COVID-19 can result in severe lung injury. It remained to be determined why diabetic individuals with uncontrolled glucose levels are more prone to develop the severe form of COVID-19. The molecular mechanism underlying SARS-CoV-2 infection and what determines the onset of the cytokine storm found in severe COVID-19 patients are unknown. Monocytes and macrophages are the most enriched immune cell types in the lungs of COVID-19 patients and appear to have a central role in the pathogenicity of the disease. These cells adapt their metabolism upon infection and become highly glycolytic, which facilitates SARS-CoV-2 replication. The infection triggers mitochondrial ROS production, which induces stabilization of hypoxia-inducible factor-1α (HIF-1α) and consequently promotes glycolysis. HIF-1α-induced changes in monocyte metabolism by SARS-CoV-2 infection directly inhibit T cell response and reduce epithelial cell survival. Targeting HIF-1ɑ may have great therapeutic potential for the development of novel drugs to treat COVID-19.

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Foamy macrophages, which have prominent lipid droplets (LDs), are found in a variety of disease states. Toll-like receptor agonists drive triacylglycerol (TG)-rich LD development in macrophages. Here we explore the basis and significance of this process. Our findings indicate that LD development is the result of metabolic commitment to TG synthesis on a background of decreased fatty acid oxidation. TG synthesis is essential for optimal inflammatory macrophage activation as its inhibition, which prevents LD development, has marked effects on the production of inflammatory mediators, including IL-1β, IL-6 and PGE2, and on phagocytic capacity. The failure of inflammatory macrophages to make PGE2 when TGsynthesis is inhibited is critical for this phenotype, as addition of exogenous PGE2 is able to reverse the anti-inflammatory effects of TG synthesis inhibition. These findings place LDs in a position of central importance in inflammatory macrophage activation.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the agent of a major global outbreak of respiratory tract disease known as coronavirus disease-2019 (COVID-19). SARS-CoV-2 infects the lungs and may cause several immune-related complications such as lymphocytopenia and cytokine storm which are associated with the severity of the disease and predict mortality . The mechanism by which SARS-CoV-2 infection may result in immune system dysfunction is not fully understood. Here we show that SARS-CoV-2 infects human CD4+ T helper cells, but not CD8+ T cells, and is present in blood and bronchoalveolar lavage T helper cells of severe COVID-19 patients. We demonstrated that SARS-CoV-2 spike glycoprotein (S) directly binds to the CD4 molecule, which in turn mediates the entry of SARS- CoV-2 in T helper cells in a mechanism that also requires ACE2 and TMPRSS2. Once inside T helper cells, SARS-CoV-2 assembles viral factories, impairs cell function and may cause cell death. SARS-CoV-2 infected T helper cells express higher amounts of IL-10, which is associated with viral persistence and disease severity. Thus, CD4-mediated SARS-CoV-2 infection of T helper cells may explain the poor adaptive immune response of many COVID- 19 patients.

Macrophages are integral to most tissues. Foam cells, macrophages with lipid droplets (LDs) which are stores of triacylglycerols (TGs) and cholesterol esters (CEs), are found in various disease states 1 . LDs can act as energy stores since TG lipolysis releases fatty acids (FAs) for mitochondrial oxidation (FAO), a process that relies on long-chain FA conversion into acylcarnitines by the enzyme Cpt1a 2 . However, in macrophages, proinflammatory signals result in diminished FAO and increased TG synthesis with LD development 3,4 . We explored the significance of LDs in cells that do not utilize FAO. We show that macrophages stimulated with lipopolysaccharide (LPS) plus interferon-g (IFNg) accumulate TGs in LDs, and long-chain acylcarnitines. In these cells, inhibition of TG synthesis results in diminished LD development, and increased long chain acylcarnitine levels, suggesting that FA fate is balanced between TG and acylcarnitine synthesis. Nevertheless, TG-synthesis is required for inflammatory macrophage function, since its inhibition negatively affects production of proinflammatory IL-1b, IL-6 and PGE2, and phagocytic capacity, and protects against LPS-induced shock in vivo. Failure to make PGE2 is critical for this phenotype, since exogenous PGE2 reverses the anti-inflammatory effects of TG-synthesis inhibition. These findings place LDs in a position of central functional importance in inflammatory macrophages. EJP and ELP are Founders of Rheos Medicines MethodsMice and in vivo experiments C57BL/6 mice (RRID: IMSR_JAX:000664) were from The Jackson Laboratory, and were maintained in specific pathogen-free conditions under protocols approved by the animal care committee of the Regierungspräsidium Freiburg, Germany, in compliance with all relevant ethical regulations. Animals were 6-8 weeks old when used. They were euthanized by carbon dioxide asphyxiation followed by cervical

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Obesity is a pandemic disease affecting around 15% of the global population. Obesity is a major risk factor for other conditions, such as type 2 diabetes and cardiovascular diseases. The adipose tissue is the main secretor of leptin, an adipokine responsible for the regulation of food intake and energy expenditure. Obese individuals become hyperleptinemic due to increased adipogenesis. Leptin acts through the leptin receptor and induces several immunometabolic changes in different cell types, including adipocytes and Mϕs. Adipose tissue resident Mϕs (ATMs) are the largest leukocyte population in the adipose tissue and these ATMs are in constant contact with the excessive leptin levels secreted in obese conditions. Leptin activates both the JAK2‐STAT3 and the PI3K‐AKT‐mTOR pathways. The activation of these pathways leads to intracellular metabolic changes, with increased glucose uptake, upregulation of glycolytic enzymes, and disruption of mitochondrial function, as well as immunologic alterations, such as increased phagocytic activity and proinflammatory cytokines secretion. Here, we discuss the immunometabolic effects of leptin in Mϕs and how hyperleptinemia can contribute to the low‐grade systemic inflammation in obesity.