Metabolic approaches to abolishing cytokine storm in COVID-19

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.