The Understudied Role Of The Ephrin (Eph) Receptor In SARS-CoV-2 Infections And Pathogenesis - A Thailand Medical News Exclusive

COVID-19 News: The COVID-19 pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has shaken the world, and scientists continue to explore the intricacies of this novel virus. Among the numerous receptors involved in viral infections, one receptor has been overlooked but holds great potential in understanding SARS-CoV-2 infections and pathogenesis: the Ephrin (Eph) receptor. There have been very little studies done with regards to SARS-CoV-2 and these ephrin (Eph) receptors and there has been no mention about it in any COVID-19 News reports or discussions between researchers.


Potential role of SARS-CoV-2 with using Eph receptor as entry receptor
and stimulating downstream signaling pathways of Eph receptor in host
cell (especially tumor cells, etc.), leading to progression of cancer or
other diseases. Credit: Dr Hamidreza Zalpoor- Universal Scientific
Education & Research Network (USERN)-Iran

The Ephrin-Eph receptor pathway belongs to the largest superfamily of receptor tyrosine kinases (RTKs) in humans. These receptors play a crucial role in various cellular processes, including adhesion, proliferation, differentiation, and cell migration. Interestingly, Eph receptors and their ligands, ephrins, are widely expressed and highly conserved across different organisms and cell types.
 
When activated, Eph receptors bind to their ligands, initiating a cascade of intracellular signaling events. This activation leads to the phosphorylation of tyrosine residues on the receptors, serving as assembly and activation sites for intracellular signaling proteins.
 
The Eph receptors are classified into two classes: EphA and EphB, which bind to ephrin A and ephrin B ligands, respectively. With ten members in the EphA class and six members in the EphB class, these receptors have been found to be involved in various biological processes.
 
Surprisingly, recent studies have revealed that several RNA viruses, including SARS-CoV-2, exploit EphA2 as their primary entry receptor into host cells. This discovery suggests that the Eph receptor and ephrin ligands may serve as alternative coreceptors for viral entry or modulation of signaling cascades during SARS-CoV-2 and other related coronavirus infections, such as SARS-CoV and Middle East respiratory syndrome (MERS).
 
Beyond viral infections, Eph and ephrin proteins have been implicated in various diseases and conditions, particularly in the central nervous system (CNS). These proteins play critical roles in neurodegenerative diseases, neurodevelopmental disorders, and even wound healing and inflammation. In the CNS, different types of cells express Eph and ephrin, including astrocytes, neural stem cells, neuroblasts, and neurons. This widespread expression suggests that the Ephrin-Eph receptor signaling pathway has a significant impact on neuronal function and disease progression.
 
The intriguing connection between SARS-CoV-2 and the Ephrin-Eph receptor pathway has raised several questions. How does the virus influence these cell surface proteins? What downstream signaling pathways are stimulated by the virus? Could targeting th e Ephrin-Eph receptor pathway be a potential therapeutic strategy against COVID-19 and associated diseases?
 
Recent studies have shed light on these questions, revealing the intricate involvement of Eph receptors and ephrins in SARS-CoV-2 infections. The virus can utilize these receptors for cell entry, viral replication, and persistence. Moreover, activation of the Ephrin-Eph receptor pathway by the virus's spike protein can lead to the emergence or aggravation of neurodegenerative diseases associated with COVID-19.
 
Understanding the signaling pathways triggered by the interaction between SARS-CoV-2 and Ephrin-Eph receptors is crucial for developing targeted therapies. Activation of these receptors can initiate various downstream signaling pathways, including the JAK-signal transducer and activator of transcription (STAT) pathway and MAPK signaling pathways. These pathways regulate immune system responses and inflammation, which play crucial roles in COVID-19 pathogenesis.
 
The potential of Ephrin-Eph receptors as therapeutic targets extends beyond COVID-19. These receptors have been implicated in cancer progression, angiogenesis, vascular permeability, and even heart health. Designing agents or molecules that can target and modulate the Eph/ephrin system holds great potential for the treatment and management of various diseases, including COVID-19 and its associated complications. By specifically targeting Eph receptors and their downstream signaling pathways, it may be possible to disrupt viral entry, inhibit viral replication, and mitigate the detrimental effects of the virus on the host cells.
 
Several approaches can be explored in the development of therapeutic agents targeting the Eph/ephrin system. Small molecules such as polyphenols, doxazosin, and lithocholic acid (LCA) derivatives have shown promise in binding to the ephrin-binding site on Eph receptors. These molecules can potentially interfere with the interaction between Eph receptors and their ligands, thereby disrupting downstream signaling events.
 
Kinase inhibitors represent another avenue for targeting Eph receptors. By inhibiting the activity of the tyrosine kinase domain in Eph receptors, these inhibitors can interfere with phosphorylation events and subsequent intracellular signaling cascades. This approach has shown success in other disease contexts and could be explored for its potential effectiveness against SARS-CoV-2 and associated diseases.
 
Peptide analogs and proteins that specifically target Eph receptors can also be developed as therapeutic agents. These molecules can be designed to bind to Eph receptors with high affinity, effectively blocking the binding of viral particles and interfering with downstream signaling pathways. Specific antibodies against Eph receptors and ephrin ligands may also be developed, offering a targeted and precise approach to modulating Eph/ephrin signaling.
 
The potential benefits of targeting the Eph/ephrin system extend beyond viral infections. Eph receptors have been implicated in various diseases, including cancer, neurodegenerative disorders, and cardiovascular diseases. By developing agents that can selectively modulate the activity of Eph receptors, it may be possible to effectively treat and manage these conditions.
 
To conclude, the Eph/ephrin system represents an intriguing and understudied aspect of SARS-CoV-2 infections. The overlooked receptor potential in viral entry and the modulation of downstream signaling pathways highlight the significance of understanding the interplay between viruses and host cell receptors.
 
Furthermore, the therapeutic potential of targeting Eph receptors and their downstream signaling pathways opens up exciting possibilities for the development of novel treatments not only for COVID-19 but also for a wide range of diseases. Continued research in this field is crucial for unraveling the full potential of the Eph/ephrin system and harnessing it for therapeutic advancements that can positively impact global health.
 
References:
 
Eph Receptor Signaling and Ephrins
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3753714/
 
Ephrin Receptor
https://www.sciencedirect.com/topics/medicine-and-dentistry/ephrin-receptor
 
Emerging Roles for Eph Receptors and Ephrin Ligands in Immunity
https://www.frontiersin.org/articles/10.3389/fimmu.2019.01473/full
 
Reduced expression of erythropoietin-producing hepatocyte B6 receptor tyrosine kinase in prostate cancer
https://www.spandidos-publications.com/10.3892/ol.2015.2925
 
Ephrin-Eph signaling usage by a variety of viruses
https://www.sciencedirect.com/science/article/pii/S1043661820313463
 
Ephrin-A1 and the sheddase ADAM12 are upregulated in COVID-19
https://www.sciencedirect.com/science/article/pii/S2405844021013037
 
Ephrin (Eph) receptor and downstream signaling pathways: a promising potential targeted therapy for COVID‑19 and associated cancers and diseases
https://link.springer.com/article/10.1007/s13577-022-00697-2
 
The roles of Eph receptors, neuropilin-1, P2X7, and CD147 in COVID-19-associated neurodegenerative diseases: inflammasome and JaK inhibitors as potential promising therapies
https://cmbl.biomedcentral.com/articles/10.1186/s11658-022-00311-1
 
Hypoxia‐inducible factor 1 alpha (HIF‐1α) stimulated and P2X7 receptor activated by COVID-19, as a potential therapeutic target and risk factor for epilepsy
https://link.springer.com/article/10.1007/s13577-022-00747-9
 
Differential Gene Expression of Eph Receptors and Ephrins in Benign Human Tissues and Cancers
https://academic.oup.com/clinchem/article/50/3/490/5639809
 
ephrinB1 signals from the cell surface to the nucleus by recruitment of STAT3
https://www.pnas.org/doi/abs/10.1073/pnas.0702337104
 
Structural and non-structural proteins in SARS-CoV-2: potential aspects to COVID-19 treatment or prevention of progression of related diseases
https://biosignaling.biomedcentral.com/articles/10.1186/s12964-023-01104-5
 
Predicted structural mimicry of spike receptor-binding motifs from highly pathogenic human coronaviruses
https://www.sciencedirect.com/science/article/pii/S2001037021002798
 
Ephrin Ligands are Upregulated in the Saliva of SARS-CoV-2 Infected Patients
https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fasebj.2022.36.S1.R6055
 
Ephrin Receptor A4 is a New Kaposi’s Sarcoma-Associated Herpesvirus Virus Entry Receptor
https://journals.asm.org/doi/10.1128/mBio.02892-18
 
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