New spike NTD mutations in SARS-CoV-2 delta mutants associated with increased viral load and antigenic escape

One of the remaining concerns is the spread of the Variant of Concern (VOC), as vaccination programs help reduce the infection of Severe Acute Respiratory Syndrome Coronavirus 2019 (SARS-CoV-2). These mutants are known to evade an effective immune response against the original strain found in Wuhan, China.

study: The SARS-CoV-2 delta VOC peplomer NTD mutation G142D is associated with frequent reverse mutations, increased viral load, and antigenic escape... Image Credit: Corona Borealis Studio / Shutterstock

Of particular concern is the Delta mutant, which originated in India and soon became the world’s predominant strain. Most VOCs have mutations that affect the SARS-CoV-2 spike protein, especially the receptor binding domain (RBD) of the S1 subunit. This is because it is a region that binds to angiotensin converting enzyme 2 (ACE2) and enables membrane fusion. Viral entry into cells.

Researchers at the University of Southern California investigated mutations in the N-terminal and RBD domains of pesplomers to further investigate increased infection, viral load, and pathogenicity of delta variants.

The preprinted version of the study medRxiv* Server while the article is being peer reviewed.

the study

Scientists use reverse transcriptase-polymerase chain reaction (RT-PCR) to confirm previous infection of the sample from the Los Angeles Children’s Hospital, then sequence the entire genome of the sample and strain the mutant strain. We analyzed the occurrence and structure. The final dataset was formed from over 15,000 SARS-CoV-2 genomes, but contained only about 12,500. Phylogenetic analysis Because of quality concerns.

They initially discovered that the delta mutants showed far fewer peplomer mutations than the other mutants-an average of 9.66-10.12 missense mutations per genome. However, the delta variant strain showed a much faster increase in per-genome mutations in the genes encoding peplomers and the genes ORF7a and ORF7b.

In addition to this, the mutant spike G142D was present in almost all major delta substrains. The mutation was incorporated in late September 2020 and may have spread to most other major branches by November. Other mutations, such as T951, did not show the same pattern. If an individual is infected with a delta variant of SARS-CoV-2, both G14D2 and T951 are associated with higher viral load. If both of these mutations are present, the conversion from the beta strand to the alpha helix results in Spike protein N-terminal domain.

The group’s findings are supported by previous studies. Neutralizing antibody It is effective against the original strain of SARS-CoV-2 generated against the N-terminal domain and loses their efficiency against the delta strain. Changes in surface topography can expose residues facing the new antibody and reduce antibody binding to this region. Mutations in both T951 and G142D alter the structure of this region, but G142D appears to elicit the most important changes.

The G142D mutation appears to have been repeatedly acquired, lost, and recovered across multiple Delta strains. The widespread random RNA polymerase error in SARS-CoV-2 does not appear to be entirely the cause. The characteristics of RNA editing are clear. The change from adenosine to inosine and from cytosine to uracil suggests that APOBEC deaminase and ADAR protein, both of which play a role in host immunity, may be the underlying cause behind these mutations. is showing. Therefore, the host’s immune response may be responsible for the heterogeneity found in the SARS-CoV-2 genome. It is already believed that this may trigger the D614G mutation, which is present in all delta strain variants.

Conclusion

The authors propose that a delta variant with the mutant G142D, which alters the conformation of the N-terminal domain of the peplomer, leads to reduced binding of neutralizing antibodies. The presence of the T951 mutation exacerbates this effect.

Structural changes reduce the effectiveness of neutralizing antibodies by presenting alternative residues to the N-terminal domain epitope, which is a common target for antibodies. This increases the viral load of the host and can be a major contributor to the increased transmission rate of delta mutants. ..

Researchers have emphasized the increased frequency of peplomer mutations and raised awareness of the evolutionary trajectory of concern for SARS-CoV-2. Further mutations that alter the structure of the N-terminal domain or RBD can dramatically increase the rate of reinfection and vaccine / antigenic escape.

*Important Notices

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