How Scientists Found a New Way to Help Us Fight Coronaviruses

At the University of Pittsburgh (UPitt), a team of scientists were on a mission. While the world fought off COVID-19, these researchers asked a powerful question:

“What if we could help the body fight viruses more effectively, without directly targeting the virus itself?”

The main researchers of this story include Dr. Jennifer Martinez, Dr. Richard Kowalski, and Dr. Toren Finkel, along with their team and associates at The University of Pittsburgh’s Aging Institute and Department of Medicine. Detailed in the study, these scientists discovered a new way to help our bodies fight off coronaviruses, such as COVID-19. Instead of simply attacking the virus directly, this team thought outside of the box and looked for a way to help our cells defend themselves better.

Image: Fusion Medical Animation

                Despite vaccines and anti-virals, coronaviruses escape immune surveillance by disrupting cellular defense systems. A coronaviral infection, such as COVID-19, triggers the degradation of TFEB, the lysosomal biogenesis transcription factor within your cells, which plays a crucial regulatory role in controlling the function of lysosomes and autophagy. Essentially, it instructs the cell’s “clean-up and recycling centers” on how to perform their tasks effectively. TFEB is important in the fight against viral infections because when TFEB is active, the cell is better at cleaning out viral invaders and keeping itself healthy.  

                When a coronavirus invades our bodies, it attempts to eliminate TFEB. It activates a molecule called PAK2, which marks a target on our TFEB. Then, another molecule, DCAF7, sees the marking left by PAK2 and attacks the TFEB. When our TFEB is depleted, our cell-cleanup systems are ineffective, and the virus begins to spread rapidly.

                Dr. Jennifer Martinez and her team of researchers at UPitt put on their lab coats, asked smart questions, and eventually searched for a unique way to stop this sneaky virus attack. The team discovered a small, yet potent chemical compound called BC18630 that could inhibit DCAF7 from degrading TFEB.

                To test their ideas, scientists at the UPitt used microscopes and special tools to see what was happening to TFEB inside infected cells. Researchers screened small molecules that block DCAF7-TFEB interaction, restoring TFEB protein abundance. The scientists used their chemical BC18630 as a medicine on infected cells in their lab, and it worked. The in-vitro results showed that the treatment of epithelial cells infected with coronaviruses restored their TFEB levels and lysosomal function. Viral replication decreased significantly, supporting host-directed anti-viral potential.

Image: National Institute of Allergy and Infection

                The research group also utilized animal studies to test their findings. They found in their hamster model that oral ingestion of their medicine, BC18630, pre-and post-infection, reduced the quantity of cells related to lung viral infections and produced more vital proteins, keeping the lungs of the animals healthier looking when examined.

In their study using transgenic mice, researchers found that treated animals exhibited marked protection, as evidenced by lower lung viral loads, preserved TFEB in the airways, and improved survival compared to untreated mice exposed to the same viral infection. It is noteworthy that this study demonstrated therapeutic value even after exposure.

The implications and significance of this study are that it identifies a novel viral evasion strategy that subverts the lysosomal defense by targeting TFEB preservation using an oral medication. Dr. Martinez and the team at the University of Pittsburgh weren’t just happy about stopping the viruses’ rapid reproduction; they were excited about something bigger. Instead of fighting the virus itself, they helped the body fight smarter. This is a great deal, because most medicines target the virus directly, but viruses mutate rapidly. This new notion of protecting our natural defenses could work even if the virus mutates, or if a brand-new one appears.

Researchers at the UPitt are now working to make the chemical converted into oral medicine even safer. They hope to test BC18630 on larger animals, and possibly someday in humans too. They are also studying whether it could also help us fight other diseases.

This discovery shows how the team at the UPitt proved that innovative ideas and collaborative teamwork can make a difference not just for today, but for a better, healthier tomorrow as well.