COVID-19 Research: NIH Scientists Discover That SARS-CoV-2 Utilizes Lysosomes To Exit Cells And Not Normal Biosynthetic Secretory Pathways!
: Scientist from the U.S. National Institutes of Health have shockingly discovered that that the SARS-CoV-2 coronavirus utilizes the cell organelles called lysosomes to exit cells instead of the typical biosynthetic secretory pathways that other viruses normally adopt.
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
Beta-coronaviruses are a family of positive-strand enveloped RNA viruses that include the SARS-CoV2 virus. Much is known regarding their cellular entry and replication pathways, but their mode of egress remains uncertain. Using imaging methodologies and virus-specific reporters, the study team demonstrates that βCoronaviruses utilize lysosomal trafficking for egress, rather than the biosynthetic secretory pathway more commonly used by other enveloped viruses. This unconventional egress is regulated by the Arf-like small GTPase Arl8b and can be blocked by the Rab7 GTPase competitive inhibitor CID1067700. Such non-lytic release of β-Coronavirus results in lysosome deacidification, inactivation of lysosomal degradation enzymes and disruption of antigen presentation pathways. The β−coronavirus-induced exploitation of lysosomal organelles for egress provides insights into the cellular and immunological abnormalities observed in patients and suggests new therapeutic modalities.
The study findings were published in the journal: Cell.
This new biological pathway that the SARS-Cov-2 coronavirus appears to use to hijack and exit cells as it spreads through the body needs detailed studying as a better understanding of this important pathway may provide vital insight in stopping the transmission of the virus.
The researchers showed for the first time in cell studies, that the SARS-CoV-2 coronavirus can exit infected cells through the lysosome, an organelle known as the cells' "trash compactor."
In normal circumstances the lysosome destroys viruses and other pathogens before they leave the cells. However, the researchers found that the coronavirus deactivates the lysosome's disease-fighting machinery, allowing it to freely spread throughout the body
By targeting this lysosomal pathway, it could lead to the development of new and more effective antiviral therapies to fight COVID-19.
Experts have known for some time that viruses enter and infect cells and then use the cell's protein-making machinery to make multiple copies of themselves before escaping the cell. However, researchers have only a limited understanding of exactly how viruses exit cells.
Past studies have showed that most viruses including influenza, hepatitis C, and West Nile exit through the so-called biosynthetic secretory pathway.
The biosynthetic secretory pathway is a central pathway that cells use t
o transport hormones, growth factors, and other materials to their surrounding environment.
Researchers have long assumed that coronaviruses also use this pathway.
However in this in a pivotal experiment, Dr Nihal Altan-Bonnet, Ph.D., chief of the Laboratory of Host-Pathogen Dynamics at the NIH's National Heart, Lung, and Blood Institute (NHLBI) and her post-doctoral fellow Dr Sourish Ghosh, Ph.D., the study's main authors, found something different.
Dr Altan-Bonnet and her team exposed coronavirus-infected cells (specifically, mouse hepatitis virus) to certain chemical inhibitors known to block the biosynthetic pathway.
She told Thailand Medical News, "To our shock, these coronaviruses got out of the cells just fine. This was the first clue that maybe coronaviruses were using another pathway."
In order to identify that pathway, the study team designed additional experiments using microscopic imaging and virus-specific markers involving human cells. They discovered that coronaviruses somehow target the lysosomes, which are highly acidic, and congregate there.
These new study findings raised yet another question for Altan-Bonnet's team: If coronaviruses are accumulating in lysosomes and lysosomes are acidic, why are the coronaviruses not destroyed before exiting?
Significantly in a series of advanced experiments, the study team demonstrated that lysosomes get de-acidified in coronavirus-infected cells, significantly weakening the activity of their destructive enzymes. As a result, the viruses remain intact and ready to infect other cells when they exit.
Dr Altan-Bonnet added, "These coronaviruses are very sneaky. They're using these lysosomes to get out, but they're also disrupting the lysosome so it can't do its job or function."
The study team also discovered that disrupting normal lysosome function appears to harm the cells' immunological machinery
Dr Altan-Bonnet further added, "We think this very fundamental cell biology finding could help explain some of the things people are seeing in the clinic regarding immune system abnormalities in COVID patients. This includes cytokine storms, in which an excess of certain pro-inflammatory proteins in the blood of COVID patients overwhelm the immune system and cause high death rates.”
She continued, “Now that this mechanism has been identified, researchers may be able to find ways to disrupt this pathway and prevent lysosomes from delivering viruses to the outside of the cell; or re-acidify lysosomes in order to restore their normal functions in coronavirus-infected cells so they can fight COVID.”
The study team has already identified one experimental enzyme inhibitor that potently blocks coronaviruses from getting out of the cell.
Dr Altan-Bonnet said, "The lysosome pathway offers a whole different way of thinking about targeted therapeutics. Further studies will be needed to determine if such interventions will be effective and whether existing drugs can help block this pathway. “
The study team noted the findings could go a long way toward stemming future pandemics caused by other coronaviruses that may emerge.
In summary the study findings reveal that β-coronaviruses use an unexpected lysosome based egress pathway and this potentially opens up new therapeutic avenues to mitigate coronavirus infections and slow virus spread, by targeting regulators of lysosomal trafficking and biogenesis such as Arl8b and Rab7, and by reversing deacidification and/or enhancing immune responses geared against lysosomal defects.
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