Human SARS-CoV-2 infection is characterized by a high mortality rate due to some patients developing a large innate immune response associated with a cytokine storm and acute respiratory distress syndrome (ARDS). This is characterized at the molecular level by decreased energy metabolism, altered redox state, oxidative damage, and cell death. Therapies that increase levels of (R)-beta-hydroxybutyrate (R-BHB), such as the ketogenic diet or consuming exogenous ketones, should restore altered energy metabolism and redox state. R-BHB activates anti-inflammatory GPR109A signaling and inhibits the NLRP3 inflammasome and histone deacetylases, while a ketogenic diet has been shown to protect mice from influenza virus infection through a protective γδ T cell response and by increasing electron transport chain gene expression to restore energy metabolism. During a virus-induced cytokine storm, metabolic flexibility is compromised due to increased levels of reactive oxygen species (ROS) and reactive nitrogen species (RNS) that damage, downregulate, or inactivate many enzymes of central metabolism including the pyruvate dehydrogenase complex (PDC). This leads to an energy and redox crisis that decreases B and T cell proliferation and results in increased cytokine production and cell death. It is hypothesized that a moderately high-fat diet together with exogenous ketone supplementation at the first signs of respiratory distress will increase mitochondrial metabolism by bypassing the block at PDC. R-BHB-mediated restoration of nucleotide coenzyme ratios and redox state should decrease ROS and RNS to blunt the innate immune response and the associated cytokine storm, allowing the proliferation of cells responsible for adaptive immunity. Limitations of the proposed therapy include the following: it is unknown if human immune and lung cell functions are enhanced by ketosis, the risk of ketoacidosis must be assessed prior to initiating treatment, and permissive dietary fat and carbohydrate levels for exogenous ketones to boost immune function are not yet established. The third limitation could be addressed by studies with influenza-infected mice. A clinical study is warranted where COVID-19 patients consume a permissive diet combined with ketone ester to raise blood ketone levels to 1 to 2 mM with measured outcomes of symptom severity, length of infection, and case fatality rate.

中文翻译：

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COVID-19：提出以酮为基础的代谢疗法作为减弱细胞因子风暴的治疗方法

人类 SARS-CoV-2 感染的特点是死亡率高，因为一些患者会产生与细胞因子风暴和急性呼吸窘迫综合征 (ARDS) 相关的大量先天免疫反应。这在分子水平上的特点是能量代谢降低、氧化还原状态改变、氧化损伤和细胞死亡。增加 (R)-β-羟基丁酸 (R-BHB) 水平的疗法，例如生酮饮食或消耗外源性酮，应该可以恢复能量代谢和氧化还原状态的改变。R-BHB 激活抗炎 GPR109A 信号并抑制 NLRP3 炎症小体和组蛋白脱乙酰酶，而生酮饮食已被证明可以通过保护性γδ保护小鼠免受流感病毒感染T细胞反应并通过增加电子传递链基因表达来恢复能量代谢。在病毒诱导的细胞因子风暴期间，由于活性氧 (ROS) 和活性氮 (RNS) 水平升高，会损害、下调或灭活许多中枢代谢酶，包括丙酮酸脱氢酶复合物 (PDC)，从而损害代谢灵活性. 这会导致能量和氧化还原危机，从而降低 B 和 T 细胞增殖并导致细胞因子产生和细胞死亡增加。据推测，在呼吸窘迫的最初迹象时，适度高脂肪饮食和外源性酮补充剂将通过绕过 PDC 的阻滞来增加线粒体代谢。R-BHB 介导的核苷酸辅酶比率和氧化还原状态的恢复应减少 ROS 和 RNS，以减弱先天免疫反应和相关的细胞因子风暴，从而允许负责适应性免疫的细胞增殖。拟议疗法的局限性包括：未知酮症是否会增强人体免疫和肺细胞功能，必须在开始治疗前评估酮症酸中毒的风险，以及允许外源性酮的膳食脂肪和碳水化合物水平以增强免疫功能尚未建立。第三个限制可以通过对流感感染小鼠的研究来解决。一项临床研究是必要的，其中 COVID-19 患者食用宽松的饮食与酮酯相结合，以将血酮水平提高至 1 至 2 mM，并测量症状严重程度的结果，