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Source: Latest COVID-19 Research  Nov 28, 2020  3 years, 4 months, 1 day, 9 hours, 6 minutes ago

Latest COVID-19 Israel Research Shows That SARS-CoV-2 Utilizes A Multipronged Attack To Paralyze Human Host Protein Synthesis

Latest COVID-19 Israel Research Shows That SARS-CoV-2 Utilizes A Multipronged Attack To Paralyze Human Host Protein Synthesis
Source: Latest COVID-19 Research  Nov 28, 2020  3 years, 4 months, 1 day, 9 hours, 6 minutes ago
Latest COVID-19 Research: Israeli scientists from the Weizmann Institute of Science, Rehovot-Israel and the Israel Institute for Biological Research, Ness Ziona-Israel have uncovered new details that show that the SARS-CoV-2 coronavirus deploys a multipronged strategy to suppress the mechanism of human host protein synthesis that often leads to disease progression or even to long term COVID-19 effects.


 
To date researchers still do not have a complete perspective and still do not fully understand the molecular basis of SARS-CoV-2 pathogenesis and its ability to antagonize innate immune responses.
 
In this study, the researchers use RNA-sequencing and ribosome profiling along SARS-CoV-2 infection and comprehensively define the mechanisms that are utilized by SARS-CoV-2 to shutoff cellular protein synthesis.
 
The study team shows that SARS-CoV-2 infection leads to a total reduction in translation but that viral transcripts are not preferentially translated. Instead, the team reveals that infection leads to accelerated degradation of cytosolic cellular mRNAs which facilitates viral takeover of the mRNA pool in infected cells.
 
Furthermore the study team shows that the translation of transcripts whose expression is induced in response to infection, including innate immune genes, is impaired, implying infection prevents newly transcribed cellular mRNAs from accessing the ribosomes.
 
Overall, the study findings uncover the multipronged strategy employed by SARS-CoV-2 to commandeer the translation machinery and to suppress host defenses.
 
The research findings are published on a preprint server but are currently being peer reviewed. https://www.biorxiv.org/content/10.1101/2020.11.25.398578v1

In the case of SARS-CoV-2, interferon response seems to play a critical role in pathogenesis. https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1008737
 
https://www.nature.com/articles/d41586-020-03070-1
 
https://pubmed.ncbi.nlm.nih.gov/32661059/
 
https://pubmed.ncbi.nlm.nih.gov/32972996/
 
In addition, the extent to which SARS-CoV-2 suppresses the IFN response is a key characteristic that distinguishes it from other respiratory viruses.
https://pubmed.ncbi.nlm.nih.gov/32416070/
 
https://www.x-mol.com/paper/1260106673524244480
 
The new study throws a flood of light on how the SARS-CoV-2 coronavirus accomplishes its mission to infect and replicate within host cells while evading the host immune response.

px">HELP! Please help support this website by kindly making a donation to sustain this website and also all in all our initiatives to propel further researchhttps://www.thailandmedical.news/p/sponsorship
 
The findings show the virus not only suppresses translation of cellular proteins but increases the rate of breakdown of cellular messenger ribonucleic acids (mRNAs) that defend the host against the virus.
 
The SARS-CoV-2 coronavirus has a single-stranded ribonucleic acid (RNA) genome of about 30 kb, which encodes two polyproteins on two open reading frames, ORF1ab. These are translated into peptides that are cleaved into 16 functional viral proteins eventually. These are the nonstructural proteins (nsps) like RNA-dependent RNA polymerase (RdRp), which mediates the transcription of subgenomic RNA into the same 5’ leader sequence but different segments of the 3’ end of the viral RNA genome.
 
Importantly these different segments of subgenomic RNA encode the structural viral proteins such as the spike (S) and nucleocapsid (N) proteins, as well as accessory proteins. Such proteins can be translated from the subgenomic RNA only by the cell’s own translation apparatus, which is hijacked by the virus for its own purposes. The virus simultaneously keeps the host immune response at bay.
 
Typically the infected cell uses the interferon (IFN) pathway. The infected cell senses the presence of viral RNA transcripts and responds by promoting the entry of transcription factors into the nucleus to induce the production of type I IFNs. These bind to their receptors on the same and other cells to increase the signal strength, thus causing the secretion of hundreds of IFN-stimulated genes (ISGs) that hinder viral replication at different points.
 
Significantly the IFNs are thought to be very important in the disease process following SARS-CoV-2 infection.
 
The study team aimed at producing a picture of how the SARS-CoV-2 virus interferes with host cell translation, using RNA sequencing and ribosomal profiling to monitor both RNA production (transcription) and protein synthesis (translation) simultaneously. The experiment was carried out in duplicate to ensure the results were reproducible.
 
Surprisingly, the SARS-CoV-2 is unique in the degree of inhibition of IFN signaling. This occurs by shutting off host protein synthesis, mainly by the viral nsp1. This prevents translation by binding to the 40S ribosome, closing off the mRNA entry channel of the ribosomes. Since fewer ribosomes are available for translation, there is a global reduction in protein synthesis.
 
It was found that at  about 3 hours following infection, viral mRNA was translated at the same kind of efficiency as the host mRNA (similar translation efficiency, TE). At 8 hours post-infection, TE was shifted significantly to inhibit viral transcripts. This reduced translation efficiency perhaps because some viral mRNAs are not available for translation, being enclosed in the double-membrane compartments within which replication occurs.
 
Interestingly, this reduction in TE was focused on the ORFs at the 3’ end but not those in the middle, while those at the 5’ end had an increase in their TE relative to the others. The 5’ UTR being the same for all these ORFs, this may be because of either differing length of viral transcripts or some function of the 3’ UTR.
 
Utilizing an indicator to measure nascent protein synthesis levels, the study team found that overall, translation was already reduced at 3 hours post-infection, declining further over time until it was only 50% normal. However, total RNA remained unchanged, as did ribosomal RNA (rRNA).
 
The team found that by 8 hours post-infection, the amount of cellular and viral mRNA (indicating transcription) exceeded that of rRNA (indicating translation), due to high viral transcription. At the same time, the cellular mRNA was reduced to half. Some cellular mRNAs, however, were at higher levels, including those related to the immune response like TLR signaling, chemokines and cytokines such as IL6 and IL8, as well as several ISGs.
 
Hence, host protein synthesis was shut off by a “general reduction in the translation capacity of infected cells and reduction in the levels of most cellular mRNAs.”
 
It was also found that the cellular transcripts that were reduced were mostly cytosolic, rather than nuclear, especially those being translated.
 
Interestingly mitochondrial transcripts were also relatively spared. The study team observed that the viral nsp1 not only shuts off host cell translation on a broad scale, but accelerates the breakdown of cellular mRNAs.
 
The team also found that this increased turnover of mature cellular transcripts causes exonic reads to be reduced at a higher rate relative to intronic reads.
 
Also the viral RNA transcribed from its genome resists this breakdown, probably protected by their 5’ UTR regions.
 
This new finding is important, in that previous studies showed that the viral 5’ UTR helped viral mRNAs to be translated more efficiently by evading the global inhibition of translation.
 
The study showed that the increase in viral mRNAs was not due to the preferential translation of viral RNA in infected cells, but rather the 5’-UTR-mediated refractoriness of these mRNAs to nsp1-induced degradation.
 
Alarmingly the total mRNA content was made up of approximately 90% viral RNA, and only 10% cellular mRNA. However, at the ribosomal level, only a third of the RNA bound to these organelles (indicating active translation to proteins) comprised viral mRNA. The effect is that viral translation products become dominant in the mRNA pool within the cell.
 
Lastly, it was found that the SARS-CoV-2 coronavirus preferentially inhibits the translation of genes that are induced by the infection, including those concerned with innate immunity. Therefore, despite the increase in RNA, its inability to achieve an increase in translation may explain how the IFN response fails.
 
The study team concluded that the virus exerts “unprecedented dominance” over the type of transcription and translation that occurs following infection of a host cell.
 
The team commented, “Disruption of cellular protein production using these three components may represent a multipronged mechanism that synergistically acts to suppress the host antiviral response. Other factors like ORF6, which disrupts the transport of molecules from the nucleus to the cytosol, may also help suppress the antiviral response genes, which, though transcribed at higher levels in the nucleus, cannot induce an efficient antiviral response without being exported to the cytosol.”
 
They added, “Overall, our study provides an in-depth picture of how SARS-CoV-2 efficiently interferes with cellular gene expression, leading to shutdown of host protein production using a multipronged strategy.”
 
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