BREAKING! SARS-CoV-2 Upregulates Proteins ADGRD1/GPR133 And ADGRG7/GPR128 That Are Linked To Cancer Progression!

COVID-19 News: The COVID-19 pandemic, caused by the novel coronavirus SARS-CoV-2, has sparked intense research efforts globally to understand its pathogenesis and identify potential therapeutic targets. Recent studies have explored the involvement of adhesion G protein-coupled receptors (aGPCRs) in viral infections, shedding light on their potential role in SARS-CoV-2 infection. This COVID-19 News report delves into the findings of a study conducted by researchers from the Czech Academy of Sciences and Charles University in Prague, Czech Republic, which investigated the upregulation of specific aGPCRs in SARS-CoV-2-infected lung adenocarcinoma cells.

Infection with SARS-CoV-2 increased the mRNA expression of several aGPCRs. (A) Heatmap of relative mRNA expression of aGPCRs in cells of the lung adenocarcinoma cell line Calu-3 and of the colorectal adenocarcinoma cell line Caco-2. Lighter shades represent low relative expression (high ΔCt values) and darker shades stand for high relative expression (low ΔCt values). Relative expression changes in the aGPCRs in cells of the Calu-3 (B) and Caco-2 (C) cell lines upon infection with SARS-CoV-2. Calu-3 and Caco-2 cells were infected with SARS-CoV-2 with MOI of 2 and harvested 6 and 12 h post infection (h.p.i.). The values shown represent means of three (Calu-3 cells) and six (Caco-2 cells) independent biological replicates. Outliers were identified and eliminated based on the ROUT method (Q = 1%). aGPCRs with significantly altered relative expression upon infection with SARS-CoV-2 at an MOI of 2 in cells of the Calu-3 (D) and Caco-2 (E) cell lines according to ANOVA. The graphs present medians with the interquartile range from three (Calu-3 cells) and six (Caco-2 cells) independent biological replicates performed in technical duplicates. The relative expression of aGPCRs at 6 h.p.i. and 12 h.p.i. vs. 0 h.p.i. and 6 h.p.i. vs. 12 h.p.i. were compared by one-way ANOVA (n = 3 for Calu-3 cells and n = 6 for Caco-2 cells, * p < 0.05, ** p < 0.01) in GraphPad Prism 10.0.2.

Understanding Adhesion G Protein-Coupled Receptors (aGPCRs)
Adhesion G protein-coupled receptors (aGPCRs) are a diverse class of cell surface receptors that regulate various physiological processes, including organogenesis, angiogenesis, neurodevelopment, immune defense, and cancer progression.
 
Adhesion G protein-coupled receptors (aGPCRs) form the second-largest category among G protein-coupled receptors (GPCRs), playing pivotal roles in various biological processes like organ development, blood vessel formation (angiogenesis), brain development (neurodevelopment), immune system defense, and the progression of cancer.
 
Within humans, there are 33 identified members of the aGPCR class. Despite most being classified as orphan receptors due to their unknown functions, recent research has associated three aGPCRs with specific human diseases. These diseases include Usher syndrome type II, a common condition marked by combined deafness and blindness; bilateral frontoparietal polymicrogyria, a congenital brain abnormality; and vibratory urticaria, a skin condition characterized by allergic reactions to vibration.
 
Moreover, aGPCRs have been linked to diverse pathophysiological phenomena such as infertility, issues with embryonic development leading to lethality, psychiatric disorders, and various types of cancers like glioblastoma, leukemia, and lymphoma. These findings underscore the significance of aGPCRs in human health and disease.
 
The Unexplored Role of aGPCRs in Viral Infections
Despite their significance in human health and disease, the role of aGPCRs in viral infections has largely remained unexplored until recently. Viruses often exploit host cell receptors, including G protein-coupled receptors (GPCRs), to facilitate entry and replication within host cells. Understanding how viruses interact with aGPCRs can provide valuable insights into viral pathogenesis and potential therapeutic interventions.
 
Investigating aGPCRs in SARS-CoV-2 Infection
The study focused on identifying specific aGPCRs involved in SARS-CoV-2 infection using human epithelial cell lines derived from lung adenocarcinoma (Calu-3) and colorectal carcinoma (Caco-2). The researchers infected these cell lines with SARS-CoV-2 and analyzed changes in mRNA levels of individual aGPCRs post-infection.
 
The researchers identified four potential aGPCR candidates, namely ADGRB3/BAI3, ADGRD1/GPR133, ADGRG7/GPR128, and ADGRV1/GPR98. Among these receptors, ADGRD1/GPR133 and ADGRG7/GPR128 exhibited the most significant rise in mRNA levels within SARS-CoV-2-infected Calu-3 cells.
 
Interestingly, there was no increase observed when cells were exposed to heat-inactivated SARS-CoV-2 or virus-cleared conditioned media. Subsequently, employing specific siRNA, we reduced the expression of these aGPCR candidates and thoroughly assessed their impact on SARS-CoV-2 entry, replication, and infectivity across both cell lines. The outcomes were remarkable: cells with diminished levels of ADGRD1/GPR133 and ADGRG7/GPR128 demonstrated a noteworthy decrease in newly released SARS-CoV-2 into the culture medium. Additionally, employing a plaque assay, we observed a decline in SARS-CoV-2 infectivity specifically in Calu-3 cells.
 
In essence, the study findings show that aGPCRs protein expressions of ADGRD1/GPR133 And ADGRG7/GPR128 were upregulated during SARS-CoV-2 infections and hint at a plausible role for selected aGPCRs in the context of SARS-CoV-2 infection in mammalian cells.

Role of ADGRD1/GPR133 and ADGRG7/GPR128 in SARS-CoV-2 Infection
Further experiments involved downregulating ADGRD1/GPR133 and ADGRG7/GPR128 using specific siRNA to assess their impact on SARS-CoV-2 entry, replication, and infectivity. The results indicated a significant decrease in SARS-CoV-2 replication and infectivity in cells with downregulated ADGRD1/GPR133 and ADGRG7/GPR128, suggesting a potential role for these aGPCRs in facilitating viral infection.
 
Mechanisms of SARS-CoV-2 Entry and Interaction with Host Cells
The study also explored the mechanisms through which SARS-CoV-2 enters host cells, highlighting the importance of the angiotensin-converting enzyme 2 (ACE2) receptor and TMPRSS2 proteases in viral entry. Additionally, hypotheses were proposed regarding the modulation of GPCR signaling pathways by SARS-CoV-2, potentially affecting lung cell function and contributing to disease pathogenesis.
 
Comparative Analysis and Relevance of Findings
A comparative analysis of aGPCR expression data from published RNAseq datasets corroborated the upregulation of ADGRD1/GPR133 in SARS-CoV-2-infected cells, further supporting the relevance of this aGPCR in viral infections. While ADGRG7/GPR128 showed varied expression patterns across datasets, the study underscored the need for continued research into the role of aGPCRs in viral pathogenesis.
 
Implications for Future Research and Therapeutic Development
The findings from this study provide valuable insights into the interplay between aGPCRs and SARS-CoV-2 infection. Further research into the mechanisms underlying aGPCR-mediated viral interactions could lead to the development of targeted therapies for COVID-19 and other viral infections. Moreover, understanding the broader role of aGPCRs in viral pathogenesis may unveil novel therapeutic strategies against emerging infectious diseases.
 
The study findings also have serious and alarming implications, as it indicates that SARS-CoV-2 infections can cause the new onset of certain cancers and also accelerate the progression of existing cancers due the upregulation of these proteins.
 
Conclusion
In conclusion, the study highlights the potential involvement of ADGRD1/GPR133 and ADGRG7/GPR128 in SARS-CoV-2 infection and underscores the importance of exploring aGPCRs as potential therapeutic targets in viral infections. Continued research in this area could yield valuable insights into host-virus interactions and inform the development of innovative antiviral strategies.
 
The study findings were published in the peer reviewed journal: Cells.
https://www.mdpi.com/2073-4409/13/10/791
 
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