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BREAKING NEWS
Source: Coronavirus News  Jun 25, 2021  2 years, 8 months, 3 weeks, 3 days, 6 hours, 18 minutes ago

BREAKING! Washington University Study Shows That SARS-CoV-2 Is Alarmingly Evolving To Find New Ways Besides ACE2 To Infect Human Host Cells Using 484 Mutations!

BREAKING! Washington University Study Shows That SARS-CoV-2 Is Alarmingly Evolving To Find New Ways Besides ACE2 To Infect Human Host Cells Using 484 Mutations!
Source: Coronavirus News  Jun 25, 2021  2 years, 8 months, 3 weeks, 3 days, 6 hours, 18 minutes ago
Coronavirus News: More good news as Scientists from Washington University School of Medicine in St. Louis have now discovered that the SARS-CoV-2 coronavirus is evolving even faster and is now developing its own strategies to infect human host cells no longer through the ACE2 receptors but by other receptors and means! It is doing so by causing a variety of mutations involving amino acid bases at position 484 of the spike protein.


This new study warns that current antibody-based therapeutics and vaccines might actually end up no longer being effective. Already numerous variants of concerns or VOCs and variants of interest or VOIs are found to be possessing mutations such as the E484K on them and to date most researchers do not really know the true significance of this mutation. It is only a matter of time (If it has not already occurred and it is just mankind is still too slow in catching up via genomic surveillance) that an even more potent mutation has occurred at this position before the virus totally does not need to rely on any ACE2 receptors for viral entry.
 
In screening for new models of SARS-CoV-2 infection, the study team identified human H522 lung adenocarcinoma cells as naturally permissive to SARS-CoV-2 infection despite complete absence of ACE2 expression. Remarkably, H522 infection requires the E484D S variant; viruses expressing wild-type S are not infectious. Anti-S monoclonal antibodies differentially neutralize SARS-CoV-2 E484D S in H522 cells as compared to ACE2-expressing cells. Sera from vaccinated individuals did block this alternative entry mechanism, whereas convalescent sera was less effective. Though the H522 receptor remains unknown, depletion of surface heparan sulfates block H522 infection. Temporally resolved transcriptomic and proteomic profiling reveal alterations in cell cycle and the antiviral host cell response, including MDA5-dependent activation of type-I interferon signaling.
 
Importantly these findings establish an alternative SARS-CoV-2 host cell receptor for the E484D SARS-CoV-2 variant, which may impact tropism of SARS-CoV-2 and consequently human disease pathogenesis.
 
The study findings were published on the peer reviewed journal: Cell Reports By Elsevier Group. https://www.cell.com/cell-reports/pdf/S2211-1247(21)00762-2.pdf?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2211124721007622%3Fshowall%3Dtrue
 
Initially in the COVID-19 outbreak, researchers identified how SARS-CoV-2 coronavirus gets inside cells to cause infection. All current COVID-19 vaccines and antibody-based therapeutics were designed to disrupt this route into cells, which requires a receptor called ACE2.
 
Alarmingly the study team has now found that a single mutation gives SARS-CoV-2 the ability to enter cells through another route ie one that does not require ACE2.
 
Importantly, the ability to use an alternative entry pathway opens up the possibility of evading COVID-19 antibodies or vaccines.
 
Most significantly the study findings indicate that the virus can chan ge in unexpected ways and find new ways to cause infection.
 
Co-senior author Dr Sebla Kutluay, PhD, an assistant professor of molecular microbiology at Washington University told Thailand Medical News, “This mutation occurred at one of the spots that changes a lot as the virus circulates in the human population. Most of the time, alternative receptors and attachment factors simply enhance ACE2-dependent entry. But in this case, we have discovered an alternative way to infect a key cell type-a human lung cell and that the virus acquired this ability via a mutation that we know arises in the population. This is something we definitely need to know more about.”
 
This new alarming finding was serendipitous. Last year, Dr Kutluay and co-senior author Dr M. Ben Major, PhD, the Alan A. and Edith L. Wolff Distinguished Professor of Cell Biology & Physiology, planned to study the molecular changes that occur inside cells infected with SARS-CoV-2.
 
Typically most researchers study SARS-CoV-2 in primate kidney cells because the virus grows well in them, but Dr Kutluay and Dr Major felt it was important to do the study in lung or other cells similar to the ones that are naturally infected.
 
In order to find more relevant cells capable of growing SARS-CoV-2, Dr Kutluay and Dr Major screened a panel of 10 lung and head-and-neck cell lines.
 
Dr Major added, “The only one that was able to be infected was the one I had included as a negative control. It was a human lung cancer cell line with no detectable ACE2. So that was a crazy surprise.”
 
Dr Kutluay, Dr Major and the rest of the study team including co-first authors and postdoctoral researchers Dr Maritza Puray-Chavez, PhD, and Dr Kyle LaPak, PhD, as well as co-authors Dr Dennis Goldfarb, PhD, an assistant professor of cell biology & physiology and of medicine, and Dr Steven L. Brody, MD, the Dorothy R. and Hubert C. Moog Professor of Pulmonary Diseases in Medicine, and a professor of radiology, discovered that the virus they were using for experiments had picked up a mutation.
 
This virus had originally been obtained from a person in Washington State with COVID-19, but as it was grown over time in the laboratory, it had acquired a mutation that led to a change of a single amino acid at position 484 in the virus’s spike protein.
 
The SARS-CoV-2 coronavirus uses spike to attach to ACE2, and position 484 is a hot spot for mutations. A variety of mutations at the same position have been found in viral variants from people and mice, and in virus grown in the lab.
 
Interestingly some of the mutations found in virus samples taken from people are identical to the one Dr Kutluay and Dr Major found in their variant. The Alpha and Beta variants of concern have mutations at position 484, although those mutations are different.
 
Dr Major warned, “This position is evolving over time within the human population and in the lab. Given our data and those of others, it is possible that the virus is under selective pressure to get into cells without using ACE2. In so many ways, it is scary to think of the world’s population fighting a virus that is diversifying the mechanisms by which it can infect cells.”
 
In order to determine whether the ability to use an alternative entry pathway allowed the virus to escape COVID-19 antibodies or vaccines, the study team screened panels of antibodies and blood serum with antibodies from individuals who have been vaccinated for COVID-19 or recovered from COVID-19 infection. There was some variation, but in general, the antibodies and blood sera were only slightly effective against the virus with the mutation.
 
It should be noted that it is not yet clear whether the alternative pathway comes into play under real-world conditions when individuals are infected with SARS-CoV-2. Before the study team can begin to address that question, they must first find the alternative receptor that the virus is using to get into cells.
 
Dr Kutluay added, “It is possible that the virus uses ACE2 until it runs out of cells with ACE2, and then it switches over to using this alternative pathway. This might have relevance in the body, but without knowing the receptor, we cannot say what the relevance is going to be.”
 
Dr Major added, “That’s where we’re going right now. What is the receptor? If it’s not ACE2, what is it?”
 
Thailand Medical News will continue to provide updates on the second phase of this study.
 
For the latest Coronavirus News, keep on logging to Thailand Medical News.

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