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 over-view 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.

The Transmembrane Protease TMPRSS2 as a Therapeutic Target for COVID-19 Treatment

“…This process is required for TMPRSS2 activation of S at the S2 site upon receptor binding and is crucial for infecting cells of the respiratory tract [13,[76][77][78][79]. Of note, in addition to TMPRSS2 several other TTSPs were able to prime SARS-CoV-2 S in vitro [80][81][82]. Although based on their expression levels TMPRSS11D, TMPRSS11E and TMPRSS11F as well as TMPRSS13 are unlikely to act in the lung, they might contribute to the extrapulmonary spread of SARS-CoV-2 [83].…”

Human Cell Organelles in SARS-CoV-2 Infection: An Up-to-Date Overview

“…In the human cell culture, the infectivity of SARS-CoV-2 was enhanced by NRP1 due to increased entry into human cells [ 64 , 65 ]. The other possible co-factor of SARS-CoV-2 cell invasion is metabotropic glutamate receptor subtype 2 (mGluR2), which binds directly to the S protein [ 66 ]. A study of the mGluR2 knockout mice reported decreased infectivity of SARS-CoV-2 among mice lacking the receptor.…”

“…However, further analysis of this entry pathway is needed to evaluate its exact role. Other compounds involved in SARS-CoV-2 cell entry are heat shock protein A5 (HSAP5), basigin (CD147), heparan sulfate (HS), ADAM metallopeptidase domain 17 (ADAM17), and Toll-like receptor 4 (TLR4) [ 66 , 69 , 70 , 71 ].…”

“…Nanobodies and mini proteins that interact with S protein are also being investigated [ 72 ]. The surfactant protein D (SP-D) is physiologically involved in innate immune response, clearing the respiratory tract from pathogens and necrotic cells [ 66 , 75 ]. In vitro studies showed that SP-D could recognize the S protein of SARS-CoV-2 and inhibit cell invasion [ 76 ].…”

Increased Serum Mir-150-3p Expression Is Associated with Radiological Lung Injury Improvement in Patients with COVID-19

“…Viruses 2022, 14, 1363 2 of 11 MicroRNAs (miRNAs) are a class of small non-coding RNAs (22 nucleotides) with the function of controlling specific genes by modulating the pathways to which the target genes belong. miRNAs can modulate the function of various cells and are involved in the pathophysiology of responses to viral infections [4,5] and respiratory diseases [6,7]. In addition, these molecules have been used as biomarkers of diverse diseases [8,9].…”