Role of TOMM34 on NF-κB activation-related hyperinflammation in severely ill patients with COVID-19 and influenza

作者：Qiwen Shi, Pengfei Zhang, Qingtao Hu, Tianxin Zhang, Ruixia Hou, Shengxiang Yin, Yilin Zou, Fenghua Chen, Shuang Jiao, Lanlan Si, Bangjin Zheng, Yichao Chen, Tingzhu Zhan, Yongxiang Liu, Wenting Zhu, Nan Qi · 发表于：EBioMedicine · 年份：2024 · DOI：10.1016/j.ebiom.2024.105343 · 被引用次数：11 · 研究领域：COVID-19 Clinical Research Studies、interferon and immune responses、RNA regulation and disease

BACKGROUND: Highly pathogenic respiratory RNA viruses such as SARS-CoV-2 and its associated syndrome COVID-19 pose a tremendous threat to the global public health. Innate immune responses to SARS-CoV-2 depend mainly upon the NF-κB-mediated inflammation. Identifying unknown host factors driving the NF-κB activation and inflammation is crucial for the development of immune intervention strategies. METHODS: Published single-cell RNA sequencing (scRNA-seq) data was used to analyze the differential transcriptome profiles of bronchoalveolar lavage (BAL) cells between healthy individuals (n = 27) and patients with severe COVID-19 (n = 21), as well as the differential transcriptome profiles of peripheral blood mononuclear cells (PBMCs) between healthy individuals (n = 22) and severely ill patients with COVID-19 (n = 45) or influenza (n = 16). Loss-of-function and gain-of-function assays were performed in diverse viruses-infected cells and male mice models to identify the role of TOMM34 in antiviral innate immunity. FINDINGS: TOMM34, together with a list of genes encoding pro-inflammatory cytokines and antiviral immune proteins, was transcriptionally upregulated in circulating monocytes, lung epithelium and innate immune cells from individuals with severe COVID-19 or influenza. Deficiency of TOMM34/Tomm34 significantly impaired the type I interferon responses and NF-κB-mediated inflammation in various human/murine cell lines, murine bone marrow-derived macrophages (BMDMs) and in vivo....