Metabolic approaches to abolishing cytokine storm in COVID-19

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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.