Making Sense of Medical Science (MSMS)

Two ways to infect cells: An elegant study recently published in the journal Cell, reports that when the SARS-CoV-2 virus infects a human cell, it causes the cells to sprout appendages studded with viral particles. These disfigured cells appear use those appendages, or filopodia, to reach still-healthy neighboring cells. The protuberances then bore into the adjacent cells’ bodies and inject their viral venom creating a newly infected neighbor.

Image shows filopodia and viral buds in a CoV-2 infected cells. An uninfected cell would be much smoother and not show the appendages or buds. The Electron micrograph was taken by Dr. Elizabeth Fischer at the National Institute of Allergy and Infectious Disease Rocky Mountain Laboratory.

Until now, it was assumed that the process by which the coronavirus spreads in a body was pretty standard: It binds to receptors on cells that line humans’ mouth, nose, respiratory tract, gut, lungs and blood vessels. Then it docks to the receptor and the cell engulfs it. It then takes over cellular machinery to produce new viruses that bud out of the cell and enter the host’s circulation in search of a new target cell, perhaps far from the cell from which it budded. While effective, this mechanism of viral spread also exposes the free-floating viruses to the host’s immune defenses. Hence, the close-quarters attack mediated by viral-studded filopodia provides a second, more secure way for the virus to spread. It enhances the efficiency of establishing an infection.

While this is a new finding for CoV-2, other viruses are also known to use the filopodia infection mechanism. Vaccinia virus, which causes smallpox, HIV, and some flu viruses use filopodia to enhance their ability to break-and-enter into cells. But these viruses do not seem to set off the prolific growth of filaments to the extent that was observed on coronavirus-infected cells.

Practical benefits of the research finding: The research emerges from an ambitious effort to identify potential COVID-19 treatments using “quantitative biology,” and “proteomics” to identify global changes in protein expression and function that are affected by infection with the virus. This can provide a snapshot of how cellular biochemical pathways and processes are rewired upon infection. This is in silico, or computer-based, research that mines vast databases on protein structure, protein function, protein interaction, and chemical (drug) interference to find chemicals that can inhibit CoV-2 activity. These databases were generated over the last two-to-three decades and still grow rapidly. 

UC San Francisco scientists examined global changes in cell protein expression and function and found wide ranging effects of CoV-2 infection in cells, including a shutdown of proteins that drive cell growth, and activation of an enzyme that causes changes in the cytoskeleton and promotes filopodia production. They, and their collaborators, then mined information from the databases that led them to several compounds known to interfere with the biochemical changes caused by the virus.

With this in silico research, the investigators identified several potential drugs that could disrupt the chemical signals that activate filopodia production, thereby possibly crippling this mechanism of viral spread. Several of the compounds showed ability to inhibit virus production in tissue culture experiments. Among the seven drugs they identified as potentially useful against the virus are Silmitasertib, an experimental drug in early clinical trials as a treatment for bile duct cancer and a form of childhood brain cancer; ralimetinib, a cancer drug developed by Eli Lilly; and gilteritinib (marketed as Xospata), a drug in use already to treat acute myeloid leukemia.

This is how drug discovery is done now days.

The research was a collaboration between scientists from UC San Francisco, Mt. Sinai in New York City, the NIH Rocky Mountain Labs in Montana, the Pasteur Institute in Paris and the University of Freiburg in Germany.