BREAKING! COVID-19 Research: Study Challenge Claims That SARS-CoV-2 Infects Lung Cells Through ACE-2. New Receptors CD147 And GRP78 Involved
Source: COVID-19 Research Aug 12, 2020 4 years, 4 months, 1 week, 3 days, 8 hours, 36 minutes ago
COVID-19 Research: Scientists from University of Waterloo, McMaster University, University of British Columbia, University of Nottingham, and Okinawa Institute of Science are now challenging previous accepted findings about how the SARS-CoV-2 coronavirus affects lungs. It was previously assumed that all entry of SARS-CoV-2 into cells occurs through a receptor on the cell surface, known as ACE2. But the collaborative team of researchers found that the ACE2 receptor is at very low levels in human lung tissue.
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Dr Jeremy Hirota, Assistant Professor, Medicine, McMaster University told Thailand Medical News, “Our finding is somewhat controversial, as it suggests that there must be other ways, other receptors for the virus, that regulate its infection of the lungs. We were surprised that the fundamental characterization of the candidate receptors in human lung tissue had not yet been done in a systematic way with modern technologies."
Co-lead Andrew Doxey, Professor of Biology at the University of Waterloo. "Finding such low levels of ACE2 in lung tissue has important implications for how we think about this virus. ACE2 is not the full story and may be more relevant in other tissues such as the vascular system."
The researchers that found that other receptors could also perhaps facilitate SARS-CoV-2 binding and entry into the cells including ADAM17, cathepsin L, CD147, and GRP78.
The research paper and the findings were published in the European Respiratory Journal after being reviewed by numerous other researchers in Molecular Systems Biology and represents a major research finding wit again massive findings and literally changes the whole ‘game.’
https://erj.ersjournals.com/content/early/2020/07/06/13993003.01123-2020
In the study, in order to determine the expression and
in situ localization of candidate SARS-CoV-2 receptors in the respiratory mucosa, the study team analyzed gene expression datasets from airway epithelial cells of 515 healthy subjects, gene promoter activity analysis using the FANTOM5 dataset containing 120 distinct sample types, single cell RNA sequencing (scRNAseq) of 10 healthy subjects, proteomic datasets, immunoblots on multiple airway epithelial cell types, and immunohistochemistry on 98 human lung samples.
The team demonstrated absent to low ACE2 promoter activity in a variety of lung epithelial cell samples and low
ACE2 gene expression in both microarray and scRNAseq datasets of epithelial cell populations.
Consistent with gene expression, rare ACE2 protein expression was observed in the airway epithelium and alveoli of human lung, confirmed with proteomics.
The researchers presented confirmatory evidence for the presence of TMPRSS2, CD147, and GRP78 protein
in vitro in airway epithelial cells and confirm broad
in situ protein expression of CD147 and GRP78 in the respiratory mucosa.
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Proposed functions of host airway epithelial cell molecules for interaction with SARS-CoV-2. Proteins associated (or suggested to be associated) with host cell entry of SARS-CoV-2 and the activation of the SARS-CoV-2 spike protein (SARS-S) are displayed. ACE2 is suggested as the primary SARS-S receptor for viral entry (interaction of ACE2 receptor-binding domain (RBD) with SARS-S leading to endosomal viral uptake) followed by activation of SARS-S via pH-dependent CTSL-mediated cleavage. Secondary methods of viral entry and SARS-S activation are likely to involve proteases (e.g. TMPRSS2 and ADAM17) and/or secondary receptors (CD147 and GRP78). Dashed lines indicate mechanisms that have not been fully validated. Figure adapted from with updates and additional information on candidate host molecules. Created with BioRender.com.
As a whole the research data suggest the presence of a mechanism dynamically regulating ACE2 expression in human lung, perhaps in periods of SARS-CoV-2 infection, and also suggest that alternate receptors for SARS-CoV-2 exist to facilitate initial host cell infection.
The researchers concluded, “Our data demonstrate rare ACE2 protein expression in human airway epithelial cells
in vitro and
in situ, consistent with low ACE2 promoter activity and
ACE2 gene expression in bronchial epithelial cells. We present confirmatory evidence for the presence of TMPRSS2, CD147, and GRP78 protein
in vitro in airway epithelial cells and confirm broad
in situ protein expression of CD147 and GRP78 in the respiratory mucosa. Due to the overwhelming evidence that SARS virus interacts with ACE2, there are likely to be alternate mechanisms regulating ACE2 in the respiratory mucosa in the context of SARS-CoV-2 infection, and/or, perhaps other co-receptors, beyond what is expressed under basal conditions at the protein level.”
The new study could have massive ramifications even current drug, antibody and vaccine developments as the identified possible receptors of the SARS-CoV-2 coronavirus such as CD147 and GRP78 have different types of cellular mechanisms.
We would like readers to note that Thailand Medical News brought attention to these two receptors in two articles as early as the 9
th of March and the 15
th of March.
https://www.thailandmedical.news/news/breaking-preprint-research-shows-that-sars-cov-2-has-third-binding-mode,-making-it-a-truly-potent-coronavirus-that-is-in-a-league-of-its-own
https://www.thailandmedical.news/news/breaking-new-coronavirus-research-shows-that-the-sars-cov-2-coronavirus-has-a-fourth-route-of-attacking-human-host-cells-making-it-a-real-super-virus
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