Journal Article

ACE2-dependent and -independent SARS-CoV-2 entries dictate viral replication and inflammatory response during infection

Xing, Changsheng, Duan, Tianhao, Qian, Chen, Hu, Yuzhou, Yin, Bingnan, Deng, Xiangxue, Wang, Helen Y., Wang, Rong-Fu, Chu, Junjun, Liu, Xin, Du, Yang

2024

Overview

Excessive inflammation is the primary cause of mortality in patients with severe COVID-19, yet the underlying mechanisms remain poorly understood. Our study reveals that ACE2-dependent and -independent entries of SARS-CoV-2 in epithelial cells versus myeloid cells dictate viral replication and inflammatory responses. Mechanistically, SARS-CoV-2 NSP14 potently enhances NF-κB signalling by promoting IKK phosphorylation, while SARS-CoV-2 ORF6 exerts an opposing effect. In epithelial cells, ACE2-dependent SARS-CoV-2 entry enables viral replication, with translated ORF6 suppressing NF-κB signalling. In contrast, in myeloid cells, ACE2-independent entry blocks the translation of ORF6 and other viral structural proteins due to inefficient subgenomic RNA transcription, but NSP14 could be directly translated from genomic RNA, resulting in an abortive replication but hyperactivation of the NF-κB signalling pathway for proinflammatory cytokine production. Importantly, we identified TLR1 as a critical factor responsible for viral entry and subsequent inflammatory response through interaction with E and M proteins, which could be blocked by the small-molecule inhibitor Cu-CPT22. Collectively, our findings provide molecular insights into the mechanisms by which strong viral replication but scarce inflammatory response during the early (ACE2-dependent) infection stage, followed by low viral replication and potent inflammatory response in the late (ACE2-independent) infection stage, may contribute to COVID-19 progression. Duan et al. show that ACE2-dependent and ACE2-independent entry of SARS-COV-2 in epithelial cells versus myeloid cells differentially regulates viral replication and inflammatory responses, thereby contributing to COVID-19 progression and pathology.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/109 / 13/89 / 13/95 / 14/19 / 38/22 / 38/23 / 38/77 / 38/90 / 631/250/256 / 631/250/516/1909 / 631/80/304 / 64/60 / 82/29 / 82/80 / 82/83 / ACE2 / Angiotensin-Converting Enzyme 2 / Biomedical and Life Sciences / Cancer Research / Cell Biology / COVID-19 / COVID-19 - metabolism / COVID-19 - virology / Developmental Biology / Epithelial cells / Epithelium / Host-Parasite Interactions / Humans / Infections / Inflammation / Inflammatory response / Life Sciences / Myeloid cells / NF-kappa B - metabolism / NF-κB protein / Phosphorylation / Proteins / Replication / SARS-CoV-2 - physiology / Severe acute respiratory syndrome coronavirus 2 / Signal transduction / Stem Cells / Structural proteins / TLR1 protein / Toll-like receptors / Viral diseases / Virus Replication