Tight junction protein LSR is a host defense factor against SARS-CoV-2 infection in the small intestine
The identification of host factors with antiviral potential is important for developing effective prevention and therapeutic strategies against SARS-CoV-2 infection. Here, by using immortalized cell lines, intestinal organoids, ex vivo intestinal tissues and humanized ACE2 mouse model as proof-of-principle systems, we have identified lipolysis-stimulated lipoprotein receptor (LSR) as a crucial host defense factor against SARS-CoV-2 infection in the small intestine. Loss of endogenous LSR enhances ACE2-dependent infection by SARS-CoV-2 Spike (S) protein-pseudotyped virus and authentic SARS-CoV-2 virus, and exogenous administration of LSR protects against viral infection. Mechanistically, LSR interacts with ACE2 both in cis and in trans, preventing its binding to S protein, and thus inhibiting viral entry and S protein-mediated cell-cell fusion. Finally, a small LSR-derived peptide blocks S protein binding to the ACE2 receptor in vitro. These results identify both a previously unknown function for LSR in antiviral host defense against SARS-CoV-2, with potential implications for peptide-based pan-variant therapeutic interventions.
Authors
- Shu Zhang (ORCID: https://orcid.org/0000-0001-5157-6702)
- Peng Jiao (ORCID: https://orcid.org/0000-0001-9799-3894)
- Shengtian Zhao (ORCID: https://orcid.org/0000-0003-4458-6202)
- Yongfeng Gong (ORCID: https://orcid.org/0000-0001-5151-2346)
- Baozhen Fan
- Hui Sun (ORCID: https://orcid.org/0000-0002-7576-3278)
- Kaige Du
- Yanan An
- Ying Li (ORCID: https://orcid.org/0000-0002-2693-6056)
- Ziqi Wang (ORCID: https://orcid.org/0009-0007-6701-5177)
- Kong Feng
- Liang Yin (ORCID: https://orcid.org/0000-0001-7653-7718)
- Mingxia Wang (ORCID: https://orcid.org/0000-0003-2340-8941)
- Min Jiang (ORCID: https://orcid.org/0000-0001-8418-5847)
- Chao-Yang Wang (ORCID: https://orcid.org/0000-0003-1050-3798)
- Jie Lei
- Chengjun Zhou
- Ti Liu (ORCID: https://orcid.org/0009-0000-0528-9374)
- Hao Liu (ORCID: https://orcid.org/0000-0003-4271-1567)
Institutions
- Binzhou Medical University (CN)
- Shandong University of Aeronautics (CN)
- Shandong University (CN)
- Second Hospital of Shandong University (CN)
- Shandong Provincial Hospital (CN)
- Qilu Hospital of Shandong University (CN)
- Shandong First Medical University (CN)
- Shandong Center for Disease Control and Prevention (CN)
- Shandong Institute of Business and Technology (CN)
Publication Details
- Journal
- The EMBO Journal
- Published
- 2024-10-23
- DOI
- https://doi.org/10.1038/s44318-024-00281-4
- Citations
- 1
- Primary Topic
- COVID-19 Clinical Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 0.39
Funders
- Shandong University
- National Natural Science Foundation of China
- Chinese Academy of Sciences
- Natural Science Foundation of Shandong Province
- Taishan Scholar Foundation of Shandong Province
- Shandong First Medical University