RNA, DNA, and COVID-19

As my co-blogger Jeff Hsu, MD, PhD said to me this week, the COVID-19 pandemic has created the ultimate hackathon – the world’s smartest people hyperfocused on the same problem. For this month’s blog, I am outlining few ways that genomics researchers are hoping to advance our understanding of SARS-CoV-2.

Pathogen Evolution and Transmission

Scientists around the world have pledged to openly share genetic data to aid in the understanding of pathogen spread, and one of these collections of open-source tools is Nextstrain.1 Nextstrain is a database of viral genomes, a bioinformatics pipeline for phylodynamics analysis, and an interactive visualization platform that presents a real-time view of the evolution and spread of seasonal endemic viral pathogens (e.g. influenza) and emergent viral outbreaks (e.g. SARS-CoV-2, Zika, Ebola).1 Over time, viruses naturally accumulate random mutations into their genomes, and these mutations can be used to identify infection clusters that are closely genetically related. Therefore, this can lend insight into introduction events and growth rates. The Nextstrain 2019-nCoV page shows incredible graphical displays of the inferred phylogeny, global transmission events, and genomic diversity over time. At the time of their most recent Situation Report and Executive Summary (dated 3/27/2020), the Nextstrain team had analyzed 1,495 publicly shared SARS-CoV-2 genomes and provided transmission pattern reports for North America, Europe, Central and South America, Asia, Africa, and Oceania.

For a great introduction to the importance of genomics in identifying the emergence of SARS-CoV-2, check out this Cell Leading Edge Commentary, authored by two of the scientists who were involved in the initial genomic sequencing of the virus.2

Global map of inferred 2019-nCoV transmission from Nexstrain.

Genetic Influences on Disease Outcomes

In addition to collecting data on viral genomics, researchers have come together to pool genetic data from patients to try to answer urgent questions regarding the variability in clinical outcomes across patients with COVID-19. To investigate the genetic susceptibility to disease, these researchers will be comparing the DNA of different cohorts of patients with COVID-19, for example, those with serious disease to those with more mild manifestations. The COVID-19 Host Genetics Initiative is one of the largest collaborative initiatives with now over 75 biobanks and studies from around the world listed as partners. Their aims are to facilitate sharing of COVID-19 host genetics research, identify genetic determinants of COVID-19 susceptibility and severity, and provide a platform to share the results to the scientific community. Other large national biobanks like UK Biobank and Iceland’s deCODE Genetics are also planning to add COVID-19-related data to their genomic databases.

The COVID-19 Host Genetics Initiative at http://covid19hg.org

How can you keep up with the explosion of data in this space? The Centers for Disease Control and Prevention has created an online Coronoavirus Disease Portal, which is a continuously updated database of scientific literature, CDC and NIH resources, and other materials that pertain to genomics, molecular and other precision medicine and precision public health tools in the investigation and control of coronaviruses, such as COVID-19, MERS-CoV, and SARS.


  1. Hadfield et al., Nextstrain: real-time tracking of pathogen evolution, Bioinformatics(2018).
  2. Zhang and Holmes, A Genomic Perspective on the Origin and Emergence of SARS-CoV-2, Cell (2020), https://doi.org/10.1016/j.cell.2020.03.035

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”


Form over Abundance: The interesting case of how RNA isoforms in immune cells affect atherosclerosis.

The immune system plays a vital role in heart disease. In my last blog, I wrote about the role of complements in hypertension and lightly mentioned that it affected regulatory T cells. In this post, I would like to shine the spotlight on regulatory T cells, their function and their role in atherosclerosis, drawing attention to a recent publication that describes how the different forms of the RNA material in these cells correlates to cardiac incidents.

Regulatory T cells, or commonly known as Treg cells, belong to the T cell family, a part of the adaptive immune system. Treg cells play an important role in reducing inflammation and keeping the immune system in check. They are involved in multiple inflammatory diseases and their presence is crucial for controlling unnecessary immune activation that can lead to disease. Treg cells are protective in multiple heart conditions. Treg cells play a big role in controlling atherosclerosis progression and reducing the inflammation that occurs during plaque build up. Experiments, where researchers got rid of Treg cells, exacerbate atherosclerosis. Meanwhile transferring Treg cells into animals, reduce the severity of atherosclerosis. In addition to reducing inflammation, Treg cells also play a role in tissue repair as well as modulating lipoprotein metabolism.  Reduction in Treg cells have been shown to correlate with increased risk for myocardial infarction and their numbers are either reduced or they switch to other inflammatory T cells in atherosclerotic lesions.

Treg cells function is dependent on their master transcription factor and regulator, Foxp3. Foxp3 is also the main molecule that defines these cells from other T cells. While only one form of transcribed Foxp3 mRNA is found in mouse cells, in humans, Foxp3 mRNA exists in more than one isoform. The two most dominant isoforms are the full length Foxp3 mRNA (foxp3fl) and a truncated form lacking exon 2 (foxp3Δ2). In a recent research article published in Circulation Research, a group of researchers from Karolinska Insitute in Sweden, examined the role of these two isoforms on Treg cells function and whether their presence correlated with disease incidents. The researchers first found that the activation of Treg cells resulted in more expression of the truncated isoform of foxp3. When they examined patients with atherosclerosis, the researchers found that patients who had unstable plaques; those defined as having one or more cardiac incidents; had lower expression of the truncated isoform of Foxp3 despite the fact that the total mRNA levels of Foxp3 was the same. This suggested that the Treg cells that express this truncated form are more protective against atherosclerosis.

This new research is very interesting and leads to many questions in the field. Does the same hold true with other cardiac disease like myocardial infarction? Can manipulating the Treg cells by expressing only the truncated isoform of Foxp3 reduce cardiac incidents? The researchers found that the truncated isoform of Foxp3 induced a specific glycoprotein that tethered TGFβ, an inhibitory cytokine, to the membrane of Treg cells. If this tethering were achieved differently, would it lead to the same results? There are still a lot more questions to be answered but the current research definitely points to the idea that it is all about form over abundance when it comes to the expression of Foxp3 in Treg cells.

Dalia Gaddis Headshot

Dalia Gaddis is a postdoctoral fellow at the La Jolla Institute for Allergy and Immunology. She has a Ph.D. in microbiology and immunology. She is currently working on understanding the interactions between the immune system and atherosclerosis development.