SARS-CoV-2 Disrupts Human RNA Expression, Splicing and Polyadenylation Mechanisms. Extreme Effects Seen in Severe Cases
Nikhil Prasad Fact checked by:Thailand Medical News Team Apr 20, 2025 16 hours, 21 minutes ago
Medical News: Severe COVID Alters Genes and Blood Signals in Ways That Could Explain Why Some Get Critically Ill
In a major scientific breakthrough, researchers from Canada and the United States have uncovered significant changes in gene activity, RNA splicing, and polyadenylation patterns in the blood of patients suffering from severe and critical COVID-19. This detailed study sheds new light on how the virus hijacks the human body at the molecular level, potentially explaining why some people become dangerously ill while others recover quickly.
SARS-CoV-2 Disrupts Human RNA Expression, Splicing and Polyadenylation Mechanisms.
Extreme Effects Seen in Severe Cases
The massive study was conducted by experts from the Research Centre of the Centre Hospitalier de l’Université de Montréal (CRCHUM), Université de Montréal, McGill University, Genome Quebec, the Jewish General Hospital, and the University of California, San Francisco. It examined blood samples from 739 hospitalized, unvaccinated COVID-19 patients in Canada, separated into moderate (367 patients), severe (173 patients), and critical (199 patients) categories. Using advanced RNA sequencing and bioinformatics tools, the team analyzed how COVID-19 severity impacts gene expression and post-transcriptional RNA modifications in the bloodstream. This
Medical News report explores their findings in detail.
Gene Expression Increases with Disease Severity
The researchers found that as COVID-19 progresses from moderate to severe and critical, the number of altered genes in the blood increases dramatically. In severe cases, 90 genes showed significant changes in activity, with most being upregulated. In critical cases, this number surged to 674 genes. The gene S100A9, linked to inflammation and immune response, and ZDHHC19, involved in immune signaling, were especially overexpressed in critical patients and were confirmed through RT-qPCR analysis.
Interestingly, immunoglobulin genes like IGKV4-1 and IGKV1-39—important for the body’s antibody response—were highly expressed in severe patients but not as much in moderate ones. This suggests an overactive or dysregulated immune reaction in more serious cases.
Rare RNA Splicing Events Spike in Critical Patients
One of the most striking findings was the surge in alternative splicing (AS) events, especially of a rare type called “mutually exclusive exons” (MXEs), in critical patients. AS is a process where RNA segments are stitched together in different ways, producing various protein versions from the same gene. While moderate cases showed fewer splicing alterations, critical patients had over 10,000 splicing events, and more than 78% of these were MXEs.
This rare form of splicing could significantly change how certain proteins function or interact with other cellular machinery. In particular, genes like ADGRE2, IKZF1, and SON were spliced differently in critical cases. SON is linked to neu
rological disorders, further supporting concerns about COVID-19’s effects on the brain, especially in the most severely ill patients.
Changes in Polyadenylation Suggest Further Gene Control Disruption
Besides splicing, the team also looked at alternative polyadenylation (APA), a lesser-known but equally important process that controls how long the tail of an RNA molecule is. This tail affects how long the RNA lasts and how much protein it can produce.
In severe cases, only minor APA changes were observed. But in critical patients, 94 genes showed significant lengthening of the poly(A) tail, and 16 genes had shortened tails. Interestingly, genes like SARAF and PTMA had longer tails but were less active—suggesting a dysfunctional RNA processing mechanism.
Moreover, several human leukocyte antigen (HLA) genes—crucial for immune system function—were found to be altered in critical patients through APA changes. HLA-E, in particular, showed consistent changes in tail length with increasing disease severity.
Key Genes Affected on All Fronts in Critical Patients
Perhaps the most important discovery was the identification of 11 genes that were altered at all three levels—gene expression, splicing, and polyadenylation—in critical patients. These include:
-TUBA4A: Involved in cytoskeleton structure
-NRGN: Related to brain signaling
-BSG and CD300A: Linked to immune regulation
-EVI2B: Associated with immune cell differentiation
These genes play vital roles in inflammation, neuronal development, and immune function—offering a potential explanation for the neurological and systemic complications seen in severe COVID-19.
Inflammatory Pathways Strongly Enriched in Critical Illness
Using KEGG pathway analysis, the researchers mapped how these gene alterations influence biological processes. In critical patients, over 260 biological pathways were disrupted, including many associated with immune signaling, cytokine storms, apoptosis, and cellular stress responses.
Key immune pathways such as IL-17, Toll-like receptor, TNF, and chemokine signaling were all hyperactive in critical cases. These pathways have been linked to the uncontrolled inflammation seen in severe COVID-19, which can cause lung damage, organ failure, and death.
Why This Matters for Diagnosis and Treatment
By integrating data on gene expression, RNA splicing, and polyadenylation, the study presents a comprehensive view of how COVID-19 wreaks havoc at the molecular level. It reveals a gradual increase in transcriptomic chaos as disease severity escalates. This layered disruption of gene regulation likely contributes to why some patients develop complications like neurological damage, immune system collapse, or prolonged illness.
Importantly, many of these changes were detected in blood samples—making it feasible to develop new diagnostic tools or biomarkers. For instance, tracking the presence of specific MXE splicing events or measuring the levels of genes like S100A9 or EVI2B could help doctors predict who is at risk of developing critical illness.
Conclusions
This landmark study provides a multi-dimensional view of the molecular chaos triggered by COVID-19, especially in patients who become critically ill. It shows that gene activity does not simply increase or decrease, but becomes wildly distorted through rare splicing events and alterations in RNA tail processing. These disruptions impact immune function, inflammation, and possibly the brain, offering a scientific explanation for the severe complications seen in critical COVID-19 cases. The study also highlights the potential for using blood-based transcriptomic markers to guide clinical decision-making. As COVID-19 continues to evolve and long COVID remains a concern, these findings may pave the way for more precise diagnostics and targeted treatments. However, further research and validation in diverse populations are needed before these discoveries can be translated into clinical practice.
The study findings were published in the peer reviewed journal: Scientific Reports.
https://www.nature.com/articles/s41598-025-95905-y
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