BREAKING! COVID-19 News: Scientists Discover That SARS-CoV-2 Spike Protein Activates the Epidermal Growth Factor Receptor-Mediated Signaling!

COVID-19 News: Scientists from United Arab Emirates University-UAE have in a new study shockingly found that the SARS-CoV-2 spike 1 proteins are able to activate the EGFR or Epidermal Growth Factor Receptor-mediated signaling.


Image Credit: Kateryna Kon/Shutterstock

The study findings has numerous implications in both pathogenesis of SARS-CoV-2 and also in Post COVID dangers.
 
The ongoing COVID-19 pandemic is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). At the molecular and cellular levels, the SARS-CoV-2 uses its envelope glycoprotein, the spike S protein, to infect the target cells in the lungs via binding with their transmembrane receptor, the angiotensin-converting enzyme 2 (ACE2).
 
While it is already an established fact that SARS-CoV-2 primarily targets the ACE2 receptors for viral entry, it is also known to bind to various other receptors in the human host.
 
Co-receptors/attachment factors, such as neuropilins, heparan sulfate, and sialic acids or putative alternative receptors, such as CD147 and GRP78 are also believed be involved in the entry of SARS-CoV-2 and contribute to tropism.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7652413/
 
This has already been covered in past COVID-19 News coverages.

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
 
https://www.thailandmedical.news/news/must-read-covid-19-research-sars-cov-2-virus-can-target-332-human-proteins,-have-variety-of-binding-sites-40-new-prospective-drug-candidates-identifie

https://www.thailandmedical.news/news/breaking-news-covid-19-research-shows-that-sars-cov-2-spike-proteins-also-targets-nicotine-acetycholine-receptors-in-human-host,-massive-alarming-impl
 
g-covid-19-research-study-challenge-claims-that-sars-cov-2-infects-lung-cells-through-ace-2-new-receptors-cd147-and-grp78-involved">https://www.thailandmedical.news/news/breaking-covid-19-research-study-challenge-claims-that-sars-cov-2-infects-lung-cells-through-ace-2-new-receptors-cd147-and-grp78-involved
 
https://www.thailandmedical.news/news/breaking-coronavirus-news-saudi-arabia-study-shows-that-dopamine-receptors-might-be-targeted-by-sars-cov-2-coronavirus
 
https://www.thailandmedical.news/news/covid-19-news-u-s-nih-funded-study-discovers-that-sars-cov-2-spike-protein-binds-and-modulates-estrogen-receptors,-increasing-risk-of-thrombosis
 
https://www.thailandmedical.news/news/study-reveals-sars-cov-2-also-binds-with-stra6-receptors,-providing-explanation-for-symptoms-and-long-covid-conditions-with-unknown-aetiology
 
https://www.thailandmedical.news/news/study-reveals-sars-cov-2-binding-to-host-dpp4-receptors-causes-dysregulation-of-proteins-associated-with-diabetes,-leading-to-severe-covid
 
https://www.thailandmedical.news/news/breaking-university-of-sydney-study-discovers-a-new-receptor-lrrc15-that-binds-with-sars-cov-2-and-suppresses-infection-and-regulates-fibrosis
 
Other suspected possible receptors include the the G protein-coupled receptors (GPCRs) and receptor tyrosine kinase (RTKs) due to their tissue abundance and pivotal roles in human and animal physiology.
 
Numerous past studies reported the hijacking of GPCRs and RTKs and their function by various pathogens during pathogenesis. This includes microbial pathogens such as bacteria and viruses such as the SARS-CoV and the adrenergic receptor and the epidermal growth factor receptor (EGFR) as the targets .
https://pubmed.ncbi.nlm.nih.gov/28390872/

https://www.frontiersin.org/articles/10.3389/fcell.2019.00200/full

https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.201600701R
 
Hence the study team hypothesize that during SARS-CoV-2 infectivity, the virus may also use EGFR expressed on the epithelial lung cells as the receptor/co-receptor target for its entry.
 
The study team investigated if other molecular targets and pathways may be used by SARS-CoV-2.
 
The study team focused on the possibility of the spike 1 S protein and its receptor-binding domain (RBD) to target the epidermal growth factor receptor (EGFR) and its downstream signaling pathway in vitro.
 
As a cellular model, the study team used cancer cell lines known for their expression of EGFR and differential expression of ACE-2 including ACE-2 expressing lung (A549) and colon (HT-29) cancer cell and ACE-2 non-expressing Cervix (HeLa) adenocarcinoma cells.
 
The study team examined the effect of the full-length SARS-CoV-2 and RDB Spike 1 protein on the activation of EGFR and its related downstream signaling pathways consisting of AKT and ERK1/2 phosphorylation in ACE2 expressing lung (A549).
 
Protein expression and phosphorylation were examined upon cell treatment with the recombinant full spike 1 S protein or RBD.
 
Shockingly, the study findings showed the activation of EGFR by the Spike 1 protein associated with the phosphorylation of the canonical Extracellular signal-regulated kinase1/2 (ERK1/2) and AKT kinases and an increase in survivin expression controlling the survival pathway.
 
The study findings suggest the putative implication of EGFR and its related signaling pathways in SARS-CoV-2 infectivity and COVID-19 pathology. This may open new perspectives in the treatment of COVID-19 patients by targeting EGFR.
 
The study findings were published in the peer reviewed journal:
https://www.mdpi.com/2076-393X/11/4/768#B22-vaccines-11-00768
 
The study findings revealed for the first time thehijacking of EGFR and its related downstream signaling pathways by SARS-CoV-2 Spike 1 protein and its RBD in lung cancer cells (A549).
 
The study findings demonstrated that Spike 1-induced AKT activation occurred in an EGFR-dependent manner since it was drastically blocked by AG1478.
 
The study findings also showed that that Spike 1 and RBD also elicited the activation of the survival pathway in A549 cells.
 
Interestingly, both Spike 1 and RBD induced the expression and the activation of the anti-apoptotic protein, survivin, which belongs to the inhibitor of apoptosis (IAP) family and is considered the key marker for the activation of the survival pathway in cancer cells.
 
Such a response was very consistent with the phosphorylation of AKT in these cancer cells. Such a response was very consistent with the phosphorylation of AKT in these cancer cells.
 
This may constitute a solid molecular and cellular rationale to explain the increased risk of infectivity by SARS-CoV-2 and its severity in cancer patients as recently reported by several groups.
https://pubmed.ncbi.nlm.nih.gov/35121871/
 
https://pubmed.ncbi.nlm.nih.gov/32345594/
 
The study findings correlated with recent studies that showed cancer patients were more vulnerable to the SAR-COV-2 infection. Although COVID-19 was reported to have a low death rate of ~2% in the general population, patients with cancer and COVID-19, have at least a three-fold increase in the death rate.
 
One study showed that patients with lung cancer, gastrointestinal cancer, or breast cancer had the highest frequency of critical symptoms including the highest death rates. Patients with lung cancer and gastrointestinal cancer had a death rate of 18.18% and 7.69%, respectively. Interestingly, they showed that cancer patients that received targeted therapy that includes the EGFR-tyrosine kinase inhibitors showed the lowest death rate compared to cancer patients who received immunotherapy, chemotherapy, or surgery.
https://pubmed.ncbi.nlm.nih.gov/32345594/
 
A study carried out at the Gustave Roussy Cancer Centre (France) showed that 27% of the cancer patients with COVID-19 developed clinical worsening and 17.4% died.
https://pubmed.ncbi.nlm.nih.gov/35121871/
 
Here, the current study team showed that SARS-CoV-2 activates the EGFR and its downstream signaling pathways controlling cell survival and proliferation. The study findings also showed that the inhibition of EGFR abolished the SARS-CoV-2 activation of AKT.
 
The in vitro study findings at the molecular level, for the first time provides evidence that SARS-CoV-2 Spike 1 protein activates EGFR and its downstream signaling pathways, AKT and ERK1/2. This is very consistent with the well-established concept of the hijacking of cell surface receptors and their activity/signaling by pathogens including viruses and bacteria.
https://www.sciencedirect.com/science/article/pii/S2352396418301919
 
https://www.sciencedirect.com/science/article/abs/pii/S0006295216300028
 
https://www.nature.com/articles/nrm1529
 
https://pubmed.ncbi.nlm.nih.gov/21183077/
 
This implies that pathogens use GPCRs and RTKs at the cell surface of the target cells during the infection process leading to their entry into the target cells.
 
Past studies also showed the role of EGFR and its downstream signaling pathways in viruses/bacteria pathogenicity being consistent with the findings on SARS-CoV-2 spike protein.
https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.201600701R
 
Interestingly, EGFR was shown to be important during influenza infection.
https://www.frontiersin.org/articles/10.3389/fcell.2019.00200/full

Similarly, to the current study data, the Salmonella Rck membrane protein has been reported to bind and activate EGFR and its mediated signaling resulting in receptor/bacteria co-internalization and cell infection.
https://faseb.onlinelibrary.wiley.com/doi/abs/10.1096/fj.201600701R
 
This also occurs with GPCRs since both viruses and bacteria were demonstrated to bind and activate GPCRs resulting in the co-internalization of viruses or bacteria with the target receptors.
https://www.nature.com/articles/nrm1529
 
https://pubmed.ncbi.nlm.nih.gov/21183077/
 
The current study findings showed that the Spike 1-induced AKT activation occurred in an EGFR-dependent manner in A549 cells since it was blocked by EGFR blockade (AG1478). This supports the conclusion that the activation of the AKT/survival axis by Spike 1 depends on EGFR activation. Moreover, the differential effects of Spike 1 and RBD suggests a different mode of activation and/or molecular pathways involved.
 
A possible explanation is that Spike 1 may directly target EGFR while RBD uses other targets at the cancer cell surface including ACE2 resulting in AKT and ERK1/2 phosphorylation independently of EGFR.
 
The time-course analysis indicated interesting differences in the phosphorylation kinetics in A549 cells when compared EGFR, AKT, and ERK1/2, on one side and Spike 1 versus RBD on the other. Indeed, Spike 1 mediated EGFR and ERK1/2 phosphorylation in a transient manner since it was observed within 5 minutes of stimulation and declined after. This was different with EGF inducing the phosphorylation at 15 minutes of stimulation. However, AKT phosphorylation was more sustained and remained significantly high even after 60 minutes of stimulation. The effect of RBD on AKT and ERK1/2 phosphorylation was more or less similar to Spike 1. However, and surprisingly, RBD did not promote any EGFR phosphorylation. This suggests the implication of other EGFR-independent pathways with or without the implication of ACE2. This aspect requires further investigation.
 
The study findings are consistent with direct targeting of the EGFR/AKT pathway, but this does not rule out the alternative pathway consisting of the implication of the canonical ACE2 pathway via transactivation of EGFR at the cell surface or intracellular crosstalk between their intracellular pathways. Of course, further studies are required to demonstrate whether Spike protein directly binds to EGFR or not and what would be the implication of the canonical ACE2 pathway.
 
Although the study team did not investigate all the aspects of EGFR-dependent pathways and SARS-CoV-2 infectivity, it is believed that the study findings will pave the way for further investigation of the exact role of EGFR in SARS-CoV-2 infection and pathogenicity.
 
The study using cancer cells reveals a possible molecular basis for COVID-19′s complications and severity observed in cancer patients by considering EGFR as a potential target for the management of such pathological and clinical situations.
 
More importantly, urgent studies are warranted to see if SARS-CoV-2 spike 1 hijacking of the EGFR will lead to over expression or damaged EGFR that could contribute to cancer development or cancer acceleration in Post COVID individuals.
 
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