SARS-CoV-2 Entry: At the Crossroads of CD147 and ACE2.

Claudio Fenizia,Tiziana Daniele,Silvia Galbiati,Mario Clerici,Carlo Tacchetti,Claudia Vanetti,Riccardo Vago

doi:10.3390/cells10061434

Abstract

In late 2019, the betacoronavirus SARS-CoV-2 was identified as the viral agent responsible for the coronavirus disease 2019 (COVID-19) pandemic. Coronaviruses Spike proteins are responsible for their ability to interact with host membrane receptors and different proteins have been identified as SARS-CoV-2 interactors, among which Angiotensin-converting enzyme 2 (ACE2), and Basigin2/EMMPRIN/CD147 (CD147). CD147 plays an important role in human immunodeficiency virus type 1, hepatitis C virus, hepatitis B virus, Kaposi’s sarcoma-associated herpesvirus, and severe acute respiratory syndrome coronavirus infections. In particular, SARS-CoV recognizes the CD147 receptor expressed on the surface of host cells by its nucleocapsid protein binding to cyclophilin A (CyPA), a ligand for CD147. However, the involvement of CD147 in SARS-CoV-2 infection is still debated. Interference with both the function (blocking antibody) and the expression (knock down) of CD147 showed that this receptor partakes in SARS-CoV-2 infection and provided additional clues on the underlying mechanism: CD147 binding to CyPA does not play a role; CD147 regulates ACE2 levels and both receptors are affected by virus infection. Altogether, these findings suggest that CD147 is involved in SARS-CoV-2 tropism and represents a possible therapeutic target to challenge COVID-19.

Highlights

In December 2019, a new member of the beta genus of coronaviruses was identified and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) because of its similarity to SARS-CoV [1]
To test whether SARS-CoV-2 infection depends on the same mechanism, we treated CaLu3 cells with an anti-CD147 antibody able to block the immunophilin binding to the receptor [17] before cell incubation with the virus, and evaluated infection efficiency
These results suggest that cyclophilin A (CyPA) binding to CD147 does not play a role in virus entry and that CD147 role in SARS-CoV-2 is likely different from the one in SARS-CoV infection

Summary

Introduction

In December 2019, a new member of the beta genus of coronaviruses was identified and named severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) because of its similarity to SARS-CoV [1]. At the end of 2020, Wang et al reported for the first time the interaction between SARS-CoV-2 Spike protein and the host cell receptor CD147, and showed that modulation of the receptor levels affected the ability of the virus to infect target cells They showed that CD147 receptor was involved in SARS-CoV-2 infection of immune cells, which do not express ACE2, and proposed this pathway as a novel entry route [6]. We show that the CD147-CyPA complex does not play a role in SARS-CoV-2 infection, and demonstrate that silencing of CD147 reduces viral entry into pulmonary cells, either directly or indirectly via the reduction of the levels of expression of ACE2 These results indicate that the CD147 pathway of infection followed by SARS-CoV and SARS-CoV-2 is different, and suggest the potential usefulness of targeting CD147 in preventing COVID-19

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Results

Conclusion