The gene CIART is a major factor in the establishment of a COVID-19 infection, according to a new study from researchers at Weill Cornell Medicine and New York University (NYU) Grossman School of Medicine.
In the study, which appears this week in Nature Cell Biology, the researchers used multiple organoids to search for general host factors that influence infections by SARS-CoV-2. CIART was a strong SARS-CoV-2-enabling factor in both lung and heart tissue organoids. The gene’s effect on SARS-CoV-2 infection, they found, was due to its stimulation of fatty acid synthesis.
“This finding demonstrates the power of a multi-organoid approach, by revealing a pathway that could be targeted with future drugs to treat or prevent SARS-CoV-2 infection across multiple organ systems,” said study co-senior author Shuibing Chen, the Kilts Family Professor of Surgery at Weill Cornell Medicine.
SARS-CoV-2, like other respiratory viruses, typically initiates infection in the throat and sinuses. But it often spreads from the respiratory tract to other parts of the body, such as the gut, liver, heart, kidneys, brain, blood vessels and pancreas. Infections in these tissues are frequently seen in severe COVID-19 and can cause fatal complications including blood clots and organ failure. COVID-19 biology is under a lot of study, including by the COVID-19 Disease Map community.
“Different organs tend to respond differently to SARS-CoV-2 infection,” said Weill Cornell associate dean for research Todd Evans, also a co-author. “So, our idea was to look for factors that are relevant not just in one but in multiple organs.”
Starting with human stem cells, the researchers grew organoids to model bronchial airway tissue, gas-exchanging alveoli tissue deep in the lungs, and heart muscle, all of which can be infected by SARS-CoV-2.
The team exposed these organoids to different quantities of the virus and identified 18 genes that they found were consistently more active during infection, in multiple organoids, and at different viral doses.
They then deleted these genes from the organoids, one by one, to see the effect on virus levels. The results suggested that while 13 of the genes appear to have some role in enabling SARS-CoV-2, the strongest enabler by far was CIART, which encodes a transcription factor protein that normally works in the cell nucleus to regulate the activity of other genes. This gene had never before been linked to disease.
Further tests indicated that CIART enhances the ability of SARS-CoV-2 to reproduce by boosting the production of certain fatty acids, via a pathway known as the RXR pathway. Treating the organoids with experimental RXR inhibitor compounds before exposure to SARS-CoV-2 effectively blocked the virus’s ability to establish infection in the tissues.
The team’s findings suggest that targeting RXR or its upstream controller, the CIART protein, could be an effective way to treat SARS-CoV-2 infection, or even to prevent it over the short-term.
A big advantage of this approach, the researchers say, is that it alters the host side of the virus-host interaction.
“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,” said Schwartz, who is also a hepatologist at NewYork-Presbyterian/Weill Cornell Medical Center. “It can be a lot harder for the virus to adapt to changes on the host side.”
