The Lipolysis-Stimulated Lipoprotein Receptor Contributes to Direct and Antibody-Enhanced SARS-CoV-2 Pathogenicity

Severe COVID-19 damages alveolar lung cells that lack the angiotensin-converting enzyme 2 (ACE2) but express the lipolysis-stimulated lipoprotein receptor (LSR). Here we show that LSR enabled SARS-CoV-2 to produce infectious progenies and cause cell death. LSR-mediated cytolysis resulted from cathepsin L cleavage of the spike protein and occurred when the viral load reached a critical threshold. Monoclonal antibodies targeting the ACE2 binding domain did not attenuate LSR-mediated cytolysis. Human IgG induced by COVID-19 and two out of five monoclonals lowered tenfold SARS-CoV-2 cytolytic threshold. Antibody-enhanced cytolysis persisted with variant escaping their ACE2 neutralizing effect. A recombinant decoy of the LSR binding domain (LBDx) selectively suppressed LSR-mediated replication, neutralized cytolysis caused by six variants, and protected primary human pneumocytes from SARS-CoV-2 cytopathic effects. LBDx treatments starting days after a lethal SARS-CoV-2 infection improved K18-hACE2 mouse survival. These findings open novel strategies to tackle severe COVID-19 and investigate post-acute sequelae.

Note:
Funding Information: The work was funded by Genclis SA.

Declaration of Interests: Genclis SA has filed a patent covering the applications of the discoveries reported here; BT, OR, and BEB are employees and shareholders of Genclis SA. Other Genclis employees are indicated. All other authors are affiliated with academic institutions and did not receive compensation from GENCLIS SA.

Ethical Approval Statement: The animal ethic committee approved all procedures (APAFIS project #31992- 2020101616517580 v7) that were performed in the level 3 biological confinement laboratory. br>
Healthy volunteers and moderate Covid-19 patients signed an informed consent authorizing the use of their samples for research purposes. The regulatory approvals for collecting and storing human samples for research were obtained from France’s Ministry of Health (AC2008-449 and CCTIRS 15.616 bis). In the case of severe Covid-19 patients, only oral non-opposition was requested (ClinicalTrials.gov Identifier NCT04405726).

Keywords: SARS-CoV-2, Lipolysis-stimulated lipoprotein receptor, Angiotensin-converting enzyme 2, Free fatty acid, Primary human pneumocytes, Cytolysis, K18-hACE2 mouse

Suggested Citation: Suggested Citation

Pierre, Florian and Jeulin, Hélène and Roitel, Olivier and Thouvenot, Benoit and Bonnard, Lionel and Hartard, Cédric and Tomasina, Julie and Lambert, Delphine and Matelski, Thibaut and Hilselberger, Benoit and Vatier, Pierre and Oster, Thierry and Franck, Patricia and Schvoerer, Evelyne and Berrone, Céline and Moreau, Flavie and Tacquard, Charles and Mertes, Paul-Michel and Yen, Frances T. and Bihain, Bernard E., The Lipolysis-Stimulated Lipoprotein Receptor Contributes to Direct and Antibody-Enhanced SARS-CoV-2 Pathogenicity. Available at SSRN: https://ssrn.com/abstract=4512950 or http://dx.doi.org/10.2139/ssrn.4512950

This version of the paper has not been formally peer reviewed.