The relationship between diabetes and COVID-19 is bi-directional: while individuals with diabetes and high blood glucose (hyperglycemia) are predisposed to severe COVID-19, SARS-CoV-2 infection can also cause hyperglycemia and exacerbate underlying metabolic syndrome. Therefore, interventions capable of breaking the network of SARS-CoV-2 infection, hyperglycemia, and hyper-inflammation, all factors that drive COVID-19 pathophysiology, are urgently needed. Here, we show that genetic ablation or pharmacological inhibition of mitochondrial pyruvate carrier (MPC) attenuates severe disease following influenza or SARS-CoV-2 pneumonia. MPC inhibition using a second-generation insulin sensitizer, MSDC-0602 K (MSDC), dampened pulmonary inflammation and promoted lung recovery, while concurrently reducing blood glucose levels and hyperlipidemia following viral pneumonia in obese mice. Mechanistically, MPC inhibition enhanced mitochondrial fitness and destabilized HIF-1α, leading to dampened virus-induced inflammatory responses in both murine and human lung macrophages. We further showed that MSDC enhanced responses to nirmatrelvir (the antiviral component of Paxlovid) to provide high levels of protection against severe host disease development following SARS-CoV-2 infection and suppressed cellular inflammation in human COVID-19 lung autopsies, demonstrating its translational potential for treating severe COVID-19. Collectively, we uncover a metabolic pathway that simultaneously modulates pulmonary inflammation, tissue recovery, and host metabolic health, presenting a synergistic therapeutic strategy to treat severe COVID-19, particularly in patients with underlying metabolic disease.

中文翻译：

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抑制线粒体丙酮酸载体可同时减轻 COVID-19 的过度炎症和高血糖

糖尿病和 COVID-19 之间的关系是双向的：虽然患有糖尿病和高血糖（高血糖症）的人容易患上严重的 COVID-19，但 SARS-CoV-2 感染也会引起高血糖并加剧潜在的代谢综合征。因此，迫切需要能够打破 SARS-CoV-2 感染、高血糖和过度炎症网络的干预措施，这些都是驱动 COVID-19 病理生理学的因素。在这里，我们表明线粒体丙酮酸载体 (MPC) 的基因消融或药物抑制可减轻流感或 SARS-CoV-2 肺炎后的严重疾病。使用第二代胰岛素增敏剂 MSDC-0602 K (MSDC) 抑制 MPC，抑制肺部炎症并促进肺部恢复，同时降低肥胖小鼠病毒性肺炎后的血糖水平和高脂血症。从机制上讲，MPC 抑制增强了线粒体适应性并使 HIF-1α 不稳定，从而导致小鼠和人类肺巨噬细胞中病毒诱导的炎症反应减弱。我们进一步表明，MSDC 增强了对 nirmatrelvir（Paxlovid 的抗病毒成分）的反应，以提供高水平的保护，防止 SARS-CoV-2 感染后严重的宿主疾病发展，并抑制人类 COVID-19 肺尸检中的细胞炎症，证明了其转化潜力用于治疗重症 COVID-19。总的来说，我们发现了一种同时调节肺部炎症、组织恢复和宿主代谢健康的代谢途径，