The severe acute respiratory syndrome (SARS) like coronaviruses SARS-CoV and SARS-CoV-2 utilize the human cell surface carboxypeptidase angiotensin-converting enzyme 2 (ACE2) as entry receptor (Donoghue et. al. 2000, Li et. al. 2003, Hoffmann et. al. 2020).
Angiotensin-converting enzyme ACE2 is a zinc dependent metalloprotease anchored in the cell membrane. It is part of the Renin-Angiotensin-Aldosterone System (RAAS) and Kinin-Kallikrein System (KKS) and therefore involved in regulation of vasodilation, inflammation, tissue repair and cell proliferation (Cooper et. al. 2021). ACE2 is expressed in intestines, kidney, heart, adipose tissue, lungs, and blood vessels to different levels (Cooper et. al. 2021).
Interaction with the cellular receptor is mediated by the receptor binding domain (RBD) on the S1 subunit of the coronaviral spike (S) glycoprotein (Li et. al. 2003, Du et. al. 2009, Hoffmann et. al. 2020). SARS-CoV-2 infectivity is augmented by the cell surface receptor neuropilin-1, potentially facilitating virus-receptor interactions in respiratory and olfactory cells with low ACE2 expression (Cantuti-Castelvetri et. al. 2020). Beside the main cell surface receptor ACE2, SARS-CoV viruses can also bind to host cell receptors DC-SIGN (dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin) and L (liver/lymph node) - SIGN, promoting the infection of cells with low or absent ACE2 expression (Amraei et. al. 2021, Du et. al. 2009). After establishment of the receptor interaction, the S glycoprotein undergoes priming by the host protease furin at S1/S2 and transmembrane protease serine protease -2 (TMPRSS) at the S2’ site as a prerequisite for the fusion of viral and cellular membranes (Hoffmann et. al. 2020, Vkovski et. al. 2021, Hoffmann et. al. 2020 - 2). SARS-CoV-2 can also be internalized via the clathrin-mediated endocytosis (Jackson et. al. 2022).
Antibodies raised against the spike protein prevent SARS-CoV-2 infection and demonstrate the crucial role of its interaction with the host cell receptor for infection initiation (Hoffmann et. al. 2020).
The Virus Entry Receptor Binding (VERB) assay developed by Covirabio mimics the major initiation step of SARS-CoV-2 infection which is the binding of the virus to ACE2 on the surface of host cells.
References
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