Source: COVID-19 Research  Dec 14, 2020  2 years ago
New COVID-19 Research Identifies TMEM41B Transmembrane Protein As Key Component Needed For SARS-CoV-2 Replication. East Asians At Advantage!
New COVID-19 Research Identifies TMEM41B Transmembrane Protein As Key Component Needed For SARS-CoV-2 Replication. East Asians At Advantage!
Source: COVID-19 Research  Dec 14, 2020  2 years ago
A new COVID-19 research study by scientists from the Rockfeller University-New York, New York University School of Medicine and Heidelberg University-Germany  have identified a single protein that appears necessary for the COVID-19 virus to reproduce and spread to other cells.

The current COVID-19 pandemic has claimed the lives of over 1.61 million individuals worldwide. The causative agent, SARS-CoV-2, is a member of the Coronaviridae family of viruses that can cause respiratory infections of varying severity. The cellular host factors and pathways co-opted during SARS-CoV-2 and related coronavirus life cycles remain ill-defined.
In order to address this gap, the study team performed genomescale CRISPR knockout screens during infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-OC43, HCoV-NL63, and HCoV-229E).
These screens uncovered host factors and pathways with pan-coronavirus and virus-specific functional roles, including major dependency on glycosaminoglycan biosynthesis, SREBP signaling, BMP signaling, and glycosylphosphatidylinositol biosynthesis, as well as a requirement for several poorly characterized proteins.
The study team identified an absolute requirement for the VTT-domain containing protein TMEM41B for infection by SARS-CoV-2 and three seasonal coronaviruses. This human Coronaviridae host factor compendium represents a potential weakness of the virus and a rich resource to develop new therapeutic strategies for acute COVID-19 and potential future coronavirus pandemics.
The study findings were published in the peer reviewed journal: Cell.
This molecule, known as transmembrane protein 41 B (TMEM41B), is believed to help shape the fatty outer membrane that protects the virus' genetic material while it replicates inside an infected cell and before it infects another.
The study team revealed that TMEM41B was essential for SARS-CoV-2 to replicate. In a series of experiments, the study team compared how the SARS-CoV-2 coronavirus reproduces in infected cells to the same processes in two dozen deadly flaviviruses, including those responsible for yellow fever, West Nile, and Zika disease.
The study team also compared how it reproduces in infected cells to three other seasonal coronaviruses known to cause the common cold.
The research represent the first evidence of transmembrane protein 41 B as a critical factor for infection by flaviviruses and, remarkably, for coronaviruses, such as SARS-CoV-2, as well."
Dr John T. Poirier, PhD, Co-Senior Investigator, NYU Langone Health / NYU School of Medicine told Thailand Medical News, "An important first step in confronting a new contagion like COVID-19 is to map the molecular landscape to see what possible targets you have to fight it."
Dr Poirier, an assistant professor of medicine at NYU Langone Health added, "Comparing a newly discovered virus to other known viruses can reveal shared liabilities, which we hope serve as a catalogue of potential vulnerabilities for future outbreaks.& amp;quot;
He further added," While inhibiting transmembrane protein 41 B is currently a top contender for future therapies to stop coronavirus infection, our results identified over a hundred other proteins that could also be investigated as potential drug targets."
Dr Poirier also serves as director of the Preclinical Therapeutics Program at NYU Langone and Perlmutter Cancer Center.
In the research, the study team used the gene-editing tool CRISPR to inactivate each of more than 19,000 genes in human cells infected with each virus, including SARS-CoV-2.
The team then compared the molecular effects of each shutdown on the virus' ability to replicate.
Interestingly, in addition to TMEM41B, some 127 other molecular features were found to be shared among SARS-CoV-2 and other coronaviruses.
Among the included were common biological reactions, or pathways, involved in cell growth, cell-to-cell communication, and means by which cells bind to other cells. However, researchers say, TMEM41B was the only molecular feature that stood out among both families of viruses studied.
Importantly, Dr Poirier notes, mutations, or alterations, in TMEM41B are known to be common in one in five East Asians, but not in Europeans or Africans. He cautions, however, that it is too early to tell if this explains the relatively disproportionate severity of COVID-19 illness among some populations in the United States and elsewhere.
Also another study finding was that cells with these mutations were more than 50 percent less susceptible to flavivirus infection than those with no gene mutation.
Dr Poirier says more research is needed to determine if TMEM41B mutations directly confer protection against COVID-19 and if East Asians with the mutation are less vulnerable to the disease.
The study team next plans to map out TMEM41B's precise role in SARS-CoV-2 replication so they can start testing treatment candidates that may block it.
The researchers also has plans to study the other common pathways for similar potential drug targets.
Dr Poirier adds that the research team's success in using CRISPR to map the molecular weaknesses in SARS-CoV-2 serves as a model for scientists worldwide for confronting future viral outbreaks.
The Study team concluded, “In summary, we identified complex, interconnected networks of coronavirus host factors and pathways that are essential for virus infection, nominating hundreds of host proteins that represent liabilities for SARS-CoV-2 and potential opportunities for therapeutic intervention. This represents an extensive functional catalog of host factors required for infection by SARS-CoV-2 and three seasonal coronaviruses (HCoV-229E, HCoV-NL63, and HCoV-OC43), providing a larger context in which to interpret ongoing and future large scale CRISPR studies. Future efforts will focus on dissecting the complex interplay between virus and host and direct medicinal chemistry and drug repurposing resources toward the most chemically-tractable targets.”
For the latest on COVID-19 Research, keep on logging to Thailand Medical News.


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