CD147 (BSG) but not ACE2 expression is detectable in vascular endothelial cells within single cell RNA sequencing datasets derived from multiple tissues in healthy individuals

Abstract

Coronavirus disease 2019 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is associated with a wide range of systemic manifestations.Several observations support a role for vascular endothelial dysfunction in the pathogenesis including an increased incidence of thrombotic events and coagulopathy and the presence of vascular risk factors as an independent predictor of poor prognosis. It has recently been reported that endothelitis is associated with viral inclusion bodies suggesting a direct role for SARS-CoV-2 in the pathogenesis. The ACE2 receptor has been shown to mediate SARS-CoV-2 uptake and it has been proposed that CD147 (BSG) can function as an alternative cell surface receptor. To define the endothelial cell populations that are susceptible to infection with SARS-CoV-2, we investigated the expression of ACE2 as well as other genes implicated in the cellular entry of SARS-Cov-2 in the vascular endothelium through the analysis of single cell sequencing data derived from multiple human tissues (skin, liver, kidney, lung and intestine).We found that CD147 (BSG) but not ACE2 is detectable in vascular endothelial cells within single cell sequencing datasets derived from multiple tissues in healthy individuals. This implies that either ACE2 is not expressed in healthy tissue but is instead induced in response to SARS-Cov2 or that SARS-Cov2 enters endothelial cells via an alternative receptor such as CD147.

C-type Lectin CD209L/L-SIGN and CD209/DC-SIGN: Cell Adhesion Molecules Turned to Pathogen Recognition Receptors

“…Human ACE2 is considered an important entry receptor for SARS-CoV-2 [ 76 , 101 , 102 ] and was previously reported to be widely expressed in the lung, vascular system and other organs [ 103 ]. However, a recent study demonstrated that ACE2 is expressed at very low levels and only in a small subset of lung epithelial cells [ 104 ] and low-to-undetectable levels in endothelial cells [ 105 ]. In agreement with the recent observations, our analysis of ACE2 mRNA through the Human Expression Atlas revealed that ACE2 is highly expressed only in intestinal tissues (small intestine, colon and duodenum) and at the low levels in the hearth muscles, kidney, gallbladder and testis, but undetectable in lung ( Figure 4 D).…”

CD209L/L-SIGN and CD209/DC-SIGN act as receptors for SARS-CoV-2

“…is widely expressed in the lung, vascular system and other organs 14 , a recent study demonstrated that ACE2 is expressed at very low levels and only in a small subset of lung epithelial cells 15 and low-toundetectable levels in endothelial cells 16 , suggesting that SARS-CoV-2 entry into and infection of certain human cells may be occurring via alternative receptors or a combination of multiple receptors and/or enhancers Consistent with this idea, Neuropilin receptors [17][18] , CD147/Basigin 19 and heparin sulfate 20 are reported to facilitate SARS-CoV-2 entry. Neuropilin receptors are highly expressed in endothelial and neuronal cells, and play major roles in vascular endothelial growth factor (VEGF)-dependent angiogenesis and semaphorin-dependent axon guidance 21 .…”

Multifunctional angiotensin converting enzyme 2, the SARS-CoV-2 entry receptor, and critical appraisal of its role in acute lung injury

“…Thus, in addition to ACE2, several other membrane components have been proposed to function as co-receptors or attachment sites for SARS-CoV and SARS-CoV-2. These include Cluster of Differentiation 147 (CD147), also known as Basigin (BSG) [ [242] , [243] , [244] , [245] ], Dendritic Cell-Specific Intercellular adhesion molecule-3-Grabbing Non-integrin (DC-SIGN), also known as Cluster of Differentiation 209 (CD209) [ [246] , [247] , [248] , [249] , [250] , [251] ], Neuropilin-1 [ 252 , 253 ], glycosaminoglycans [ 254 ], heparan sulphate [ 255 ], and kidney injury molecule-1 [ 256 ]. Interestingly, in reconstituted lipid membranes devoid of ACE2, binding of the S1 subunit of SARS-CoV-2 spike protein to neutral phospholipid membranes and liposomes was reported to cause mechanical destabilization and membrane permeabilization in a receptor-independent manner [ 257 ].…”