Coronaviruses hijack lysosomes to exit cells

The components of the normal biosynthetic secretory pathway (top) and the lysosome pathway (bottom), which this study found coronaviruses use to exit cells. NIH

COVID-19 cases are surging worldwide. With U.S. deaths nearing 225,000, scientists are working to better understand how the virus that causes the disease infects cells and spreads through the body. SARS-CoV-2, like most viruses, enters and infects cells, and then uses the cell’s protein-making machinery to make multiple copies of itself. It must then escape the cell. While researchers have learned a great deal about how the virus infects cells, they have only a limited understanding of how it exits them.

Most viruses—including hepatitis C, Dengue, and West Nile—exit through the “biosynthetic secretory” pathway. That’s the central pathway that cells use to transport hormones, growth factors, and other materials to their surrounding environment.

A research team led by Drs. Nihal Altan-Bonnet and Sourish Ghosh at NIH’s National Heart, Lung, and Blood Institute (NHLBI) and Dr. Gregoire Altan-Bonnet at NIH’s National Cancer Institute (NCI) investigated whether coronaviruses also use this pathway to exit cells. For their experiments, they used a related coronavirus called MHV as well as SARS-COV-2. The study, which was funded by several NIH Institutes, was published on October 27, 2020 in Cell.

The researchers chemically blocked the biosynthetic secretory pathway in MHV-infected cells. Using microscopic imaging and virus-specific markers, they discovered that the viruses still left cells with this pathway blocked.

Further experiments revealed that the viruses instead exited infected cells through the lysosome, an organelle that serves as the cells’ trash disposal system. Normally, the lysosome’s acidic environment helps destroy viruses and other pathogens before leaving cells. SARS-CoV-2 was also found in the lysosomes of infected cells.

The scientists discovered that lysosomes were de-acidified in coronavirus-infected cells. This significantly weakened the activity of their destructive enzymes. As a result, the coronaviruses remained intact and ready to infect other cells when they exited.

Certain immune system cells rely on lysosomes to degrade proteins into short pieces that help trigger other immune cells to respond. The researchers found that the coronavirus deactivated this disease-fighting function of the lysosome. De-acidification of the lysosome may alter other immune system functions as well. The findings could help explain some of the immune system abnormalities seen with COVID-19 patients.

“These coronaviruses are very sneaky,” Dr. Nihal Altan-Bonnet says. “They’re using these lysosomes to get out, but they’re also disrupting the lysosome so it can’t do its job or function.”

Now that this mechanism has been identified, researchers may be able to find ways to disrupt the pathway. The authors identified one experimental compound that potently blocked coronaviruses from getting out of cells. However, more studies are needed to determine whether this drug or others that block the lysosome pathway could be used to combat COVID-19.