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L-SIGN is a receptor on liver sinusoidal endothelial cells for SARS-CoV-2 virus
Yuji Kondo1, Jason L Larabee2, Liang Gao1
1Cardiovascular Biology Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma, USA.
Abstract:
Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), remains a pandemic. Severe disease is associated with dysfunction of multiple organs, but some infected cells do not express ACE2, the canonical entry receptor for SARS-CoV-2. Here, we report that the C-type lectin receptor L-SIGN interacted in a Ca2+-dependent manner with high-mannose-type N-glycans on the SARS-CoV-2 spike protein. We found that L-SIGN was highly expressed on human liver sinusoidal endothelial cells (LSECs) and lymph node lymphatic endothelial cells but not on blood endothelial cells. Using high-resolution confocal microscopy imaging, we detected SARS-CoV-2 viral proteins within the LSECs from liver autopsy samples from patients with COVID-19. We found that both pseudo-typed virus enveloped with SARS-CoV-2 spike protein and authentic SARS-CoV-2 virus infected L-SIGN-expressing cells relative to control cells. Moreover, blocking L-SIGN function reduced CoV-2-type infection. These results indicate that L-SIGN is a receptor for SARS-CoV-2 infection. LSECs are major sources of the clotting factors vWF and factor VIII (FVIII). LSECs from liver autopsy samples from patients with COVID-19 expressed substantially higher levels of vWF and FVIII than LSECs from uninfected liver samples. Our data demonstrate that L-SIGN is an endothelial cell receptor for SARS-CoV-2 that may contribute to COVID-19-associated coagulopathy.
Insights
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the L-SIGN receptor on liver cells to infect cells, contributing to COVID-19 coagulopathy.
Area of Science:
- Immunology
- Virology
- Pathology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19, a pandemic associated with multi-organ dysfunction.
- The canonical SARS-CoV-2 entry receptor, ACE2, is not expressed on all infected cells, suggesting alternative entry pathways.
- Liver sinusoidal endothelial cells (LSECs) play a role in COVID-19-associated coagulopathy through vWF and FVIII production.
Purpose of the Study:
- To identify novel cellular receptors for SARS-CoV-2.
- To investigate the role of L-SIGN in SARS-CoV-2 infection of endothelial cells.
- To explore the potential link between L-SIGN-mediated SARS-CoV-2 infection and COVID-19-associated coagulopathy.
Main Methods:
- Investigated the interaction between SARS-CoV-2 spike protein and L-SIGN using Ca2+-dependent binding assays.
- Assessed L-SIGN expression on various human endothelial cells.
- Utilized high-resolution confocal microscopy to detect SARS-CoV-2 proteins in LSECs from COVID-19 patient autopsy samples.
- Performed viral infection assays using pseudotyped and authentic SARS-CoV-2 on L-SIGN-expressing cells.
- Evaluated the effect of L-SIGN blocking on viral infection.
- Measured vWF and FVIII levels in LSECs from COVID-19 patients.
Main Results:
- L-SIGN binds to high-mannose N-glycans on the SARS-CoV-2 spike protein in a Ca2+-dependent manner.
- L-SIGN is highly expressed on LSECs and lymph node lymphatic endothelial cells, but not blood endothelial cells.
- SARS-CoV-2 viral proteins were detected within LSECs from COVID-19 patient liver autopsy samples.
- L-SIGN-expressing cells showed increased susceptibility to SARS-CoV-2 infection.
- Blocking L-SIGN function reduced SARS-CoV-2 infection.
- LSECs from COVID-19 patients exhibited significantly higher levels of vWF and FVIII.
Conclusions:
- L-SIGN serves as an endothelial cell receptor for SARS-CoV-2.
- L-SIGN-mediated infection of LSECs may contribute to the coagulopathy observed in COVID-19 patients.
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