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Source: SARS-CoV-2 Research News  Jan 11, 2021  16 days ago
SARS-CoV-2 Research News: University Of Cambridge And NIH Led Study Shows That SARS-CoV-2 Downregulates Tetherin Which Enhances Its Spread
SARS-CoV-2 Research News: University Of Cambridge And NIH Led Study Shows That SARS-CoV-2 Downregulates Tetherin Which Enhances Its Spread
Source: SARS-CoV-2 Research News  Jan 11, 2021  16 days ago
SARS-CoV-2 Research News: A new study led by scientist from the University of Cambridge and also the National Institute of Allergy and Infectious Diseases at the National Institutes of Health along with researchers from the University of Sheffield have discovered that the SARS-CoV-2 coronavirus is capable of downregulating a critical human host protein called Tetherin which in turns enhances it spread.


 
According to the study abstract, the antiviral restriction factor, Tetherin, blocks the release of several different families of enveloped viruses, including the Coronaviridae. Tetherin is an interferon-induced protein that forms parallel homodimers between the host cell and viral particles, linking viruses to the surface of infected cells and inhibiting their release.
 
The stud team demonstrated that SARS-CoV-2 downregulates tetherin to aid its release from cells, and investigate potential proteins involved in this process. Loss of Tetherin from cells caused an increase in SARS-CoV-2 viral titre.
 
The study team finds SARS-CoV-2 spike protein to be responsible for Tetherin downregulation, rather than ORF7a as previously described for the 2002-2003 SARS-CoV. They instead find ORF7a to be responsible for Golgi fragmentation, and expression of ORF7a in cells recapitulates Golgi fragmentation observed in SARS-CoV-2 infected cells.
 
The study findings were published on a preprint server and are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2021.01.06.425396v1
 
The current COVID-19 pandemic is not showing any signs of letting up with more than 90.4 million infections and 1.94 million COVID-19 deaths so far. Even with the initiation of vaccination efforts, scientists continue to work on effective antivirals to prevent and treat this disease, which requires a better understanding of how and why it spreads.
 
This new study describes the role of a host protein called Tetherin in the spread of the novel coronavirus.
 
The SARS-CoV-2 coronavirus gains entry to the host cell via the spike protein, which binds to the host cell receptor, the angiotensin-converting enzyme 2 (ACE2). This virus differs from earlier pathogenic coronaviruses in possessing a novel polybasic furin cleavage site that allows the spike to split into its two subunits when exposed to the host protease, furin.
 
It has been found that the two spike fragments, S1 and S2, remain covalently bound, and the latter undergoes cleavage by another host protease, TMPRSS2. The S1 now binds to the host receptor neuropilin-1, allowing the virus to enter the cell. The virus bound at the cell's surface is enveloped within a complete fold of membrane, the endosome, that fuses with the viral envelope to liberate the viral capsid into the cytoplasm.
 
In the last action stages, viral RNA hijacks the cell organelles to replicate itself, synthesize other viral components, and assemble the new virions within the ERGIC (endoplasmic reticulum-Golgi intermediate compartment) organelles. The viral replication hubs within the cell are double-membrane vesicles (DMVs) composed of modified host organelles.
 
Importantly viruses can be classified based on whet her or not they have a host-derived lipid envelope. The envelope protects the viral capsid from the host immune response and thus enhances viral entry to new cells.
 
However, on the other hand, the host cell can use this to incorporate antiviral factors into the new viral particles. Many enveloped viruses can tether themselves to the plasma membrane of cells once they reach the cell surface, hindering further spread and infection. This is mediated by Tetherin, a host protein.
 
The protein Tetherin is an integral type II membrane protein with a GPI anchor at the membrane, with a short tail inside the cytosol, and a large coiled domain outside the cell. It is expressed by many types of cells, but type I interferon increases Tetherin levels.
 
The Tetherin molecules link the cell and the virus via homodimer formation, using three cysteine residues in the extracellular loop to create disulfide bonds.
 
This in return holds the newly forming virions on the surface of the infected cells, allowing endosomes to hold on to them and preventing their spread.
 
It has been found that Tetherin restricts the spread of several enveloped viruses, including HIV-1, Ebola, Kaposi's sarcoma-associated herpesvirus and human coronavirus 229E (HCoV-229E). Thus, several enveloped viruses use several mechanisms to lose Tetherin and thus allow viral release. SARS-CoV downregulates Tetherin, causing the increased spread of the virus, but the mechanism is unclear. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3793644/
 
https://pubmed.ncbi.nlm.nih.gov/18200009/
 
https://pubmed.ncbi.nlm.nih.gov/19179289/
 
https://jvi.asm.org/content/83/19/9672
 
https://pubmed.ncbi.nlm.nih.gov/24418563/
 
https://jvi.asm.org/content/89/23/11820.abstract
 
https://pubmed.ncbi.nlm.nih.gov/31199522/
 
In order for Tetherin to restrict the virus, these molecules must be built into the virus during the single enveloping step within ERGIC. However, the researchers found that while Tetherin moves through these organelles, it does finally distribute at the plasma membrane and the endosomes. This further supports the hypothesis that Tetherin restricts viral release when the endosomes or other DMVs fuse with the plasma membrane.
 
It has also been found that type I IFN responses are attenuated in COVID-19 as in other coronavirus infections. Interferons have been tried out to treat this condition, perhaps by increasing the concentration of Tetherin and thus hindering Tetherin release. However, this is not the only mechanism by which Tetherin is downregulated.
 
This research demonstrates that with SARS-CoV-2, the virions are bound to the infected cell surfaces by Tetherin. The infection of these cells results in a steep decline in the level of expression of Tetherin on the cell surface. They found that the viral spike protein mediates the downregulation of Tetherin, while the ORF7a causes fragmentation of the Golgi.
 
The study team found that uninfected human cells display Tetherin on the plasma membrane and within the perinuclear compartments. After infection, Tetherin was lost from the plasma membrane, and staining points appeared within the cell at higher concentrations. Some areas of the cell membrane appeared to be stained, indicating areas where the virus was tethered to the cell surface.
 
Utilizing transmission electron microscopy (TEM), they found that the viruses were clustered on the membrane and not uniformly distributed. Viruses within ERGICs were found near such sites. DMVs were also seen. However, Golgi cisternae were absent, indicating disruption of the biosynthesis of proteins.
 
Bu the study team found that surface protein synthesis was not universally suppressed.
 
Rather specific proteins are affected. They discovered reduced Tetherin concentrations. When Tetherin expression is reduced, they found a dramatic decline in surface-associated virions, though virions inside DMVs were found in the perinuclear region in infected cells.
 
Interestingly when Tetherin expression was decreased, the infected cells released many more viral particles, indicating their inability to restrain the new virions during assembly.
 
The study team concluded, "Tetherin exerts a broad restriction against numerous enveloped viruses, regardless of whether budding occurs at the plasma membrane or within intracellular compartments."
 
The study team also examined the role of the viral ORF7a protein, which showed that it was associated with the fragmentation of the Golgi apparatus. This interrupted protein biosynthesis within the cell. This does not appear to make it critical in human infection, however. A higher expression of viral ORF3a leads to the accumulation of Tetherin within the cell. This could reflect the fact that Tetherin is trafficked to the lysosomes but degraded slower than usual.
 
However on the other hand, viral spike protein leads to Tetherin loss from the cell surfaces. This is in addition to its known role in engaging to the host cell surface and causing cell to cell fusion following infection.
 
Corresponding author D Edgar JR Department of Pathology, University of Cambridge, told Thailand Medical News, "The convergent evolution displayed by different families of enveloped viruses to downregulate Tetherin highlights how important overcoming cellular restriction is to the success of enveloped viral pathogens. Since Tetherin loss is associated with increased viral titer, this finding may facilitate the development of novel therapeutics that target Tetherin inhibition or downregulation to offer an effective way of managing many such disease conditions.”
 
The study team concluded, “Although we did not detect any downregulation of Tetherin from the surface of cells upon expression of the SARS-CoV-2 ORFs examined, we did observe the intracellular accumulation of Tetherin upon expression of ORF3a. SARS-CoV-1 ORF3a acts as a viroporin at lysosomes, causing a loss of acidification, and ORF3a similarly localizes to lysosomes. The enhanced intracellular Tetherin in ORF3a expressing cells likely represents Tetherin which has been trafficked to lysosomes but has not been degraded at a normal rate. SARS-CoV-2 spike has well documented roles in facilitating SARS-CoV-2 viral entry, and in driving the formation of syncytia. We also find that SARS-CoV-2 spike causes downregulation of tetherin from the surface of cells. The molecular mechanism behind SARS-CoV-2 spike’s downregulation of Tetherin remains unclear. The convergent evolution displayed by different families of enveloped viruses to downregulate Tetherin highlights how important overcoming cellular restriction is to the success of enveloped viral pathogens. Enhancing cellular Tetherin levels during such pathogenesis remains a viable and attractive strategy for the management of a multitude of diseases, including COVID-19.
 
For the latest SARS-CoV-2 Research News, keep on logging to Thailand Medical News.
 
 

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