A new study, published this week in Nature Cell Biology, describes the role of the CIART gene in COVID-19 infection. The gene, which is already known to be involved in circadian-associated gene regulation, enables SARS-CoV-2 infection by regulating production of certain fatty acids.
Far from over
Although it is easy to think the COVID-19 pandemic is over, this is far from reality. Official statistics suggest that the virus is implicated in over 4% of deaths in the UK currently. As such, it is vital that research into the disease does not dissipate.
In a bid to increase understanding of how COVID-19 infection takes hold in the lungs and other organs, the team of researchers from Weill Cornell Medicine and the New York University Grossman School of Medicine set out to identify genes that enable COVID-19 infection. Using lab-grown, human stem cell-derived organoids, the team analysed transcriptional changes following SARS-CoV-2 infection.
The value of organoids
The researchers first exposed the organoids – which included lung alveolar, lung airway and cardiomyocyte models – to the SARS-CoV-2 virus to determine the impact of infection on different cell types. Discussing the choice to investigate infection outside of the lung, author Todd Evans noted: “Different organs tend to respond differently to SARS-CoV-2 infection. Our idea was to look for factors that are relevant not just in one but in multiple organs.”
A transcriptomic analysis revealed 18 genes whose expression increased following infection in multiple organoids. To pinpoint exactly what was causing the increase, and the overall effect this had on the organoid, the team methodically knocked-out expression of each gene. They found that, whilst most of the genes had some influence on the virus’ ability to infect cells, the most significant impact was seen when the gene CIART was depleted.
CIART is a transcription factor responsible for regulation of the circadian clock. Whilst the gene itself has not been previously implicated in human disease, it has a key role in the regulation of downstream gene expression. In homozygous CIART knock-out organoids, the virus struggled to take hold, with the cells displaying a resistance phenotype. Single-cell RNA sequencing revealed that viral load was also significantly decreased in lung alveolar cells. Further transcriptomic analyses revealed that CIART regulates the Retinoid X Receptor pathway, which is involved in fatty acid metabolism. The team concluded that depletion of the CIART gene regulates COVID-19 infection by decreasing the production of fatty acids necessary for the virus to take hold.
Ongoing research
With COVID-19 continuing to move through the population, this work serves as a stark reminder of how little we really know about the virus. Elucidating the mechanisms behind infection can potentially help add to the, still relatively small, repertoire of treatments for the disease. Discussing the relevance of the results, author Robert Schwartz stated: “Most antiviral approaches to SARS-CoV-2 have focused on targeting some component of the virus itself, but the virus usually can evolve rapidly around that. It can be a lot harder for the virus to adapt to changes on the host side.” The team’s next steps will be to uncover the exact mechanism through which CIART and fatty-acid production enables COVID-19 infection, and hopefully discover a clinical application of the work.
