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“Escape Mutation” May Help SARS-CoV-2 Avoid Immune Attacks

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Researchers in the United States have identified mutations within Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) – a drug that causes coronavirus disease 2019 (COVID-19). This may reduce the binding of antibodies to the virus and mediate the escape from the virus. Immune attack.

The team used a technique called Phage-DMS to profile this antibody escape with a surface structure called Phage-DMS. Spike protein, Used by viruses to bind to and infect host cells.

The team used blood samples from patients who recovered from COVID-19 to test all possible mutations within the spike protein. Convalescent plasma..

Team – from Fred Hutchinson Cancer Research Center And that University of Washington – Antibody binding was common in the two immune-dominant regions, but we found that there are many unique escape pathways within these regions.

These escape mutations also vary from individual to individual, suggesting that antibody binding sites and escape variants can vary widely from person to person.

“We identified a spectrum of single mutants capable of reducing antibody binding and found human-to-human variability in the effects of mutations within immune-dominant epitopes,” writes Julie Oberbo and the team. I have.

Researchers suggest that the findings suggest that people’s response to vaccines that target spike proteins is unlikely to be uniform, the researchers say.

“In the arms race between the humoral immune response and SARS-CoV-2, these results can predict the pathway of escape and the emergence of escape mutants,” the team writes.

The preprinted version of the paper bioRxiv* Servers and articles have been peer reviewed.

SpikePhage-A schematic diagram of the design of the DMS library.  (A) Structure of S protein and location of important protein domains. The structure was created at BioRender.com (PDB: 6VXX). The (B) sequence encodes a peptide with a length of 31 amino acids and steps through the Wuhan-Hu-1 SARS-CoV-2S protein external domain one amino acid at a time. It was designed computationally to line up. In the central position, there are 20 peptides representing all 20 possible amino acids, including either wild-type residues (shown in black) or mutant residues (shown in red).  Within the 31 amino acid region surrounding the D614G mutation, peptides were also produced in G614 in addition to the central 20 amino acid variant.  (C) The designed sequence was cloned into a T7 phage display vector and amplified to create the final S protein Phage-DMS library. This library was subsequently used in downstream immunoprecipitation and deep sequencing experiments with human plasma.

SpikePhage-A schematic diagram of the design of the DMS library. (A) Structure of S protein and location of important protein domains. The structure was created at BioRender.com (PDB: 6VXX). The (B) sequence encodes a peptide with a length of 31 amino acids and steps through the Wuhan-Hu-1 SARS-CoV-2S protein external domain one amino acid at a time. It was designed computationally to line up. In the central position, there are 20 peptides representing all 20 possible amino acids, including either wild-type residues (shown in black) or mutant residues (shown in red). Within the 31 amino acid region surrounding the D614G mutation, peptides were also produced in G614 in addition to the central 20 amino acid variant. (C) The designed sequence was cloned into a T7 phage display vector and amplified to create the final S protein Phage-DMS library. This library was subsequently used in downstream immunoprecipitation and deep sequencing experiments with human plasma.

Researchers are uncertain whether SARS-CoV-2 immunity will last

Determining whether immunity against SARS-CoV-2 can be protected in the long term is one of the most pressing challenges facing researchers working on the development of vaccines against SARS-CoV-2.

To answer this question, it is important to understand how the virus can evolve and escape immune defenses.

The main viral target of interest to researchers is the spike protein. This is a structure that initiates host cell binding and fusion to allow virus invasion.

Spike proteins are made up of two subunits. Subunit 1 (S1) contains the N-terminal domain (NTD) and the receptor binding domain (RBD). Subunit 2 (S2) contains a fusion peptide (FP) separated by a linker region and two seven repeating regions (HR1 and HR2) that facilitate the fusion of the virus to the host membrane.

When S1 binds to the host cell via RBD, proteolytic cleavage occurs within S2, exposing the FP and triggering a series of conformational changes that allow membrane fusion.

Neutralizing antibody Targeting RBD is the main focus of efforts to develop vaccines and antibody therapies. These neutralizing antibodies have been shown to block viral invasion in vitro and prevent infections and diseases in preclinical models.

“But other coronavirus studies have shown that infection-induced antibodies can target the outer epitope region of RBD,” says Overbaugh and colleagues. “”Therefore, there may be multiple regions within the SARS-CoV-2 spike protein that can form a viral immune response. “

In addition, the unusually high infection rate of SARS-CoV-2 and the high variability of previous coronaviruses may lead to mutants that can evade the immune response.

What did the researchers do?

Earlier, Overbaugh and his team developed a method called Phase-DMS that comprehensively maps escape mutations that allow HIV to avoid binding by monoclonal antibodies.

The team is now using this technique to identify mutations in the SARS-CoV-2 spike protein that may reduce antibody binding and mediate the escape of antibodies present in the plasma of COVID-19 patients. did.

What did they find?

The team found that antibody binding was common in two regions, the linker region upstream of FP and HR2.

This study reveals a series of single mutants that can reduce antibody binding within these regions.

However, escape mutations showed variability within these immune-dominant regions, and from person to person.

What is the meaning of research?

Findings suggest that the evolutionary pattern of the virus is unlikely to be driven by a single antibody-escape mutation. They also suggest that there are individual differences in antibody-mediated evolution of the virus.

“Therefore, the response to the SARS-CoV-2 spike protein vaccine is likely to be non-uniform and there is no escape route,” the team wrote.

Researchers say that FP and linker region / HR2 epitopes may serve as alternative targets for vaccine and immunotherapy development that may complement RBD-focused efforts.

According to the team, the entire S2, especially the FP, is highly conserved with the coronavirus. These more conserved areas can be important targets for designing optimal and durable vaccines.

“These studies defined common and variable escape mutations across COVID-19 patients that help monitor virus, especially when SARS-CoV-2 spike protein-based vaccines are introduced into the population.” The researcher is writing.

In addition, Taylor and colleagues suggest that the spiked protein phage-DMS library used in this study can be used to examine larger cohorts that may include individuals with different clinical outcomes at different ages. doing.

This could help define whether mutations that disrupt antibody binding change systematically between populations and whether this correlates with the risk of clinical outcome or reinfection, “the team said. Concludes.

*Important Notices

bioRxiv Publish preliminary scientific reports that should not be considered definitive as they are not peer-reviewed, guide clinical / health-related behaviors, and should not be treated as established information.

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