SARS-CoV-2 Achieves Immune Escape by Destroying Mitochondrial Quality: Comprehensive Analysis of the Cellular Landscapes of Lung and Blood Specimens From Patients With COVID-19

Abstract

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.

Notoginsenoside R1 improves intestinal microvascular functioning in sepsis by targeting Drp1-mediated mitochondrial quality imbalance

“… 2022 ), infection, and inflammation (Duan et al. 2022 ) may lead to mitochondrial fragmentation, resulting in decreased ATP production, disrupted calcium metabolism, and eventually, mitochondrial dysfunction. Mitochondrial dysfunction plays a crucial role in the pathogenesis of sepsis, particularly severe sepsis, and is a major contributing factor to poor prognosis, multiple-organ failure, and death (Zhang H et al.…”

Identification of dynamic gene expression profiles during sequential vaccination with ChAdOx1/BNT162b2 using machine learning methods

“…Transcriptome results showed that vaccinated patients had significantly attenuated IFN responses compared to unvaccinated Omicron and Alpha-infected patients, represented by IFI27, which controls antiviral responses (Lee et al, 2022b). The results of RNA sequencing data analysis showed that macrophages in the blood of SARS-CoV-2infected patients released a large number of IFNs, activated mitochondrial IFI27 expression, and disrupted energy metabolism in immune cells, ultimately aggravating viral immune evasion and replication (Duan et al, 2022). Based on existing research reports and our analysis, we speculate that after vaccination, the release of IFN increases, which promotes an increase in mitochondrial protein IFI27, inhibits SARS-CoV-2 replication and gene expression, and enhances antiviral immunity.…”

The use of bioinformatics methods to identify the effects of SARS-CoV-2 and influenza viruses on the regulation of gene expression in patients

“…Studies have found that IFFI44, IFI6, RSAD2, and OSAL are significantly upregulated in COVID-19 patients and are involved in immune regulation (41). The infected macrophages of COVID-19 patients release large amounts of interferon into the blood, which activates mitochondrial IFI27 expression and disrupts the energy metabolism of immune cells (42). Genes such as IFI27 that exert antiviral effects and neutrophil activation are downregulated during treatment in COVID-19 patients, which is consistent with the dynamically enhanced inflammatory response of COVID-19 patients (43).…”