19. Moreover, sequela studies of individuals 6 months after having COVID-19 show a higher risk of metabolic comorbidities including obesity, diabetes, and kidney disease. These collectively implicate an inter-systemic dimension to understanding the association between obesity and COVID-19 and suggest an interdisciplinary intervention for relief of obesity-COVID-19 complications beyond the phase of acute infection.


Subject(s)
COVID-19/immunology , COVID-19/metabolism , Obesity/immunology , Obesity/metabolism , COVID-19/complications , Disease Progression , Host-Pathogen Interactions/immunology , Humans , Immunity , Metabolic Diseases/immunology , Metabolic Diseases/metabolism , Obesity/complications , Prognosis , SARS-CoV-2/pathogenicity , Severity of Illness Index
3.
Cells ; 10(10)2021 10 03.
Article in English | MEDLINE | ID: covidwho-1444118

ABSTRACT

The PD-L1/PD-1 immune checkpoint axis is the strongest T cell exhaustion inducer. As immune dysfunction occurs during obesity, we analyzed the impact of obesity on PD-L1/PD-1 expression in white adipose tissue (WAT) in mice and in human white adipocytes. We found that PD-L1 was overexpressed in WAT of diet-induced obese mice and was associated with increased expression of PD-1 in visceral but not subcutaneous WAT. Human in vitro cocultures with adipose-tissue-derived mesenchymal stem cells (ASC) and mononuclear cells demonstrated that the presence of ASC harvested from obese WAT (i) enhanced PD-L1 expression as compared with ASC from lean WAT, (ii) decreased Th1 cell cytokine secretion, and (iii) resulted in decreased cytolytic activity towards adipocytes. Moreover, (iv) the implication of PD-L1 in obese ASC-mediated T cell dysfunction was demonstrated through PD-L1 blockade. Finally, (v) conditioned media gathered from these cocultures enhanced PD-L1 expression in freshly differentiated adipocytes, depending on IFNγ. Altogether, our results suggest that PD-L1 is overexpressed in the WAT of obese individuals during IFNγ secretion, leading to T cell dysfunction and notably reduced cytolytic activity. Such a mechanism could shed light on why adipose-tissue-infiltrating viruses, such as SARS-CoV-2, can worsen disease in obese individuals.


Subject(s)
Adipose Tissue, White/metabolism , B7-H1 Antigen/biosynthesis , Gene Expression Regulation , Mesenchymal Stem Cells/cytology , Obesity/metabolism , T-Lymphocytes/immunology , Animals , COVID-19/immunology , Cell Differentiation , Coculture Techniques , Humans , Immunohistochemistry , Inflammation , Interferon-gamma/metabolism , Leukocytes, Mononuclear/cytology , Male , Mice , Mice, Inbred C57BL , Obesity/immunology , SARS-CoV-2 , T-Lymphocytes/cytology
4.
Front Immunol ; 12: 739025, 2021.
Article in English | MEDLINE | ID: covidwho-1417086

ABSTRACT

A rise in adiposity in the United States has resulted in more than 70% of adults being overweight or obese, and global obesity rates have tripled since 1975. Following the 2009 H1N1 pandemic, obesity was characterized as a risk factor that could predict severe infection outcomes to viral infection. Amidst the SARS-CoV-2 pandemic, obesity has remained a significant risk factor for severe viral disease as obese patients have a higher likelihood for developing severe symptoms and requiring hospitalization. However, the mechanism by which obesity enhances viral disease is unknown. In this study, we utilized a diet-induced obesity mouse model of West Nile virus (WNV) infection, a flavivirus that cycles between birds and mosquitoes and incidentally infects both humans and mice. Likelihood for severe WNV disease is associated with risk factors such as diabetes that are comorbidities also linked to obesity. Utilizing this model, we showed that obesity-associated chronic inflammation increased viral disease severity as obese female mice displayed higher mortality rates and elevated viral titers in the central nervous system. In addition, our studies highlighted that obesity also dysregulates host acute adaptive immune responses, as obese female mice displayed significant dysfunction in neutralizing antibody function. These studies highlight that obesity-induced immunological dysfunction begins at early time points post infection and is sustained through memory phase, thus illuminating a potential for obesity to alter the differentiation landscape of adaptive immune cells.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , Cytokines/blood , Obesity/immunology , West Nile Fever/mortality , West Nile virus/immunology , Animals , COVID-19/pathology , Disease Models, Animal , Female , Humans , Inflammation/pathology , Liver/injuries , Liver/pathology , Male , Mice , Mice, Inbred C57BL , Obesity/pathology , Severity of Illness Index , West Nile Fever/immunology , West Nile Fever/pathology
5.
Int J Mol Sci ; 22(18)2021 Sep 09.
Article in English | MEDLINE | ID: covidwho-1409706

ABSTRACT

The susceptibility and the severity of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are associated with hyperandrogenism, obesity, and preexisting pulmonary, metabolic, renal, and cardiac conditions. Polycystic ovary syndrome (PCOS), the most common endocrine disorder in premenopausal women, is associated with obesity, hyperandrogenism, and cardiometabolic dysregulations. We analyzed cardiac, renal, circulatory, and urinary SARS-CoV-2 viral entry proteins (ACE2, TMPRSS2, TMPRSS4, furin, cathepsin L, and ADAM17) and androgen receptor (AR) expression, in a peripubertal androgen exposure model of PCOS. Peripubertal female mice were treated with dihydrotestosterone (DHT) and low (LFD) or high (HFD) fat diet for 90 days. HFD exacerbated DHT-induced increase in body weight, fat mass, and cardiac and renal hypertrophy. In the heart, DHT upregulated AR protein in both LFD and HFD, ACE2 in HFD, and ADAM17 in LFD. In the kidney, AR protein expression was upregulated by both DHT and HFD. Moreover, ACE2 and ADAM17 were upregulated by DHT in both diets. Renal TMPRSS2, furin, and cathepsin L were upregulated by DHT and differentially modulated by the diet. DHT upregulated urinary ACE2 in both diets, while neither treatment modified serum ACE2. Renal AR mRNA expression positively correlated with Ace2, Tmprss2, furin, cathepsin L, and ADAM17. Our findings suggest that women with PCOS could be a population with a high risk of COVID-19-associated cardiac and renal complications. Furthermore, our study suggests that weight loss by lifestyle modifications (i.e., diet) could potentially mitigate COVID-19-associated deleterious cardiorenal outcomes in women with PCOS.


Subject(s)
COVID-19 , Obesity , Polycystic Ovary Syndrome/virology , Receptors, Coronavirus/immunology , SARS-CoV-2/physiology , Virus Internalization , Animals , COVID-19/immunology , COVID-19/virology , Female , Heart , Kidney , Mice , Mice, Inbred C57BL , Obesity/immunology , Obesity/virology
6.
Front Endocrinol (Lausanne) ; 12: 726967, 2021.
Article in English | MEDLINE | ID: covidwho-1394754

ABSTRACT

In March 2020, the WHO declared coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a global pandemic. Obesity was soon identified as a risk factor for poor prognosis, with an increased risk of intensive care admissions and mechanical ventilation, but also of adverse cardiovascular events. Obesity is associated with adipose tissue, chronic low-grade inflammation, and immune dysregulation with hypertrophy and hyperplasia of adipocytes and overexpression of pro-inflammatory cytokines. However, to implement appropriate therapeutic strategies, exact mechanisms must be clarified. The role of white visceral adipose tissue, increased in individuals with obesity, seems important, as a viral reservoir for SARS-CoV-2 via angiotensin-converting enzyme 2 (ACE2) receptors. After infection of host cells, the activation of pro-inflammatory cytokines creates a setting conducive to the "cytokine storm" and macrophage activation syndrome associated with progression to acute respiratory distress syndrome. In obesity, systemic viral spread, entry, and prolonged viral shedding in already inflamed adipose tissue may spur immune responses and subsequent amplification of a cytokine cascade, causing worse outcomes. More precisely, visceral adipose tissue, more than subcutaneous fat, could predict intensive care admission; and lower density of epicardial adipose tissue (EAT) could be associated with worse outcome. EAT, an ectopic adipose tissue that surrounds the myocardium, could fuel COVID-19-induced cardiac injury and myocarditis, and extensive pneumopathy, by strong expression of inflammatory mediators that could diffuse paracrinally through the vascular wall. The purpose of this review is to ascertain what mechanisms may be involved in unfavorable prognosis among COVID-19 patients with obesity, especially cardiovascular events, emphasizing the harmful role of excess ectopic adipose tissue, particularly EAT.


Subject(s)
COVID-19/metabolism , Cardiomyopathies/metabolism , Intra-Abdominal Fat/metabolism , Obesity/metabolism , Adipose Tissue/metabolism , Adipose Tissue/pathology , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/complications , COVID-19/immunology , Cardiomyopathies/immunology , Cardiomyopathies/pathology , Heart Diseases/immunology , Heart Diseases/metabolism , Heart Diseases/pathology , Humans , Inflammation , Intra-Abdominal Fat/pathology , Obesity/complications , Obesity/immunology , Obesity/pathology , Pericardium , Prognosis , SARS-CoV-2/metabolism , Serine Endopeptidases/metabolism
7.
Biosci Rep ; 41(8)2021 08 27.
Article in English | MEDLINE | ID: covidwho-1343479

ABSTRACT

An influenza-like virus named severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for COVID-19 disease and spread worldwide within a short time. COVID-19 has now become a significant concern for public health. Obesity is highly prevalent worldwide and is considered a risk factor for impairing the adaptive immune system. Although diabetes, hypertension, cardiovascular disease (CVD), and renal failure are considered the risk factors for COVID-19, obesity is not yet well-considered. The present study approaches establishing a systemic association between the prevalence of obesity and its impact on immunity concerning the severe outcomes of COVID-19 utilizing existing knowledge. Overall study outcomes documented the worldwide prevalence of obesity, its effects on immunity, and a possible underlying mechanism covering obesity-related risk pathways for the severe outcomes of COVID-19. Overall understanding from the present study is that being an immune system impairing factor, the role of obesity in the severe outcomes of COVID-19 is worthy.


Subject(s)
Adaptive Immunity/immunology , COVID-19/pathology , Obesity/immunology , Obesity/pathology , Humans , Inflammation/pathology , Obesity/epidemiology , Risk Factors , SARS-CoV-2/immunology
8.
Obesity (Silver Spring) ; 29(10): 1575-1579, 2021 10.
Article in English | MEDLINE | ID: covidwho-1293299

ABSTRACT

The position statement is issued by The Obesity Society in response to published literature, as well as inquiries made to the Society by patients, providers, Society members, policy makers, and others regarding the efficacy of vaccines in persons with obesity against SARS-CoV-2, the virus that causes COVID-19. The Obesity Society has critically evaluated data from published peer-reviewed literature and briefing documents from Emergency Use Authorization applications submitted by Pfizer-BioNTech, Moderna, and Johnson & Johnson. We conclude that these vaccines are highly efficacious, and their efficacy is not significantly different in people with and without obesity, based on scientific evidence available at the time of publication. The Obesity Society believes there is no definitive way to determine which of these three COVID-19 vaccines is "best" for any weight subpopulation (because of differences in the trial design and outcome measures in the phase 3 trials, elapsed time between doses, and regional differences in the presence of SARS-CoV-2 variants [e.g., South Africa B.1.351 in Johnson & Johnson trial]). All three trials have demonstrated high efficacy against COVID-19-associated hospitalization and death. Therefore, The Obesity Society encourages adults with obesity ≥18 years (≥16 years for Pfizer-BioNTech) to undergo vaccination with any one of the currently available vaccines authorized for emergency use by the US Food and Drug Administration as soon as they are able.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/immunology , COVID-19/prevention & control , Obesity/immunology , SARS-CoV-2/immunology , Societies, Medical , Adolescent , Adult , Aged , COVID-19/virology , Clinical Trials as Topic , Humans , Middle Aged , Young Adult
9.
Clin Nutr ESPEN ; 44: 475-478, 2021 08.
Article in English | MEDLINE | ID: covidwho-1242904

ABSTRACT

BACKGROUND & AIMS: Obesity is associated with low grade systemic inflammation and insulin resistance. Although metabolic and immunological changes may contribute to the increased risk for COVID-19 mortality in obese, little is known about the impact of obesity in the lungs of patients with COVID-19. METHODS: We analyzed gene expression profiles of autopsy lungs of a cohort of 14 COVID-19 patients and 4 control individuals. Patients were divided into 3 groups according to their comorbidities: hypertension, type 2 diabetes (T2D) and obesity. We then identified the molecular alterations associated with these comorbidities in COVID-19 patients. RESULTS: Patients with only hypertension showed higher levels of inflammatory genes and B-cell related genes when compared to those with T2D and obesity. However, the levels of IFN-gamma, IL22, and CD274 (a ligand that binds to receptor PD1) were higher in COVID-19 patients with T2D and obesity. Several metabolic- and immune-associated genes such as G6PD, LCK and IL10 were significantly induced in the lungs of the obese group. CONCLUSION: Our findings suggest that SARS-CoV-2 infection in the lungs may exacerbate the immune response and chronic condition in obese COVID-19 patients.


Subject(s)
COVID-19/complications , COVID-19/genetics , Gene Expression/genetics , Lung/immunology , Obesity/complications , Obesity/genetics , Autopsy , COVID-19/immunology , Cohort Studies , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/immunology , Humans , Hypertension/complications , Hypertension/genetics , Hypertension/immunology , Obesity/immunology , SARS-CoV-2
10.
Br J Nutr ; 125(6): 628-632, 2021 03 28.
Article in English | MEDLINE | ID: covidwho-1221095

ABSTRACT

As COVID-19 continues to spread worldwide, severe disease and mortality have been observed in obese patients. We discuss how obesity and obesity-associated factors such as 'meta-flammation', dietary fat intake and paradoxical suppression of the innate immune response within the pulmonary compartment may be crucial determinants in the host response to a novel viral pathogen. Modulation of immune cell bioenergetics and metabolic potential plays a central role in the innate immune response to infection, and as we strive to combat this new global health threat, immunometabolism of the innate immune system warrants attention.


Subject(s)
COVID-19/immunology , Immune System/virology , Obesity/immunology , Obesity/virology , SARS-CoV-2/immunology , COVID-19/mortality , Dietary Fats/immunology , Eating/immunology , Energy Metabolism/immunology , Humans , Immunity, Innate/immunology , Inflammation , Obesity/mortality , Respiratory System/immunology , Respiratory System/virology
11.
J Clin Endocrinol Metab ; 106(5): e2025-e2034, 2021 04 23.
Article in English | MEDLINE | ID: covidwho-1199961

ABSTRACT

PURPOSE: Comorbidities making up metabolic syndrome (MetS), such as obesity, type 2 diabetes, and chronic cardiovascular disease can lead to increased risk of coronavirus disease-2019 (COVID-19) with a higher morbidity and mortality. SARS-CoV-2 antibodies are higher in severely or critically ill COVID-19 patients, but studies have not focused on levels in convalescent patients with MetS, which this study aimed to assess. METHODS: This retrospective study focused on adult convalescent outpatients with SARS-CoV-2 positive serology during the COVID-19 pandemic at NewYork Presbyterian/Weill Cornell. Data collected for descriptive and correlative analysis included SARS-COV-2 immunoglobin G (IgG) levels and history of MetS comorbidities from April 17, 2020 to May 20, 2020. Additional data, including SARS-CoV-2 IgG levels, body mass index (BMI), hemoglobin A1c (HbA1c) and lipid levels were collected and analyzed for a second cohort from May 21, 2020 to June 21, 2020. SARS-CoV-2 neutralizing antibodies were measured in a subset of the study cohort. RESULTS: SARS-CoV-2 IgG levels were significantly higher in convalescent individuals with MetS comorbidities. When adjusted for age, sex, race, and time duration from symptom onset to testing, increased SARS-CoV-2 IgG levels remained significantly associated with obesity (P < 0.0001). SARS-CoV-2 IgG levels were significantly higher in patients with HbA1c ≥6.5% compared to those with HbA1c <5.7% (P = 0.0197) and remained significant on multivariable analysis (P = 0.0104). A positive correlation was noted between BMI and antibody levels [95% confidence interval: 0.37 (0.20-0.52) P < 0.0001]. Neutralizing antibody titers were higher in COVID-19 individuals with BMI ≥ 30 (P = 0.0055). CONCLUSION: Postconvalescent SARS-CoV-2 IgG and neutralizing antibodies are elevated in obese patients, and a positive correlation exists between BMI and antibody levels.


Subject(s)
Antibodies, Neutralizing/immunology , COVID-19/immunology , Immunoglobulin G/immunology , Metabolic Syndrome/immunology , Adult , Antibodies, Neutralizing/blood , COVID-19/blood , COVID-19/complications , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/immunology , Diabetes Mellitus, Type 2/virology , Female , Humans , Immunoglobulin G/blood , Male , Metabolic Syndrome/blood , Metabolic Syndrome/virology , Middle Aged , Obesity/blood , Obesity/immunology , Obesity/virology , Retrospective Studies
12.
Genome Med ; 13(1): 66, 2021 04 21.
Article in English | MEDLINE | ID: covidwho-1197350

ABSTRACT

BACKGROUND: The large airway epithelial barrier provides one of the first lines of defense against respiratory viruses, including SARS-CoV-2 that causes COVID-19. Substantial inter-individual variability in individual disease courses is hypothesized to be partially mediated by the differential regulation of the genes that interact with the SARS-CoV-2 virus or are involved in the subsequent host response. Here, we comprehensively investigated non-genetic and genetic factors influencing COVID-19-relevant bronchial epithelial gene expression. METHODS: We analyzed RNA-sequencing data from bronchial epithelial brushings obtained from uninfected individuals. We related ACE2 gene expression to host and environmental factors in the SPIROMICS cohort of smokers with and without chronic obstructive pulmonary disease (COPD) and replicated these associations in two asthma cohorts, SARP and MAST. To identify airway biology beyond ACE2 binding that may contribute to increased susceptibility, we used gene set enrichment analyses to determine if gene expression changes indicative of a suppressed airway immune response observed early in SARS-CoV-2 infection are also observed in association with host factors. To identify host genetic variants affecting COVID-19 susceptibility in SPIROMICS, we performed expression quantitative trait (eQTL) mapping and investigated the phenotypic associations of the eQTL variants. RESULTS: We found that ACE2 expression was higher in relation to active smoking, obesity, and hypertension that are known risk factors of COVID-19 severity, while an association with interferon-related inflammation was driven by the truncated, non-binding ACE2 isoform. We discovered that expression patterns of a suppressed airway immune response to early SARS-CoV-2 infection, compared to other viruses, are similar to patterns associated with obesity, hypertension, and cardiovascular disease, which may thus contribute to a COVID-19-susceptible airway environment. eQTL mapping identified regulatory variants for genes implicated in COVID-19, some of which had pheWAS evidence for their potential role in respiratory infections. CONCLUSIONS: These data provide evidence that clinically relevant variation in the expression of COVID-19-related genes is associated with host factors, environmental exposures, and likely host genetic variation.


Subject(s)
Bronchi , COVID-19/genetics , Respiratory Mucosa , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2/genetics , Asthma/genetics , COVID-19/immunology , Cardiovascular Diseases/genetics , Cardiovascular Diseases/immunology , Gene Expression , Genetic Variation , Humans , Middle Aged , Obesity/genetics , Obesity/immunology , Pulmonary Disease, Chronic Obstructive/genetics , Quantitative Trait Loci , Risk Factors , Smoking/genetics
13.
Cells ; 10(4)2021 04 17.
Article in English | MEDLINE | ID: covidwho-1194614

ABSTRACT

Emerging data suggest that obesity is a major risk factor for the progression of major complications such as acute respiratory distress syndrome (ARDS), cytokine storm and coagulopathy in COVID-19. Understanding the mechanisms underlying the link between obesity and disease severity as a result of SARS-CoV-2 infection is crucial for the development of new therapeutic interventions and preventive measures in this high-risk group. We propose that multiple features of obesity contribute to the prevalence of severe COVID-19 and complications. First, viral entry can be facilitated by the upregulation of viral entry receptors, like angiotensin-converting enzyme 2 (ACE2), among others. Second, obesity-induced chronic inflammation and disruptions of insulin and leptin signaling can result in impaired viral clearance and a disproportionate or hyper-inflammatory response, which together with elevated ferritin levels can be a direct cause for ARDS and cytokine storm. Third, the negative consequences of obesity on blood coagulation can contribute to the progression of thrombus formation and hemorrhage. In this review we first summarize clinical findings on the relationship between obesity and COVID-19 disease severity and then further discuss potential mechanisms that could explain the risk for major complications in patients suffering from obesity.


Subject(s)
COVID-19/complications , Obesity/complications , Animals , COVID-19/immunology , COVID-19/pathology , Chronic Disease , Humans , Immunity , Inflammation/complications , Inflammation/immunology , Inflammation/pathology , Insulin Resistance , Obesity/immunology , Obesity/pathology , Risk Factors , SARS-CoV-2/immunology , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Severity of Illness Index , Unfolded Protein Response , Virus Internalization
14.
Front Cell Infect Microbiol ; 11: 638852, 2021.
Article in English | MEDLINE | ID: covidwho-1170078

ABSTRACT

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has emerged in December 2019 and rapidly outspread worldwide endangering human health. The coronavirus disease 2019 (COVID-19) manifests itself through a wide spectrum of symptoms that can evolve to severe presentations as pneumonia and several non-respiratory complications. Increased susceptibility to COVID-19 hospitalization and mortality have been linked to associated comorbidities as diabetes, hypertension, cardiovascular diseases and, recently, to obesity. Similarly, individuals living with obesity are at greater risk to develop clinical complications and to have poor prognosis in severe influenza pneumonia. Immune and metabolic dysfunctions associated with the increased susceptibility to influenza infection are linked to obesity-associated low-grade inflammation, compromised immune and endocrine systems, and to high cardiovascular risk. These preexisting conditions may favor virological persistence, amplify immunopathological responses and worsen hemodynamic instability in severe COVID-19 as well. In this review we highlight the main factors and the current state of the art on obesity as risk factor for influenza and COVID-19 hospitalization, severe respiratory manifestations, extrapulmonary complications and even death. Finally, immunoregulatory mechanisms of severe influenza pneumonia in individuals with obesity are addressed as likely factors involved in COVID-19 pathophysiology.


Subject(s)
Body Weight , COVID-19/immunology , Immunity , Influenza, Human/immunology , Obesity/immunology , Adipokines , Adipose Tissue , Animals , COVID-19/physiopathology , Comorbidity , Diabetes Mellitus , Endotoxemia , Heart Disease Risk Factors , Hospitalization , Humans , Hyperglycemia , Inflammation , Influenza, Human/physiopathology , Metabolic Syndrome , Obesity/complications , Orthomyxoviridae Infections/immunology , Risk Factors , SARS-CoV-2
15.
Am J Respir Cell Mol Biol ; 65(1): 13-21, 2021 07.
Article in English | MEDLINE | ID: covidwho-1166652

ABSTRACT

Coronavirus disease (COVID-19), the clinical syndrome caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is currently a global health pandemic with substantial morbidity and mortality. COVID-19 has cast a shadow on nearly every aspect of society, straining health systems and economies across the world. Although it is widely accepted that a close relationship exists between obesity, cardiovascular disease, and metabolic disorders on infection, we are only beginning to understand ways in which the immunological sequelae of obesity functions as a predisposing factor related to poor clinical outcomes in COVID-19. As both the innate and adaptive immune systems are each primed by obesity, the alteration of key pathways results in both an immunosuppressed and hyperinflammatory state. The present review will discuss the cellular and molecular immunology of obesity in the context of its role as a risk factor for severe COVID-19, discuss the role of cytokine storm, and draw parallels to prior viral epidemics such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and 2009 H1N1.


Subject(s)
COVID-19 , Cardiovascular Diseases , Cytokine Release Syndrome , Obesity , SARS-CoV-2 , COVID-19/immunology , COVID-19/metabolism , COVID-19/mortality , Cardiovascular Diseases/immunology , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/mortality , Critical Illness , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/metabolism , Cytokine Release Syndrome/mortality , Cytokine Release Syndrome/virology , Disease-Free Survival , Humans , Obesity/immunology , Obesity/metabolism , Obesity/mortality , Obesity/virology , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Survival Rate
17.
Int J Mol Sci ; 22(6)2021 Mar 20.
Article in English | MEDLINE | ID: covidwho-1143520

ABSTRACT

The recent pandemic Sars-CoV2 infection and studies on previous influenza epidemic have drawn attention to the association between the obesity and infectious diseases susceptibility and worse outcome. Metabolic complications, nutritional aspects, physical inactivity, and a chronic unbalance in the hormonal and adipocytokine microenvironment are major determinants in the severity of viral infections in obesity. By these pleiotropic mechanisms obesity impairs immune surveillance and the higher leptin concentrations produced by adipose tissue and that characterize obesity substantially contribute to such immune response dysregulation. Indeed, leptin not only controls energy balance and body weight, but also plays a regulatory role in the interplay between energy metabolism and immune system. Since leptin receptor is expressed throughout the immune system, leptin may exert effects on cells of both innate and adaptive immune system. Chronic inflammatory states due to metabolic (i.e., obesity) as well as infectious diseases increase leptin concentrations and consequently lead to leptin resistance further fueling inflammation. Multiple factors, including inflammation and ER stress, contribute to leptin resistance. Thus, if leptin is recognized as one of the adipokines responsible for the low grade inflammation found in obesity, on the other hand, impairments of leptin signaling due to leptin resistance appear to blunt the immunologic effects of leptin and possibly contribute to impaired vaccine-induced immune responses. However, many aspects concerning leptin interactions with inflammation and immune system as well as the therapeutical approaches to overcome leptin resistance and reduced vaccine effectiveness in obesity remain a challenge for future research.


Subject(s)
Leptin/immunology , Leptin/metabolism , Obesity/complications , Obesity/virology , Virus Diseases/complications , Animals , Antiviral Agents/therapeutic use , COVID-19/complications , COVID-19/drug therapy , COVID-19/immunology , COVID-19/metabolism , Energy Metabolism/immunology , Humans , Immune System/metabolism , Immune System/virology , Obesity/immunology , Obesity/metabolism , Viral Vaccines/therapeutic use , Virus Diseases/drug therapy , Virus Diseases/immunology , Virus Diseases/metabolism
18.
Sci Rep ; 11(1): 6428, 2021 03 19.
Article in English | MEDLINE | ID: covidwho-1142462

ABSTRACT

Hyperactivation of the immune system through obesity and diabetes may enhance infection severity complicated by Acute Respiratory Distress Syndrome (ARDS). The objective was to determine the circulatory biomarkers for macrophage activation at baseline and after serum glucose normalization in obese type 2 diabetes (OT2D) subjects. A case-controlled interventional pilot study in OT2D (n = 23) and control subjects (n = 23). OT2D subjects underwent hyperinsulinemic clamp to normalize serum glucose. Plasma macrophage-related proteins were determined using Slow Off-rate Modified Aptamer-scan plasma protein measurement at baseline (control and OT2D subjects) and after 1-h of insulin clamp (OT2D subjects only). Basal M1 macrophage activation was characterized by elevated levels of M1 macrophage-specific surface proteins, CD80 and CD38, and cytokines or chemokines (CXCL1, CXCL5, RANTES) released by activated M1 macrophages. Two potent M1 macrophage activation markers, CXCL9 and CXCL10, were decreased in OT2D. Activated M2 macrophages were characterized by elevated levels of plasma CD163, TFGß-1, MMP7 and MMP9 in OT2D. Conventional mediators of both M1 and M2 macrophage activation markers (IFN-γ, IL-4, IL-13) were not altered. No changes were observed in plasma levels of M1/M2 macrophage activation markers in OT2D in response to acute normalization of glycemia. In the basal state, macrophage activation markers are elevated, and these reflect the expression of circulatory cytokines, chemokines, growth factors and matrix metalloproteinases in obese individuals with type 2 diabetes, that were not changed by glucose normalisation. These differences could potentially predispose diabetic individuals to increased infection severity complicated by ARDS. Clinical trial reg. no: NCT03102801; registration date April 6, 2017.


Subject(s)
COVID-19/etiology , Diabetes Mellitus, Type 2/complications , Macrophage Activation , Obesity/complications , Adult , Aged , Biomarkers/blood , COVID-19/blood , COVID-19/immunology , Cytokines/blood , Cytokines/immunology , Diabetes Mellitus, Type 2/blood , Diabetes Mellitus, Type 2/immunology , Female , Humans , Inflammation/blood , Inflammation/complications , Inflammation/immunology , Male , Middle Aged , Obesity/blood , Obesity/immunology , Pilot Projects , Prospective Studies , Risk Factors
19.
Obes Rev ; 22(6): e13216, 2021 06.
Article in English | MEDLINE | ID: covidwho-1133024

ABSTRACT

Emerging data suggest an association between obesity and infectious diseases. Although the mechanisms underlying this link are not well established, a number of potential factors may be involved. Indeed, the obesity-related vulnerability to infectious diseases could be due to chronic low-grade inflammation, hyperglycemia, hyperinsulinemia, and hyperleptinemia, which lead to a weakening of both the innate and adaptive immune responses. In addition, obesity results in anatomical-functional changes by the mechanical obstacle of excessive adipose tissue that blunt the respiratory mechanisms and predisposing to respiratory infections. Subjects with obesity are also at risk of skin folds and sweat more profusely due to the thick layers of subcutaneous fat, favoring the proliferation of microorganisms and slowing the repair of wounds down. All these factors make subjects with obesity more prone to develop nosocomial infections, surgical site, skin and soft tissue infections, bacteremia, urinary tract infections, and mycosis. Furthermore, infections in subjects with obesity have a worse prognosis, frequently prolonging hospitalization time as demonstrated for several flu viruses and recently for COVID-19. Thus, the aim of this manuscript is to provide an overview of the current clinical evidence on the associations between obesity and infectious diseases highlighting physio pathological insights involved in this link.


Subject(s)
Immunity/immunology , Infections/complications , Infections/immunology , Obesity/complications , Obesity/immunology , Humans
20.
Clin Nutr ; 40(4): 1637-1643, 2021 04.
Article in English | MEDLINE | ID: covidwho-1116485

ABSTRACT

The high prevalence of obesity and obesity-related comorbidities has reached pandemic proportions, particularly in Western countries. Obesity increases the risk to develop several chronic noncommunicable disease, ultimately contributing to reduced survival. Recently, obesity has been recognized as major risk factor for coronavirus disease-19 (COVID-19)-related prognosis, contributing to worse outcomes in those with established COVID-19. Particularly, obesity has been associated with higher hospitalization rates in acute or intensive care and greater risk for invasive mechanical ventilation than lean people. Obesity is characterized by metabolic impairments and chronic low-grade systemic inflammation that causes a pro-inflammatory microenvironment, further aggravating the cytokine production and risk of cytokine storm response during Sars-Cov2 sepsis or other secondary infections. Moreover, the metabolic dysregulations are closely related to an impaired immune system and altered response to viral infection that can ultimately lead to a greater susceptibility to infections, longer viral shedding and greater duration of illness and severity of the disease. In individuals with obesity, maintaining a healthy diet, remaining physically active and reducing sedentary behaviors are particularly important during COVID-19-related quarantine to reduce metabolic and immune impairments. Moreover, such stategies are of utmost importance to reduce the risk for sarcopenia and sarcopenic obesity, and to prevent a reduction and potentially even increase cardiorespiratory fitness, a well-known independent risk factor for cardiovascular and metabolic diseases and recently found to be a risk factor also for hospitalizations secondary to COVID-19. Such lifestyle strategies may ultimately reduce morbility and mortality in patients with infectious disease, especially in those with concomitant obesity. The aim of this review is to discuss how obesity might increase the risk of COVID-19 and potentially affect its prognosis once COVID-19 is diagnosed. We therefore advocate for implementation of strategies aimed at preventing obesity in the first place, but also to minimize the metabolic anomalies that may lead to a compromized immune response and chronic low-grade systemic inflammation, especially in patients with COVID-19.


Subject(s)
COVID-19/epidemiology , Disease Susceptibility/epidemiology , Obesity/epidemiology , Obesity/prevention & control , COVID-19/immunology , Cardiorespiratory Fitness/physiology , Comorbidity , Diet/standards , Disease Susceptibility/immunology , Exercise/physiology , Humans , Obesity/immunology , Prognosis , Risk Factors , SARS-CoV-2 , Severity of Illness Index
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