Impact of obesity and SARS-CoV-2 infection: implications for host defence - a living review

Abstract The role of obesity in the pathophysiology of respiratory virus infections has become particularly apparent during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic, where obese patients are twice as likely to suffer from severe coronavirus disease 2019 (COVID-19) than healthy weight individuals. Obesity results in disruption of systemic lipid metabolism promoting a state of chronic low-grade inflammation. However, it remains unclear how these underlying metabolic and cellular processes promote severe SARS-CoV-2 infection. Emerging data in SARS-CoV-2 and Influenza A virus (IAV) infections show that viruses can further subvert the host’s altered lipid metabolism and exploit obesity-induced alterations in immune cell metabolism and function to promote chronic inflammation and viral propagation. In this review, we outline the systemic metabolic and immune alterations underlying obesity and discuss how these baseline alterations impact the immune response and disease pathophysiology. A better understanding of the immunometabolic landscape of obese patients may aid better therapies and future vaccine design.

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Using Zebrafish Models of Human Influenza A Virus Infections to Screen Antiviral Drugs and Characterize Host Immune Cell Responses

Journal of Visualized Experiments ◽

10.3791/55235 ◽

2017 ◽

Cited By ~ 2

Author(s):

Con Sullivan ◽

Denise Jurcyzszak ◽

Michelle F. Goody ◽

Kristin A. Gabor ◽

Jacob R. Longfellow ◽

...

Keyword(s):

Influenza A Virus ◽

Influenza A ◽

Immune Cell ◽

Antiviral Drugs ◽

Virus Infections ◽

Human Influenza ◽

Cell Responses ◽

Host Immune Cell

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Changes in Nutritional Status Impact Immune Cell Metabolism and Function

Frontiers in Immunology ◽

10.3389/fimmu.2018.01055 ◽

2018 ◽

Vol 9 ◽

Cited By ~ 63

Author(s):

Yazan Alwarawrah ◽

Kaitlin Kiernan ◽

Nancie J. MacIver

Keyword(s):

Nutritional Status ◽

Immune Cell ◽

Cell Metabolism ◽

And Function

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Immunometabolism at the Nexus of Cancer Therapeutic Efficacy and Resistance

Frontiers in Immunology ◽

10.3389/fimmu.2021.657293 ◽

2021 ◽

Vol 12 ◽

Author(s):

Javier Traba ◽

Michael N. Sack ◽

Thomas A. Waldmann ◽

Olga M. Anton

Keyword(s):

Immune System ◽

Immune Cells ◽

Immune Cell ◽

Cell Metabolism ◽

Immune Surveillance ◽

Antitumor Effects ◽

Cancer Management ◽

Immunosuppressive Tumor Microenvironment ◽

And Function ◽

Main Effects

Constitutive activity of the immune surveillance system detects and kills cancerous cells, although many cancers have developed strategies to avoid detection and to resist their destruction. Cancer immunotherapy entails the manipulation of components of the endogenous immune system as targeted approaches to control and destroy cancer cells. Since one of the major limitations for the antitumor activity of immune cells is the immunosuppressive tumor microenvironment (TME), boosting the immune system to overcome the inhibition provided by the TME is a critical component of oncotherapeutics. In this article, we discuss the main effects of the TME on the metabolism and function of immune cells, and review emerging strategies to potentiate immune cell metabolism to promote antitumor effects either as monotherapeutics or in combination with conventional chemotherapy to optimize cancer management.

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Highly pathogenic avian influenza A H5N1 and pandemic H1N1 virus infections have different phenotypes in Toll-like receptor 3 knockout mice

Journal of General Virology ◽

10.1099/vir.0.066258-0 ◽

2014 ◽

Vol 95 (9) ◽

pp. 1870-1879 ◽

Cited By ~ 24

Author(s):

Y. H. Connie Leung ◽

John M. Nicholls ◽

Chuk Kwan Ho ◽

Sin Fun Sia ◽

Chris K. P. Mok ◽

...

Keyword(s):

Body Weight ◽

Influenza A ◽

Immune Cell ◽

Body Weight Loss ◽

Lung Pathology ◽

Pandemic H1n1 ◽

Virus Infections ◽

Viral Titre ◽

Highly Pathogenic

Toll-like receptors (TLRs) play an important role in innate immunity to virus infections. We investigated the role of TLR3 in the pathogenesis of H5N1 and pandemic H1N1 (pH1N1) influenza virus infections in mice. Wild-type mice and those defective in TLR3 were infected with influenza A/HK/486/97 (H5N1) or A/HK/415742/09 (pH1N1) virus. For comparison, mice defective in the gene for myeloid differential factor 88 (MyD88) were also infected with the viruses, because MyD88 signals through a TLR pathway different from TLR3. Survival and body weight loss were monitored for 14 days, and lung pathology, the lung immune-cell profile, viral load and cytokine responses were studied. H5N1-infected TLR3−/− mice had better survival than H5N1-infected WT mice, evident by significantly faster regain of body weight, lower viral titre in the lung and fewer pathological changes in the lung. However, this improved survival was not seen upon pH1N1 infection of TLR3−/− mice. In contrast, MyD88−/− mice had an increased viral titre and decreased leukocyte infiltration in the lungs after infection with H5N1 virus and poorer survival after pH1N1 infection. In conclusion, TLR3 worsens the pathogenesis of H5N1 infection but not of pH1N1 infection, highlighting the differences in the pathogenesis of these two viruses and the different roles of TLR3 in their pathogenesis.

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Mitochondrial Dynamics at the Interface of Immune Cell Metabolism and Function

Trends in Immunology ◽

10.1016/j.it.2017.08.006 ◽

2018 ◽

Vol 39 (1) ◽

pp. 6-18 ◽

Cited By ~ 77

Author(s):

Angelika S. Rambold ◽

Erika L. Pearce

Keyword(s):

Immune Cell ◽

Mitochondrial Dynamics ◽

Cell Metabolism ◽

And Function

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Parenteral glucose supply and pharmacological glycolysis inhibition determine the clinical fate of infected preterm newborns

10.1101/2021.09.03.458815 ◽

2021 ◽

Author(s):

Tik Muk ◽

Anders Brunse ◽

Nicole L Henriksen ◽

Karoline Aasmul-Olsen ◽

Duc Ninh Nguyen

Keyword(s):

Preterm Infants ◽

Immune Cell ◽

Cell Metabolism ◽

Preterm Neonates ◽

Glucose Levels ◽

Lactate Acidosis ◽

Infection Response ◽

Host Infection ◽

And Function ◽

Glucose Supply

Preterm infants are susceptible to bloodstream infection that can lead to sepsis. High parenteral glucose supplement is commonly used to support their growth and energy expenditure, but may exceed endogenous regulation during infection, causing dysregulated immune response and clinical deterioration. Using a preterm piglet model of neonatal sepsis induced by Staphylococcus epidermidis infection, we demonstrate the delicate interplay between immunity and energy metabolism to regulate the host infection response. Circulating glucose levels, glycolysis and inflammatory response to infection are closely connected across the states of tolerance, resistance and immunoparalysis. Further, high parenteral glucose provision during infection induces hyperglycemia, elevated glycolysis and inflammation, leading to lactate acidosis and sepsis, whereas glucose restricted individuals are clinically unaffected with increased gluconeogenesis to maintain moderate hypoglycemia. Finally, pharmacological glycolysis inhibition during normoglycemia enhances bacterial clearance and dampens inflammation but fails to prevent sepsis. Our results uncover how blood glucose controls immune cell metabolism and function, in turn determining the clinical fate of infected preterm neonates. This also questions the current practice of parenteral glucose supply for infected preterm infants.

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Nutritional Modulation of AMPK-Impact upon Metabolic-Inflammation

International Journal of Molecular Sciences ◽

10.3390/ijms19103092 ◽

2018 ◽

Vol 19 (10) ◽

pp. 3092 ◽

Cited By ~ 27

Author(s):

Claire Lyons ◽

Helen Roche

Keyword(s):

Immune Cell ◽

Cell Metabolism ◽

Nutrient Status ◽

Whole Body ◽

Direct Role ◽

Insulin Metabolism ◽

Metabolic Inflammation ◽

Metabolic Substrates ◽

Whole Body Metabolism ◽

And Function

Nutritional status provides metabolic substrates to activate AMP-Activated Protein Kinase (AMPK), the energy sensor that regulates metabolism. Recent evidence has demonstrated that AMPK has wider functions with respect to regulating immune cell metabolism and function. One such example is the regulatory role that AMPK has on NLRP3-inlflammasome and IL-1β biology. This in turn can result in subsequent negative downstream effects on glucose, lipid and insulin metabolism. Nutrient stress in the form of obesity can impact AMPK and whole-body metabolism, leading to complications such as type 2 diabetes and cancer risk. There is a lack of data regarding the nature and extent that nutrient status has on AMPK and metabolic-inflammation. However, emerging work elucidates to a direct role of individual nutrients on AMPK and metabolic-inflammation, as a possible means of modulating AMPK activity. The posit being to use such nutritional agents to re-configure metabolic-inflammation towards more oxidative phosphorylation and promote the resolution of inflammation. The complex paradigm will be discussed within the context of if/how dietary components, nutrients including fatty acids and non-nutrient food components, such as resveratrol, berberine, curcumin and the flavonoid genistein, modulate AMPK dependent processes relating to inflammation and metabolism.

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Is nuclear sirtuin SIRT6 a master regulator of immune function?

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00483.2020 ◽

2020 ◽

Author(s):

Vinodkumar B Pillai ◽

Mahesh P Gupta

Keyword(s):

Immune Cells ◽

Metabolic Pathways ◽

Warburg Effect ◽

Immune Cell ◽

Cell Metabolism ◽

Negative Regulator ◽

Master Regulator ◽

Energy Needs ◽

And Function ◽

The Warburg Effect

Abstract: The ability to ward off pathogens with minimal damage to the host determines the immune system's robustness. Multiple factors, including pathogen processing, identification, secretion of mediator and effector molecules, and immune cell proliferation and differentiation into various subsets, constitute the success of mounting an effective immune response. Cellular metabolism controls all of these intricate processes. Cells utilize diverse fuel sources and switch back and forth between different metabolic pathways depending on their energy needs. The three most critical metabolic pathways on which immune cells depend to meet their energy needs are oxidative metabolism, glycolysis, and glutaminolysis. Dynamic switching between these metabolic pathways is needed for optimal function of the immune cells. Moreover, switching between these metabolic pathways needs to be tightly regulated to achieve the best results. Immune cells depend on the Warburg effect for their growth, proliferation, secretory, and effector functions. Here, we hypothesize that the sirtuin, SIRT6, could be a negative regulator of the Warburg effect. We also postulate that SIRT6 could act as a master regulator of immune cell metabolism and function by regulating critical signaling pathways.

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In Vitro and In Vivo Antiviral Activity of Gingerenone A on Influenza A Virus Is Mediated by Targeting Janus Kinase 2

Viruses ◽

10.3390/v12101141 ◽

2020 ◽

Vol 12 (10) ◽

pp. 1141

Author(s):

Jiongjiong Wang ◽

Richard A. Prinz ◽

Xiufan Liu ◽

Xiulong Xu

Keyword(s):

Antiviral Activity ◽

Influenza A Virus ◽

Influenza A ◽

H5n1 Virus ◽

Immune Cell ◽

Janus Kinase ◽

Virus Infections ◽

Dual Inhibitor ◽

Cell Functions

Janus kinase (JAK) inhibitors have been developed as novel immunomodulatory drugs and primarily used for treating rheumatoid arthritis and other inflammatory diseases. Recent studies have suggested that this category of anti-inflammatory drugs could be potentially useful for the control of inflammation “storms” in respiratory virus infections. In addition to their role in regulating immune cell functions, JAK1 and JAK2 have been recently identified as crucial cellular factors involved in influenza A virus (IAV) replication and could be potentially targeted for antiviral therapy. Gingerenone A (Gin A) is a compound derived from ginger roots and a dual inhibitor of JAK2 and p70 S6 kinase (S6K1). Our present study aimed to determine the antiviral activity of Gin A on influenza A virus (IAV) and to understand its mechanisms of action. Here, we reported that Gin A suppressed the replication of three IAV subtypes (H1N1, H5N1, H9N2) in four cell lines. IAV replication was also inhibited by Ruxolitinib (Rux), a JAK inhibitor, but not by PF-4708671, an S6K1 inhibitor. JAK2 overexpression enhanced H5N1 virus replication and attenuated Gin A-mediated antiviral activity. In vivo experiments revealed that Gin A treatment suppressed IAV replication in the lungs of H5N1 virus-infected mice, alleviated their body weight loss, and prolonged their survival. Our study suggests that Gin A restricts IAV replication by inhibiting JAK2 activity; Gin A could be potentially useful for the control of influenza virus infections.

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