Metabolic approaches to abolishing cytokine storm in COVID-19

严重新冠肺炎患者对SARS-CoV-2的免疫反应的一个显著特征是细胞因子风暴：持续高水平的强有力的炎症介质(细胞因子)，使肺、心脏和肾脏等组织的功能失调。单核巨噬细胞(MNPs)是这些疾病的主要细胞来源，更好地了解导致细胞因子过度产生的机制可能会揭示下调多种细胞因子和恢复健康器官功能的治疗靶点。对于MNPs来说，要产生细胞因子，它们需要营养物质的供应，例如葡萄糖，以推动它们产生这些蛋白质以及其他细胞功能。我们已经证明，限制葡萄糖供应到MNPs会矛盾地导致多种细胞因子水平的升高，这是细胞因子风暴的标志。MNPs未能成功地与肺部其他细胞竞争关键营养物质，这可能是细胞因子风暴发生的原因。我们还表明，葡萄糖受限但不是葡萄糖充足的MNPs对其细胞代谢过程的进一步破坏很敏感：一系列代谢抑制剂，已在临床使用的药物中的对应物，诱导细胞死亡和取消细胞因子的产生。利用从重症监护机械通气新冠肺炎患者的血液和呼吸道中分离出的MNPs，我们将确定细胞代谢的变化是否支持细胞因子风暴，并为改变用途的药物提供治疗靶点。

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.