Coronaviruses Uses Lysosomes To Exit Cells

Coronaviruses Use Lysosome To Exit Cells: Key Pathway Identified

A biological pathway that appeared to be used by the SARS-CoV-2 virus for hijacking and exiting cells as it spreads through the body has been discovered by the researchers at the National Institutes of Health. Significant information about preventing the transmission of the COVID-19 causing virus can be obtained by better understanding this important pathway.

Scientists have shown that the SARS-CoV-2 virus can get out of the infected cells through an organelle termed as the cells’ “trash compactor,” the lysosome in a study published in the journal Cell. Generally, before viruses and other pathogens leave the cells, the lysosome destroys them. But, in the case of coronavirus, it was identified that the virus is allowed to freely spread throughout the body as it deactivates the lysosome’s disease-fighting machinery.

New and more potent antiviral therapies to fight COVID-19 can be developed by targeting this lysosomal pathway.

The mechanism of how exactly viruses exit cells has had only a limited understanding so far. It is considered that through the so-called biosynthetic secretory pathway, a central pathway used by cells for transporting growth factors, hormones, and other materials, most viruses including hepatitis C, West

Nile, and influenza exit the cells. This pathway was assumed to be used by coronaviruses also.

However, a key research study by the main authors, Chief of the Laboratory of Host-Pathogen Dynamics at the NIH’s NHLBI, Nihal Altan-Bonnet, Ph.D., and Sourish Ghosh, Ph.D., her post-doctoral fellow lead to new information. Certain chemical inhibitors known to block the biosynthetic pathway were exposed to cells infected with coronavirus (specifically, mouse hepatitis virus) by her team.

The illustration shows components of the lysosome exocytosis pathway, which coronaviruses use to exit cells. Also shown are components of the normal biosynthetic secretory pathway. Credit: NIH Medical Arts

Altan-Bonnet said, “Surprisingly, these coronaviruses got out of the cells just fine, which became the first clue to knowing that there could be another pathway used by the coronaviruses.”

Using virus-specific markers involving human cells, and microscopic imaging, additional experiments were designed by the researchers in order to look for that pathway. It was identified that coronaviruses target the lysosomes somehow and congregate there, with which another question was raised as to why the coronaviruses not destroyed before exiting if they are accumulating in lysosomes, as lysosomes are acidic.

The research team showed in a series of modern experiments that the activity of the lysosome’s destructive enzymes is significantly weakened as the lysosomes get de-acidified in coronavirus-infected cells. Thus, the viruses stay intact as a result, and when they exit, they are ready to infect other cells.

Altan-Bonnet said, “Coronaviruses disrupt the lysosome making it unable to do its function and are using these lysosomes to exit the cells.”

Additionally, it was also identified by the researchers that the cells’ immunological machinery appeared to be harmed while disrupting normal lysosome function. Altan-Bonnet said, “Some of the things being witnessed in the clinic regarding immune system abnormalities in COVID patients, such as cytokine storms, could be explained with the help of this very fundamental cell biology finding.”

With the identification of this mechanism, scientists can now be able to discover ways for disrupting this pathway and preventing lysosomes from delivering viruses outside the cell or could even find ways to make lysosomes in coronavirus-infected cells fight COVID by re-acidifying them to restore their normal functions. An experimental enzyme inhibitor potentially blocking the coronaviruses from exiting the cell has already been identified by the study authors.

Altan-Bonnet added, “A completely new way of thinking about targeted therapeutics is offered by this lysosome pathway, however, to know if this method will be successful and if the drugs present now can aid in blocking this pathway, further studies will be needed.”

 

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Coronaviruses Use Lysosomes To Exit Cells: Key Pathway Identified