SARS-CoV-2 infection Enabler Genes Identified

Researchers from Weill Cornell Medical and the New York University Grossman School of Medicine found that the viral infection that causes COVID-19 is established in part by the action of a gene called CIART.
In the study, which was published on March 13 in Nature Cell Biology, the researchers looked for general host characteristics that affect infections by SARS-CoV-2, the coronavirus that causes COVID-19, using several models of small, three-dimensional clusters of human tissue known as organoids.

In organoids simulating both lung and heart tissue, they discovered CIART to be a potent SARS-CoV-2 enabling factor. The researchers determined that the permissive effect of CIART on SARS-CoV-2 infection was due to its promotion of the synthesis of fatty acids in cells.

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.

Todd Evans, associate dean for research, and Peter I. Pressman, M.D. Professor in Surgery, Dr. Robert Schwartz, associate professor of medicine in the Division of Gastroenterology and Hepatology at Weill Cornell Medicine, Benjamin tenOever, director of the NYU Langone Virology Institute and professor in the departments of microbiology and medicine at NYU Grossman School of Medicine, and Dr. Todd Evans are the other co-seniors of the study.

Similar to other respiratory viruses, SARS-CoV-2 often starts an illness in the sinuses and throat. Yet, it frequently extends beyond the respiratory system to the gut, liver, heart, kidneys, brain, blood vessels, and pancreas. When COVID-19 is severe, these tissues are usually infected. These infections can lead to deadly consequences such as blood clots and organ failure. “Different organs tend to respond differently to SARS-CoV-2 infection,” Evans said. “Our idea was to look for factors that are relevant not just in one but in multiple organs.”

The scientists created organoids from human stem cells to represent the heart muscle, gas-exchanging “alveoli” tissue found deep within the lungs, and bronchial airway tissue, all of which are known to be susceptible to infection by SARS-CoV-2.

The researchers exposed these organoids to various viral dosages in a high-level biosafety facility at NYU Grossman and discovered 18 genes that consistently become more active after infection, in various organoids, and at various viral doses.

To observe the impact on viral levels, the scientists individually removed these genes from the organoids. According to the findings, CIART was by far the largest enabler of SARS-CoV-2, even though 13 of the genes seem to play some function in allowing the virus because viral levels are lower when they are lacking.

Further research revealed that the CIART gene generally increases the SARS-capacity CoV-2’s to replicate by increasing the production of certain fatty acids via the RXR pathway. Treatment the organoids with investigational RXR inhibitor chemicals before exposure to SARS-CoV-2 successfully reduced the virus’s capacity to develop infection in the tissues.

According to the research, preventing or treating SARS-CoV-2 infection in the short term may be possible by targeting RXR or its upstream regulator, the CIART protein.

According to the researchers, a significant benefit of this strategy is that it modifies the host side of the virus-host relationship.

“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.”

The researchers now are continuing to study how CIART influences the viral life cycle—and how best to block its infection-enhancing effect.

Source Link