Lysosome in cells is known as the cell’s “waste treatment plant” and produces amino acids by digesting misfolded proteins in cells, “wasted” cells, and provides raw material for cell synthesis of new proteins. Lysosome-mediated protein degradation is also one of the powerful tools for cells to eliminate viruses.
However, a team at the National Institutes of Health (NIH) recently found that β-coronavirus, including the new coronavirus, can “hijack” lysosomes as a tool for self-transmission, causing the ineration of degradation enzymes in lysosomes and disrupting antibody pathogenes. The researchers say the findings could help explain cellular and immune abnormalities in PATIENT-19 patients and could provide new ideas for developing treatments. The study was published in the journal Cell.
Scientists already know that when a virus infects a cell, it uses the cell’s protein-producing mechanism to synthesize the protein it needs to replicate itself, multiply within the cell, and eventually detach the cell to infect other cells. However, understanding of how viruses disengage from cells is still limited. It is traditionally understood that the resulting viral particles are transferred from the endoblast to the Gorki body, where they are then carried to the surface of the cell membrane by the vesicles of the biosynthetic secretion pathway secreted by the Goerki body, where they are fused with the cell membrane and disengaged from the cell. Envelope RNA viruses such as HCV, dengue virus and West Nile Virus all disengage cells in this way, and scientists think coronavirus disengages cells in the same way.
For the study, NIH scientists looked at the way the mouse hepatitis virus (MHV) disengages. This is a β-coronavirus. They first treated infected cells with inhibitors that inhibit biosynthetic path paths, which theoretically inhibit the release of viruses if MHV viruses use biosynthetic secretion paths to detach cells from cells.
“To our surprise, these coronavirus are still able to separate normally from the cells.” “This is the first clue we’ve got that coronavirus may be using another path,” said Dr. Nihal Altan-Bonnet of the NIH National Heart, Lung and Blood Institute (NHLBI), who lead the study. “
Senior author of the scientific paper, Dr Nihal Altan-Bonnet (Photo: NIH website)
Further microscope imaging studies have shown that coronavirus is transported to lysosomes and gathers there. But the environment in the lysosome is usually highly acidic, and there are many enzymes that digest proteins. If the coronavirus breaks away from the cell through the lysosome, why is it not digested by the lysosome?
Viruses “hijack” lysosomes with “sly means”
The researchers stained MHV-infected cells with dyes that showed pH, and found that in MHV-infected cells, the pH of lysosomes increased significantly, with an average pH of 4.7 in uninsored cells and an increase in pH in MHV-infected cells. Previous studies have shown that the activity of enzymes in lysate media is highly correlated with pH, and that a small increase in pH can lead to a significant decrease in protease activity. Tests of protease activity showed a 40% reduction in protease activity in cells infected with MHV.
Therefore, MHV virus infection can reduce the activity of proteases by increasing the pH of the lysosome, so that the lysosome can be used by the virus to detach from the cell. The researchers also found that the ORF3a protein of the new coronavirus also targets lysosomes and may cause the acidity of lysosomes to decrease.
The newly β-coronavirus can be separated from cells by lysosomes
New ideas for antiviral therapy
Since coronavirus breaks away from cells through lysosome paths, can inhibiting lysosome paths reduce the release of the virus? The researchers used an inhibitor called CID1067700 to inhibit the production of lysosomes. They found that while the inhibitor did not affect cell vitality, or the virus’s infection and replication, it significantly reduced the release of the virus. Reduce virus release by 100 times at 4 μM and 1000x at 40 sm!
“The lysosome pathrazy provides a new way of thinking about building targeted therapies.” Dr. Altan-Bonnet said. Her team is conducting further research to see if such drug interventions can effectively reduce the spread of coronavirus and whether approved drugs can block this pathway. She also said the study could help fight future epidemics caused by other coronavirus.