Long Non-Coding RNAs May Have Key Role in COVID-19 Cytokine Storms

Coronavirus disease of the lungs, conceptual illustration

Long non-coding RNA molecules (lncRNAs) are thought to affect the progress of several diseases, possibly through anti-viral inflammatory response regulation. In this study, researchers from the Azrieli Faculty of Medicine of Bar-Ilan University sought to identify lncRNAs co-expressed with human genes involved in immune-related processes during severe SARS-CoV-2 infection in the lungs.

The study was published in the journal Viruses.

Recent studies show that compared to patients with mild symptoms, patients with severe SARS-CoV-2 infections present increased levels of pro-inflammatory plasma cytokines. This suggests the release of inflammatory cytokines could be central to COVID-19 severity.

Why this happens is still unknown, but the response it is thought to be characterized by a “cytokine storm” induced by the interleukin-6 (I6) amplifier. That molecule regulates the nuclear factor kappa B (NF-κB) pathway and is stimulated by the activation of IL-6-signal transducer and activator of transcription 3 (STAT3) and NF-κB signaling in non-immune cells including alveolar epithelial cells and endothelial cells. (Hojyok, S et al. Inflamm Regen, Oct. 1, 2020. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527296/)

The Azrieli researchers’ work suggests that lncRNAs are indeed potential regulators of anti-viral response during severe SARS-CoV-2 infection. Using the available transcriptome data from the lung cells of severely affected COVID-19 patients and SARS-CoV-2 infected lung-cell-lines, they constructed a gene co-expression network to measure the relationship of gene expression patterns across groups of samples.

They write, “We analyzed the mRNA-long non-coding RNA (lncRNA) co-expression network derived from publicly available SARS-CoV-2-infected transcriptome data of human lung epithelial cell lines and bronchoalveolar lavage fluid (BALF) from COVID-19 patients. Through co-expression network analysis, we identified four differentially expressed lncRNAs strongly correlated with genes involved in various immune-related pathways crucial for cytokine signaling.”

The four differentially expressed lncRNAs were strongly correlated to the protein-coding genes in a novel network enriched for different immune-related processes associated with dysregulated cytokine production. These four lncRNAs were also identified as “hubs”—important nodes in this co-expression network, signifying their association with cytokine over-production due to fierce immune response.

The study results suggest that the aberrant expression of lncRNAs can be associated with cytokine storms and anti-viral responses during severe SARS-CoV-2 infection. As a result, this points to the potential associations of lncRNAs in cytokine and interferon signaling during the response to severe SARS-CoV-2 infection in the lungs. This could provide valuable insight into pro-inflammatory cytokine production and how to mitigate it. It could also potentially point toa  future drug target to combat the hyper-inflammation caused by SARS-CoV-2 infection.

“It is remarkable that a major part of the human genome is filled in by non-coding regulatory elements, formerly known as “junk DNA”. Among these are the long non-coding RNAs (lncRNAs). These lncRNAs are receiving more and more recognition as the potential regulators of several diseases,” says Milana Frenkel-Morgenstern, of Bar-Ilan University’s Azrieli Faculty of Medicine, who led the study with David Karasik.

This study sheds light on the mechanisms behind COVID-19 severity and dysfunctional immune responses. Understanding the molecular interactions behind the immune dysfunction during severe COVID-19 infection in the lungs should help inform the design and development of novel approaches for treating severe COVID-19 patients.

The researchers plan to validate their findings on human samples in collaboration with several of Israel’s health care centers. Further, they will aim to determine which drugs from their own Drug Repurposing for COVID-19 database may inhibit the cytokine storm generation in COVID-19.

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