Epithelial Galectin-3 Induced the Mitochondrial Complex Inhibition and Cell Cycle Arrest of CD8+ T Cells in Severe/Critical COVID-19

Author:

Wang Yudie1,Yang Cheng1,Wang Zhongyi1,Wang Yi1,Yan Qing1,Feng Ying1,Liu Yanping1,Huang Juan2,Zhou Jingjiao1

Affiliation:

1. Department of Biology and Genetics, College of Life Sciences and Health, Wuhan University of Science and Technology, Wuhan 430065, China

2. Department of Hematology, Maternal and Child Health Hospital of Hubei Province, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430070, China

Abstract

Previous research suggested that the dramatical decrease in CD8+ T cells is a contributing factor in the poor prognosis and disease progression of COVID-19 patients. However, the underlying mechanisms are not fully understood. In this study, we conducted Single-cell RNA sequencing (scRNA-seq) and single-cell T cell receptor sequencing (scTCR-seq) analysis, which revealed a proliferative-exhausted MCM+FASLGlow CD8+ T cell phenotype in severe/critical COVID-19 patients. These CD8+ T cells were characterized by G2/M cell cycle arrest, downregulation of respiratory chain complex genes, and inhibition of mitochondrial biogenesis. CellChat analysis of infected lung epithelial cells and CD8+ T cells found that the galectin signaling pathway played a crucial role in CD8+ T cell reduction and dysfunction. To further elucidate the mechanisms, we established SARS-CoV-2 ORF3a-transfected A549 cells, and co-cultured them with CD8+ T cells for ex vivo experiments. Our results showed that epithelial galectin-3 inhibited the transcription of the mitochondrial respiratory chain complex III/IV genes of CD8+ T cells by suppressing the nuclear translocation of nuclear respiratory factor 1 (NRF1). Further findings showed that the suppression of NRF1 translocation was associated with ERK-related and Akt-related signaling pathways. Importantly, the galectin-3 inhibitor, TD-139, promoted nuclear translocation of NRF1, thus enhancing the expression of the mitochondrial respiratory chain complex III/IV genes and the mitochondrial biogenesis of CD8+ T cells. Our study provided new insights into the immunopathogenesis of COVID-19 and identified potential therapeutic targets for the prevention and treatment of severe/critical COVID-19 patients.

Funder

Department of Science and Technology of Hubei Province

Hubei Talent Program

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference41 articles.

1. The Biological Functions and Clinical Significance of SARS-CoV-2 Variants of Corcern;Front. Med.,2022

2. The Metabolic Changes and Immune Profiles in Patients With COVID-19;He;Front. Immunol.,2020

3. The metabolic and immunological characteristics of pregnant women with COVID-19 and their neonates;Zhou;Eur. J. Clin. Microbiol. Infect. Dis.,2021

4. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19;Liu;Cell,2020

5. Functional exhaustion of antiviral lymphocytes in COVID-19 patients;Zheng;Cell Mol. Immunol.,2020

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