Researchers from Bar-Ilan University, the National Institutes of Health, Weill Cornell Medicine, The Rockefeller University, and Tel-Aviv University have collaborated on a study investigating the epigenetic changes occurring with elevated A-to-I RNA editing in individuals infected with COVID-19. Epigenetics, the study of heritable changes in gene function that do not involve changes to the underlying DNA sequence, has become a critical area of research in understanding the interaction between the SARS-CoV-2 virus and its host.
This study focused on the role of RNA editing, specifically A-to-I RNA editing, which is mediated by the ADAR family of enzymes, in the host’s immune response. Previous research has shown that viruses can manipulate these enzymes, leading to epigenetic changes in both the virus and the host. The researchers analyzed RNA sequencing data from nasopharyngeal swab specimens and whole-blood samples of COVID-19-infected individuals and found a significant increase in global RNA editing activity in COVID-19 patients compared to healthy controls. They also identified specific coding sites with heightened editing activity. Interestingly, this surge in editing activity was temporary and returned to baseline shortly after the symptomatic period.
COVID-19, caused by the SARS-CoV-2 virus, has had a devastating global impact, affecting millions of people worldwide. The severity of the disease is directly linked to the host’s immune response, particularly the cytokine storm characterized by a surge in pro-inflammatory cytokines. Understanding the factors that influence the immune response is crucial in combating the pandemic.
RNA editing, specifically A-to-I RNA editing, plays a critical role in modifying RNA molecules in the transcriptome. ADAR1, one of the enzymes involved in this process, protects the host cell against activation of the dsRNA sensor MDA5 and prevents the immune system from attacking its own cells. Viruses that contain dsRNA structures can undergo RNA editing events mediated by ADAR enzymes. This phenomenon has been observed in various viruses, including SARS-CoV-2. Increased RNA editing of the human transcriptome may occur as viruses overexpress host ADAR enzymes, leading to uncontrolled epigenetic modifications.
The researchers conducted a comprehensive analysis of A-to-I RNA editing patterns in COVID-19-infected individuals to understand the effect of SARS-CoV-2 on host RNA editing. They analyzed RNA sequencing data from nasopharyngeal swab specimens and whole-blood samples of COVID-19 patients and compared them to healthy controls. The results showed a significant increase in editing levels during the disease, particularly in the upper respiratory epithelium. The study also identified specific coding sites with higher editing levels in COVID-19 patients, some of which resulted in non-synonymous or stoploss mutations in genes related to immune regulation and signaling. Importantly, the increase in editing levels observed during the disease was temporary and returned to baseline about three weeks post-infection.
Epigenetic modifications caused by viral-induced RNA editing can have profound implications. Even minimal editing in coding sites may influence gene expression or function, potentially leading to long-term outcomes. Understanding the role of RNA editing in the immune response is vital for developing effective treatments and therapeutic strategies for COVID-19.
The study suggests that the immune response to SARS-CoV-2 is robust, with the IFN-MDA5 pathway playing a crucial role. The findings indicate that this pathway is more pronounced during COVID-19 compared to other viral infections. Further research is needed to fully understand the implications of these epigenetic modifications and their role in the pathogenesis of COVID-19. This knowledge is critical for the development of effective treatments and therapies to combat this devastating pandemic. The study’s findings were published in the peer-reviewed journal Genomics and Bioinformatics.