BREAKING! COVID-19 News: SARS-CoV-2 Infections Lead To Cellular m6A RNA Methylation Loss In Host Cells! Possible Implications For Cancer And Other Issues!

COVID-19 News: A new international study has alarmingly found that SARS-CoV-2 infections lead to cellular m6A RNA methylation loss in host cells!


 
The discovery is worrisome as accumulating evidence suggests that m6A RNA methylation modulates gene expression, thereby regulating cellular processes ranging from cell self-renewal, differentiation, invasion and apoptosis. Loss of m6A RNA methylation in infected host cells can lead to cancer and also other health issues including premature aging and the rise of aging related diseases.
https://molecular-cancer.biomedcentral.com/articles/10.1186/s12943-019-1109-9
 
https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1009086
 
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9065606/
 
https://www.nature.com/articles/s41392-020-00450-x
 
The study was conducted by researchers from Sahlgrenska University Hospital, Gothenburg University-Sweden, Institut Pasteur, Université Paris Cité-France, Development and Genetics (MRDG), Indian Institute of Sciences (IISc), Bengaluru-India, Gangnam Severance Hospital, Yonsei University College of Medicine-Korea, Karolinska Institutet-Sweden.
 
According to the study team, host-viral interactions during SARS-CoV-2 infection are needed to understand COVID-19 pathogenesis and long-term effects of such viral infections.
 
N6-methyladenosine modification (m6A), one of the most abundant cellular RNA modifications, regulates key processes in RNA metabolism during a stress response.
 
Importantly, gene expression profiles observed post-infection with different SARS-CoV-2 variants show changes in the expression of genes related to RNA catabolism, including m6A readers and erasers.
 
Shockingly, the study team found that infection with SARS-CoV-2 variants caused a loss of m6A in cellular RNAs, whereas m6A was detected abundantly in viral RNA. METTL3, the m6A methyltransferase, showed an unusual cytoplasmic localization post-infection.
 
The B.1.351 variant had a less pronounced effect on METTL3 localization and loss of m6A than the B.1 and B.1.1.7 variants.
 
The study team also observed a loss of m6A upon SARS-CoV-2 infection in air/liquid interface cultures of human airway epithelia, confirming that m6A loss is characteristic of SARS-CoV-2 infected cells.
 
Subsequent, transcripts with m6A modification were preferentially down-regulated post-infection. Inhibition of the export protein XPO1 resulted in the restoration of METTL3 localization, recovery of m6A on cellular RNA, and increased mRNA expression. Stress granule formation, which was compromised by SARS-CoV-2 infection, was restored by XPO1 inhibition and accompanied by a reduced viral infection in vitro.
 
The study findings elucidate how SARS-CoV-2 inhibits the stress response and perturbs cellular gene expression in an m6A-dependent m anner.
 
The study findings were published on a preprint server and are currently being peer reviewed.
https://www.biorxiv.org/content/10.1101/2022.12.08.519593v1
 
The study findings add to growing evidence to Thailand Medical News’ hypothesis that has been covered in past COVID-19 News coverages that claim majority exposed to the SARS-CoV-2 virus will only have about 5 to 8 years left as the virus causes the damage and dysfunction of over 380 cellular pathways, genes and critical host proteases! Those that are subjected to constant reinfections, will have their lifespans even shortened!

https://www.thailandmedical.news/news/breaking-hypothesis-that-majority-exposed-to-sars-cov-2-will-have-shortened-lifespans-validated-by-study-showing-nsp2-impairs-human-4ehp-gigyf2-comple
 
https://www.thailandmedical.news/news/most-who-have-been-exposed-to-the-proteins-of-the-sars-cov-2-virus-will-have-shortened-lifespans-stop-using-fluvoxamine-for-ba-2-infections
 
The study team observed in particular that genes associated with RNA catabolism tended to be upregulated in infected Vero cells.
 
Worryingly, several genes associated with the m6A pathway, including m6A readers and m6A erasers, were deregulated as well during infection.
 
Interestingly, changes in the RNA splicing pattern of m6A related genes were recently reported after acute depletion of METTL3, which was interpreted as a feedback loop to compensate for the acute depletion of m6A.
https://pubmed.ncbi.nlm.nih.gov/34131006/
 
It was found that in SARS-CoV-2 infected cells, depletion of m6A following METTL3 relocalization and loss of functional METTL3/METTL14 complex in the nucleus probably activates a similar feedback loop, which could explain why genes involved in RNA catabolism and m6A modification were preferentially deregulated.
 
The study team’s combined analysis of differentially expressed genes and change in m6A peak abundance suggests that, in general, loss of m6A peaks correlates with decreased RNA expression.
 
However, it is important to consider that loss of m6A was more widespread than mRNA decrease in the infected cells, and thus that loss of m6A did not always lead to decreased gene expression.
 
Urgent and detailed studies are needed to decipher the mechanisms that dictate how loss of m6A influences gene expression during viral infection.
 
Although the study team pointed out DEU events in the subset of genes with m6A loss, further study is required to understand the effect of m6A loss on the other cellular genes that show no change in expression.
 
The study findings also showed that m6A containing genes were more prone to down-regulation during infection in both Vero and HBE infection models.
 
It should be noted that the SARS-CoV-2 Nsp1 protein has been shown to inhibit nuclear export of cellular RNAs during infection and to promote host mRNA decay.
https://pubmed.ncbi.nlm.nih.gov/34315815/
 
https://pubmed.ncbi.nlm.nih.gov/33547084/
 
The nuclear export of cellular RNA is known to be regulated by m6A in an YTHDC1- and Nuclear RNA Export Factor 1- (NFX1) dependent manner.
 
However, it has been found that viral protein Nsp1 also inhibits NFX1 function, resulting in the retention of cellular mRNAs in the nucleus during SARS-CoV-2 infection.
https://pubmed.ncbi.nlm.nih.gov/33547084/
 
It will be interesting to determine if the loss of m6A and Nsp1-mediated inhibition of NFX1 act synergistically to cause nuclear retention of cellular mRNAs during infection, and if mRNAs retained in the nucleus might be more prone to rapid degradation.
 
Utilizing a strand-specific m6A RIP-seq approach, the study team found that both the viral genomic RNA (positive strand) and replicative negative-strand RNAs carried m6A modification.
 
Interestingly, in the human bronchial epithelium model, the study team detected a robust m6A peak signal in genomic RNA at 4- and 7- dpi. The m6A peaks were also present in the replicative negative strand at 4- dpi, but not at day 7, presumably because viral replication had already abated at this time point.
 
A past study showed that m6A peaks could be detected on negative-strand of SARS-CoV-2 using m6 A RIP-seq, but not with the m6A-CLIP (CrossLinking and Immunoprecipitation) technique.
https://pubmed.ncbi.nlm.nih.gov/33510385/
 
The researchers of that study suggested lack of m6A detection could be due to the limited coverage of the negative strand in CLIP data.
 
However, findings from the current study from Vero and human bronchial epithelium infection models suggest the presence of m6A peaks in the negative strand, future experiments using m6A-CLIP in the human cell infection model will be required to precisely identify the specific residues modified by m6A.
 
Viral RNA m6A modification is known to have a pro-viral effect by allowing escape from RIG-I binding and limiting the induction of inflammatory gene expression.
 
As RIG-I is known to be activated by viral double-stranded replicative intermediates, it will be interesting to check if the m6A modifications detected in the replicative negative strand of SARS-CoV-2 contribute to an escape mechanism from RIG-I.
 
Although the majority of m6A peaks were similar across the three SARS-CoV-2 variants studied, there were m6A peaks that were specific to particular variants.
 
Future detailed studies will be required to understand if the differences in m6A modification across variants contribute to changes in pathogenicity by differential recruitment of m6A reader proteins or by modulating the RIG-I-dependent escape mechanisms described above.
 
Thailand Medical News would like to add that to date, there are more than 78,000 published studies that reflect as to how the SARS-CoV-2 virus affects and disrupts more than 380 cellular pathways, genes and critical host proteases and yet not a single health authority or mainstream media is warning people about the dangers of these to their long-term health and their lifespans or even about the threats of cancer etc. All the talks about Long COVID research and focus on therapeutics is but a farce as the studies and data are already out there and it is just a matter of collating that data properly and then focusing on the development of proper therapeutics…though it might be a bit difficult and also very expensive as long COVID has to be approached from a personalized medicine approach as the conditions varies in every single individuals based on their own genetics and also the degree of damage and which cellular pathways, genes and proteases have been affected in each individual by exposure to the SARS-CoV-2 virus. If nothing is properly initiated now, we will continue to see an increase in excess deaths globally especially more so in coming years.
 
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