Metabolic approaches to abolishing cytokine storm in COVID-19

Lead Research Organisation: Swansea University


A striking feature of the immune response to SARS-CoV-2 in patients with severe COVID-19 is cytokine storm: continuous high levels of potent inflammatory mediators (cytokines) that dysregulate the function of tissues such as lungs, heart and kidneys. Mononuclear phagocytes (MNPs) are the primary cellular source of these and better understanding of the mechanisms that enable cytokine overproduction might reveal therapeutic targets for down-regulating multiple cytokines and restoration of healthy organ function. For MNPs to produce cytokines they require a supply of nutrients, e.g. glucose, to power their production of these proteins as well as other cellular functions. We have shown that restricting glucose availability to MNPs paradoxically leads to elevated levels of multiple cytokines, the hallmark of cytokine storm. Failure of MNPs to compete successfully with other cells in the lungs for key nutrients might be why cytokine storm occurs. We have also shown that glucose restricted but not glucose replete MNPs are sensitive to further disruption of their cellular metabolic processes: an array of metabolic inhibitors that have counterparts in drugs already in clinical use induced cell death and abolished cytokine production. Using MNPs isolated from blood and airways of severe COVID-19 patients who are mechanically ventilated in intensive care we will determine if changes in cellular metabolism underpin cytokine storm and offer a therapeutic target for repurposed drugs.

Technical Summary

Hyperinflammation is a feature of a severe COVID-19 underpinned by dysfunction of mononuclear phagocytes (MNPs). Highly inflammatory blood MNPs traffic to the airways and supplant reparative local MNPs to cause pulmonary damage; similarly, they travel to the heart, kidneys and other tissues. Continuous high levels of multiple cytokines contribute to auto-amplification of inflammation and increased vascular permeability, thrombosis, organ failure and death. The mechanistic determinants of cytokine storm are unknown but intracellular events, such as cellular metabolic adaptation as proposed here, that drive the hyperactivated MNP phenotype offer targets for therapeutic intervention to abolish production of multiple cytokines and provide better outcomes for more patients than mono-cytokine approaches. Recent data from the Thornton laboratory has shown that glucose deprivation of human blood monocytes paradoxically leads to elevated levels of multiple cytokines including interleukin (IL)-6, IL-10 and TNFalpha, i.e. hallmarks of cytokine storm, via increases in oxidative phosphorylation and protein translation. Further metabolic disruption using various metabolic inhibitors, which have counterparts in drugs already in use clinically, induces cell death and abolishes cytokine production. Therefore, we hypothesise that metabolic dysregulation linked to changes in cellular fuel availability underpins hyperinflammation by MNPs and provides a target for therapeutic intervention. To address this, we will use blood and airways MNPs from mechanically ventilated COVID-19 patients to investigate the link between metabolic maladaptation and cytokine hyperproduction. We will then determine if further metabolic disruption, that can be translated clinically by repurposing already approved drugs, might enable elimination of the cytokine storm for patient benefit.


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Rees A (2022) Potential protective effects of breast milk and amniotic fluid against novel coronavirus SARS-CoV-2 through decoy receptors. in Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology

Description Airways macrophages from severe COVID-19 patients have altered metabolic profiles.
Airways of severe COVID-19 patients contain small extracellular vesicles with a profile distinct from blood.
Exploitation Route We will be sharing thought publications and conference presentations. We expect follow on grant application related to therapeutic targeting of metabolic pathways in multiple disease settings
Sectors Healthcare

Title Airway aspirrates 
Description Chest physiotherapy involves instilling saline in the airways of ventilated patients and encouraging them to cough this back up. This fluid can be collected safely from the trap and used for research as a samples of the cells and microenvironment 
Type Of Material Biological samples 
Year Produced 2022 
Provided To Others? No  
Impact Cells isolated are usable in multiple assay formats from flow ctyometry to cellular bioenergetics; manuscript in preparation 
Description Anti-viral immunity of pregnant women 
Organisation Cardiff University
Country United Kingdom 
Sector Academic/University 
PI Contribution Initiating work to understand how pregnancy women respond to SARS-CoV-2 and other viruses - using monocytes and nasal epithelial cells.
Collaborator Contribution Class 3 activity with live virus exposures of cells and early processing of biological samples rendering them safe for use in class 2 laboratory.
Impact None yet
Start Year 2021
Title Exploiting small molecules that interfrere with cell metabolism for therapeutic benefit 
Description Drugs shown to be effective at blocking metabolism and functions effects still being explored before next steps. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Initial development
Year Development Stage Completed 2022
Development Status Under active development/distribution
Impact None 
Description Undergradaute recruitment webinar 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Taster session/guest lecture as part of undergraduate recruitment activities
Year(s) Of Engagement Activity 2021