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

doi:10.1038/s41556-024-01388-w

. 2024 Apr;26(4):628-644.

doi: 10.1038/s41556-024-01388-w. Epub 2024 Mar 21.

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

Tianhao Duan^#¹, Changsheng Xing^#¹, Junjun Chu^#¹, Xiangxue Deng², Yang Du¹, Xin Liu¹, Yuzhou Hu², Chen Qian¹, Bingnan Yin¹, Helen Y Wang^{1

3}, Rong-Fu Wang^{4

5

6

7}

Affiliations

¹ Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rongfuwa@usc.edu.
⁵ Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rongfuwa@usc.edu.
⁶ Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rongfuwa@usc.edu.
⁷ Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rongfuwa@usc.edu.

^# Contributed equally.

PMID: 38514841
DOI: 10.1038/s41556-024-01388-w

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

Tianhao Duan et al. Nat Cell Biol. 2024 Apr.

. 2024 Apr;26(4):628-644.

doi: 10.1038/s41556-024-01388-w. Epub 2024 Mar 21.

Authors

Tianhao Duan^#¹, Changsheng Xing^#¹, Junjun Chu^#¹, Xiangxue Deng², Yang Du¹, Xin Liu¹, Yuzhou Hu², Chen Qian¹, Bingnan Yin¹, Helen Y Wang^{1

3}, Rong-Fu Wang^{4

5

6

7}

Affiliations

¹ Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
² Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
³ Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
⁴ Department of Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rongfuwa@usc.edu.
⁵ Department of Molecular Microbiology and Immunology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rongfuwa@usc.edu.
⁶ Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rongfuwa@usc.edu.
⁷ Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA. rongfuwa@usc.edu.

^# Contributed equally.

PMID: 38514841
DOI: 10.1038/s41556-024-01388-w

Abstract

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.

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References

1. Guan, W.-J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720 (2020). - PubMed - DOI
1. Hoehl, S. et al. Evidence of SARS-CoV-2 infection in returning travelers from Wuhan. China 382, 1278–1280 (2020).
1. Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). - PubMed - PMC - DOI
1. Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). - PubMed - PMC - DOI
1. Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020). - PubMed - PMC - DOI

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[1] Guan, W.-J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720 (2020). - PubMed - DOI

[2] Guan, W.-J. et al. Clinical characteristics of coronavirus disease 2019 in China. N. Engl. J. Med. 382, 1708–1720 (2020). - PubMed - DOI

[3] Hoehl, S. et al. Evidence of SARS-CoV-2 infection in returning travelers from Wuhan. China 382, 1278–1280 (2020).

[4] Hoehl, S. et al. Evidence of SARS-CoV-2 infection in returning travelers from Wuhan. China 382, 1278–1280 (2020).

[5] Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). - PubMed - PMC - DOI

[6] Wu, F. et al. A new coronavirus associated with human respiratory disease in China. Nature 579, 265–269 (2020). - PubMed - PMC - DOI

[7] Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). - PubMed - PMC - DOI

[8] Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270–273 (2020). - PubMed - PMC - DOI

[9] Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020). - PubMed - PMC - DOI

[10] Zhu, N. et al. A novel coronavirus from patients with pneumonia in China, 2019. N. Engl. J. Med. 382, 727–733 (2020). - PubMed - PMC - DOI

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

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

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