Macrophages activated by the Gram-negative bacterial product lipopolysaccharide switch their core metabolism from oxidative phosphorylation to glycolysis. Here we show that inhibition of glycolysis with 2-deoxyglucose suppresses lipopolysaccharide-induced interleukin-1β but not tumour-necrosis factor-α in mouse macrophages. A comprehensive metabolic map of lipopolysaccharide-activated macrophages shows upregulation of glycolytic and downregulation of mitochondrial genes, which correlates directly with the expression profiles of altered metabolites. Lipopolysaccharide strongly increases the levels of the tricarboxylic-acid cycle intermediate succinate. Glutamine-dependent anerplerosis is the principal source of succinate, although the 'GABA (γ-aminobutyric acid) shunt' pathway also has a role. Lipopolysaccharide-induced succinate stabilizes hypoxia-inducible factor-1α, an effect that is inhibited by 2-deoxyglucose, with interleukin-1β as an important target. Lipopolysaccharide also increases succinylation of several proteins. We therefore identify succinate as a metabolite in innate immune signalling, which enhances interleukin-1β production during inflammation.

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Succinate is an inflammatory signal that induces IL-1β through HIF-1α

NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) is an intracellular sensor that detects a broad range of microbial motifs, endogenous danger signals and environmental irritants, resulting in the formation and activation of the NLRP3 inflammasome. Assembly of the NLRP3 inflammasome leads to caspase 1-dependent release of the pro-inflammatory cytokines IL-1β and IL-18, as well as to gasdermin D-mediated pyroptotic cell death. Recent studies have revealed new regulators of the NLRP3 inflammasome, including new interacting or regulatory proteins, metabolic pathways and a regulatory mitochondrial hub. In this Review, we present the molecular, cell biological and biochemical bases of NLRP3 activation and regulation and describe how this mechanistic understanding is leading to potential therapeutics that target the NLRP3 inflammasome.

The NLRP3 inflammasome: molecular activation and regulation to therapeutics

Immunometabolism is emerging an important area of immunological research, but for many immunologists the complexity of the field can be daunting. Here, the authors provide an overview of six key metabolic pathways that occur in immune cells and explain what is known (and what is still to be uncovered) concerning their effects on immune cell function. In recent years a substantial number of findings have been made in the area of immunometabolism, by which we mean the changes in intracellular metabolic pathways in immune cells that alter their function. Here, we provide a brief refresher course on six of the major metabolic pathways involved (specifically, glycolysis, the tricarboxylic acid (TCA) cycle, the pentose phosphate pathway, fatty acid oxidation, fatty acid synthesis and amino acid metabolism), giving specific examples of how precise changes in the metabolites of these pathways shape the immune cell response. What is emerging is a complex interplay between metabolic reprogramming and immunity, which is providing an extra dimension to our understanding of the immune system in health and disease.

A guide to immunometabolism for immunologists

https://pure.mpg.de/pubman/item/item_3230146_1/component/file_3230147/Chang%20et%20al..pdf

Posttranscriptional Control of T Cell Effector Function by Aerobic Glycolysis

https://pure.mpg.de/pubman/item/item_3230156_1/component/file_3230157/Chang%20et%20al..pdf

Metabolic Pathways in Immune Cell Activation and Quiescence

Toll-like Receptor-Induced Changes in Glycolytic Metabolism Regulate Dendritic Cell Activation

Healthcare-associated infections (HAIs) from coronavirus disease 2019 (COVID-19) have been reported worldwide, accounting for up to 8.2% of all cases in a cohort of UK hospitals during the first wave of the pandemic in 2020. 1,2 The potential for COVID-19 HAI has continued to cause concern and strategies to prevent inpatient transmission have targeted reducing aerosol spread with the use of respirators by healthcare personnel (HCP), the use of airborne iso-lation rooms for aerosol-generating procedures, 3 testing of symptomatic and asymptomatic patients at admission, 4 and standard infection prevention strategies (eg, hand hygiene). 5 The severe acute respiratory coronavirus virus 2 (SARS-CoV-2) (omicron) variant appeared at the end of 2021 and marked a shift in the pat-terns of infection, with increased transmissibility but reduced severity. 6 We investigated the impact of the different transmission properties of the SARS-CoV-2 (omicron) variant on rates and fea-tures of COVID-19 HAI in comparison to the SARS-CoV-2 δ (delta) variant.

Characterization of healthcare-associated infections with the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) omicron variant at a tertiary healthcare center

An abstract is not available for this content so a preview has been provided. Please use the Get access link above for information on how to access this content. 

Characterization of Healthcare-Associated Infections with the COVID-19 Omicron Variant at a Tertiary Healthcare Center.

Abstract The global burden of infection from MDR organisms (MDROs) disproportionately affects children residing in low- and middle-income countries and those with increased healthcare exposure. These populations have high rates of malnutrition making them increasingly vulnerable to infection with intestinal-derived pathogens. Malnourished children experience increased incidence of intestinal carriage and invasive infection with intestinal-derived MDROs including ESBL- and carbapenemase-producing Enterobacterales. However, the relationship between malnutrition and MDRO infection remains to be clearly defined. Impairment in intestinal barrier function and innate and adaptive immunity in malnutrition increases the risk for infection with intestinal-derived pathogens, and there is an increasing appreciation of the role of the intestinal microbiota in this process. Current evidence from human studies and animal models suggests that diet and the intestinal microbiota influence each other to determine nutritional status, with important implications for infectious outcomes. These insights are crucial to developing microbiota-targeted strategies aimed at reversing the growing burden of MDRO infections in malnourished populations worldwide.

Thomas Holowka

Papers

Toll-like Receptor-Induced Changes in Glycolytic Metabolism Regulate Dendritic Cell Activation

Characterization of healthcare-associated infections with the severe acute respiratory coronavirus virus 2 (SARS-CoV-2) omicron variant at a tertiary healthcare center

Characterization of Healthcare-Associated Infections with the COVID-19 Omicron Variant at a Tertiary Healthcare Center.

Impact of childhood malnutrition and intestinal microbiota on MDR infections