Department of Anesthesiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
Department of Cardiovascular Surgery, Xinqiao Hospital, Army Medical University, Chongqing, China.
Front Immunol. 2022 Jul 1;13:946731. doi: 10.3389/fimmu.2022.946731. eCollection 2022.
Mitochondria get caught in the crossfire of coronavirus disease 2019 (COVID-19) and antiviral immunity. The mitochondria-mediated antiviral immunity represents the host's first line of defense against viral infection, and the mitochondria are important targets of COVID-19. However, the specific manifestations of mitochondrial damage in patients with COVID-19 have not been systematically clarified. This study comprehensively analyzed one single-cell RNA-sequencing dataset of lung tissue and two bulk RNA-sequencing datasets of blood from COVID-19 patients. We found significant changes in mitochondrion-related gene expression, mitochondrial functions, and related metabolic pathways in patients with COVID-19. SARS-CoV-2 first infected the host alveolar epithelial cells, which may have induced excessive mitochondrial fission, inhibited mitochondrial degradation, and destroyed the mitochondrial calcium uniporter (MCU). The type II alveolar epithelial cell count decreased and the transformation from type II to type I alveolar epithelial cells was blocked, which exacerbated viral immune escape and replication in COVID-19 patients. Subsequently, alveolar macrophages phagocytized the infected alveolar epithelial cells, which decreased mitochondrial respiratory capacity and activated the ROS-HIF1A pathway in macrophages, thereby aggravating the pro-inflammatory reaction in the lungs. Infected macrophages released large amounts of interferon into the blood, activating mitochondrial IFI27 expression and destroying energy metabolism in immune cells. The plasma differentiation of B cells and lung-blood interaction of regulatory T cells (Tregs) was exacerbated, resulting in a cytokine storm and excessive inflammation. Thus, our findings systematically explain immune escape and excessive inflammation seen during COVID-19 from the perspective of mitochondrial quality imbalance.
线粒体在 2019 冠状病毒病（COVID-19）和抗病毒免疫中陷入困境。线粒体介导的抗病毒免疫代表宿主抵抗病毒感染的第一道防线，而线粒体是 COVID-19 的重要靶点。然而，COVID-19 患者中线粒体损伤的具体表现尚未得到系统阐明。本研究综合分析了 COVID-19 患者的肺组织单细胞 RNA 测序数据集、血液的两个批量 RNA 测序数据集。我们发现 COVID-19 患者中线粒体相关基因表达、线粒体功能和相关代谢途径发生了显著变化。SARS-CoV-2 首先感染宿主肺泡上皮细胞，这可能导致过度的线粒体裂变、抑制线粒体降解和破坏线粒体钙单向转运体（MCU）。II 型肺泡上皮细胞数量减少，II 型向 I 型肺泡上皮细胞的转化受阻，从而加剧 COVID-19 患者的病毒免疫逃逸和复制。随后，肺泡巨噬细胞吞噬感染的肺泡上皮细胞，降低了巨噬细胞的线粒体呼吸能力，并激活了巨噬细胞中的 ROS-HIF1A 通路，从而加重了肺部的促炎反应。受感染的巨噬细胞向血液中释放大量干扰素，激活免疫细胞中线粒体 IFI27 的表达并破坏其能量代谢。B 细胞的血浆分化和调节性 T 细胞（Tregs）的肺血相互作用加剧，导致细胞因子风暴和过度炎症。因此，我们的研究结果从线粒体质量失衡的角度系统地解释了 COVID-19 期间观察到的免疫逃逸和过度炎症。
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