COVID-19 Causes Gene Expression Changes in Immune Cells

Medical News: A groundbreaking study conducted by researchers from the Universidad Cooperativa de Colombia, Universidad de Antioquia, and Corporación Universitaria Remington in Medellín, Colombia, has provided novel insights into the intricate immune responses triggered by SARS-CoV-2. Through detailed analysis of gene expression in peripheral blood mononuclear cells (PBMCs), the team has uncovered key biological processes that shape the immune system's reaction to the virus and the gene expression changes that occur in the immune cells.


COVID-19 Causes Gene Expression Changes in Immune Cells

Decoding the Immune Response
Peripheral blood mononuclear cells, comprising immune cells like lymphocytes (T-cells, B-cells) and monocytes, play a critical role in combating infections. In this study, researchers exposed these cells to SARS-CoV-2 in a controlled laboratory setting and used RNA sequencing (RNA-seq) technology to monitor changes in gene expression. This approach allowed for a granular look at how the virus affects immune cells, even when it does not actively replicate within them.
 
The study covered in this Medical News report, identified 790 genes with altered expression in the exposed PBMCs compared to unexposed control cells. Of these, 733 were protein-coding messenger RNAs (mRNAs), which direct cellular machinery to produce proteins, and 57 were long non-coding RNAs (lncRNAs), which regulate gene activity without coding for proteins. The altered genes were primarily associated with immune activation, inflammation, antiviral defenses, and metabolic changes.
 
The Role of Inflammation
One of the most striking findings was the significant upregulation of genes involved in inflammatory pathways. This included a marked increase in pro-inflammatory cytokines such as IL-6 and IL-1β, which are often elevated in patients experiencing severe COVID-19 complications. These cytokines contribute to what is commonly referred to as a "cytokine storm," a hyperactive immune response that can lead to organ damage and death in critical cases.
 
The researchers also observed increased expression of chemokines, signaling molecules that recruit immune cells to infection sites. Genes like CCL8 and CXCL8 (also known as IL-8) were significantly activated, suggesting enhanced immune cell migration. This mechanism is essential for mounting an effective immune response but can also exacerbate inflammation if unregulated.
 
Antiviral Responses and the IL-27 Pathway
Beyond inflammation, the study highlighted unique antiviral mechanisms activated in PBMCs exposed to SARS-CoV-2. Specifically, genes associated with the IL-27 signaling pathway were upregulated. IL-27, a cytokine, plays a dual role in regulating inflammation and promoting antiviral defenses. The researchers found that IL-27-mediated pathways triggered the expression of several interferon-stimulated genes (ISGs), which help the body combat viral infections.
 
Interestingly, unlike previous studies that emphasized type I and III interferon responses in severe COVID-19, this research demonstrated that ISGs could be activated independently of interferon production through IL-27. Genes like RSAD2, which encodes an antiviral protein known to inhibit viral replication, were notably upregulated. This discovery highlights an alternative pathway for immune activation, potentially offering new therapeutic strategies.
 
Non-Coding RNAs as Key Regulators
A particularly novel aspect of this study was its focus on long non-coding RNAs (lncRNAs) and their role in immune regulation. These RNA molecules do not code for proteins but influence the activity of other genes. Several lncRNAs were found to have strong correlations with immune and antiviral genes, indicating their potential role as regulators.
 
For example, the lncRNA LINC00487 showed a positive correlation with RSAD2, suggesting that it may enhance the antiviral response. Similarly, LINC02154 was linked to TLR8, a gene that detects viral RNA and triggers downstream immune responses. These findings underscore the importance of lncRNAs in fine-tuning the immune system's reaction to SARS-CoV-2 and their potential as therapeutic targets.
 
Metabolic Changes and Immune Activation
The study also delved into metabolic changes in PBMCs exposed to SARS-CoV-2. Viral infections are known to hijack host cell metabolism to support replication and immune activation. In this study, genes involved in glucose and amino acid metabolism were significantly altered. For instance, increased expression of genes like IDO1 and HK2 suggests that SARS-CoV-2 exposure reprograms cellular metabolism to meet the energy demands of an activated immune system.
 
These metabolic shifts are a double-edged sword. While they support the immune response, they may also contribute to excessive inflammation and tissue damage. Understanding these metabolic pathways could lead to interventions that restore balance without compromising immune defense.
 
Transcription Factors and Gene Regulation
The researchers identified several transcription factors that were activated in response to SARS-CoV-2 exposure. These include STAT1, NF-κB, and AP-1, all of which play critical roles in inflammation and antiviral defense. For example, STAT1 is a key mediator of ISG activation, while NF-κB and AP-1 drive the expression of pro-inflammatory cytokines.
 
Interestingly, the study also noted the activation of anti-inflammatory pathways. Transcription factors like ATF3, which suppresses excessive inflammation, were upregulated. This suggests a natural mechanism to counterbalance the inflammatory response, although it may not always be sufficient to prevent severe symptoms.
 
Individual Variability in Immune Responses
A unique aspect of the study was its observation of individual variability in gene expression profiles. Cells from one donor showed a markedly stronger upregulation of inflammatory and antiviral genes compared to others. This finding may help explain why COVID-19 manifests so differently among patients, with some experiencing mild symptoms and others facing life-threatening complications. Future research could explore whether these genetic differences could be used to predict disease severity or tailor treatments.
 
Implications for Therapeutic Development
The discovery of IL-27 as a key player in immune activation offers a promising avenue for therapeutic interventions. Drugs that modulate the IL-27 pathway could enhance antiviral defenses without triggering excessive inflammation.
 
Similarly, targeting lncRNAs like LINC00487 could provide a novel approach to boosting the immune response or reducing inflammation.
 
Additionally, the study's insights into metabolic reprogramming suggest potential for therapies that restore metabolic balance. For instance, targeting glucose metabolism in immune cells could help reduce inflammation without impairing their ability to fight the virus.
 
Conclusion
This study provides a comprehensive view of how SARS-CoV-2 interacts with the immune system, highlighting both the beneficial and harmful aspects of the response. Key findings include the activation of inflammatory and antiviral pathways, the unique role of IL-27 in immune regulation, and the involvement of non-coding RNAs in fine-tuning these processes.
 
The researchers conclude that PBMCs play a pivotal role in shaping the immune response to SARS-CoV-2. While these cells do not support productive viral replication, their gene expression changes significantly influence the course of infection. The study emphasizes the need for further research to validate these findings in clinical settings and explore their potential for therapeutic applications.

By identifying critical pathways and regulatory molecules, this research opens doors to new strategies for managing COVID-19, particularly in severe cases. Targeting specific genes, proteins, or RNAs involved in the immune response could help mitigate the disease's impact while preserving the body's ability to fight off the virus.
 
The study findings were published in the preprint journal: PLOS ONE.
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0314754
 
For the latest COVID-19 News, keep on logging to Thailand Medical News.
 
Read Also:
https://www.thailandmedical.news/news/neutrophil-dysfunction-linked-to-long-covid-symptoms-in-children
 
https://www.thailandmedical.news/news/lingering-cd19-b-cell-depletion-effects-of-covid-19
 
https://www.thailandmedical.news/news/immune-system-responses-in-mild-covid-19-cases-revealed-through-key-genes