Host cell entry mediators implicated in the cellular tropism of SARS‑CoV‑2, the pathophysiology of COVID‑19 and the identification of microRNAs that can modulate the expression of these mediators (Review)

Abstract

The pathophysiology of coronavirus disease 2019 (COVID‑19) is mainly dependent on the underlying mechanisms that mediate the entry of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) into the host cells of the various human tissues/organs. Recent studies have indicated a higher order of complexity of the mechanisms of infectivity, given that there is a wide‑repertoire of possible cell entry mediators that appear to co‑localise in a cell‑ and tissue‑specific manner. The present study provides an overview of the 'canonical' SARS‑CoV‑2 mediators, namely angiotensin converting enzyme 2, transmembrane protease serine 2 and 4, and neuropilin‑1, expanding on the involvement of novel candidates, including glucose‑regulated protein 78, basigin, kidney injury molecule‑1, metabotropic glutamate receptor subtype 2, ADAM metallopeptidase domain 17 (also termed tumour necrosis factor‑α convertase) and Toll‑like receptor 4. Furthermore, emerging data indicate that changes in microRNA (miRNA/miR) expression levels in patients with COVID‑19 are suggestive of further complexity in the regulation of these viral mediators. An in silico analysis revealed 160 candidate miRNAs with potential strong binding capacity in the aforementioned genes. Future studies should concentrate on elucidating the association between the cellular tropism of the SARS‑CoV‑2 cell entry mediators and the mechanisms through which they might affect the clinical outcome. Finally, the clinical utility as a biomarker or therapeutic target of miRNAs in the context of COVID‑19 warrants further investigation.

Keywords: ACE2; ADAM17; COVID‑19; GRP78; NPR1; SARS‑CoV2; TLR4; TMPRSS2; TMPRSS4; miRNAs.

Figure 1

Schematic diagram of the known pathways facilitating the entry of SARS-CoV-2 into host cells. The SARS-CoV-2 spike (S) glycoproteins are instrumental for this process; S1 (being the cell connecting head of the molecule) binds to the ACE2 receptor, while S2 mediates the viral-cell membrane fusion by being exposed to TMPRSS2 and TMPRSS4 or other host cell proteases, such as furin, that is cleaved at the S1-S2 junction and allows the binding of S1 to NRP1. Additional molecules, including TLR4, CD147 and GRP78, have also been proposed as potential SARS-CoV-2 cell entry mediators. SARS-CoV2, severe acute respiratory syndrome coronavirus 2; ACE2, angiotensin converting enzyme 2; NPR1, neuropilin-1; TMPRSS2 and 4, transmembrane protease serine 2 and 4; TLR4, Toll-like receptor 4; GRP78, glucose-regulated protein 78; CD147, basigin (BSG).

Figure 2

Venn diagram describing shared miRNAs between NRP1, GRP78, ADAM17 and TLR4. NRP1 and ADAM17 share three common miRNAs: hsa-miR-148a-3p, hsa-miR-152-3p and hsa-miR-148b-3p. TLR4 and NRP1 share one common miRNA, hsa-miR-587; whereas TLR4 and GRP78 share hsa-miR-338-5p as a common miRNA.

Figure 3

Distribution and co-localisation of all potential cell entry mediators. BSG, basigin (CD147); HSPA5, heat shock protein A5; ADAM17, ADAM metallopeptidase domain 17 (also termed tumour necrosis factor-α convertase); TMPRSS2 and 4, transmembrane protease serine 2 and 4; ACE2, angiotensin converting enzyme 2; GRM2, glutamate receptor subtype 2 (mGluR2); HAVCR1, hepatitis A virus cellular receptor 1 (also termed kidney injury molecule-1, KIM1).