Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), responsible for coronavirus disease 2019 (COVID-19), has caused nearly 4.5 million deaths worldwide and infected nearly 211 million in 19 d August 2021.
To date, millions of doses of COVID-19 vaccines have been deployed worldwide, which has significantly reduced the rate of COVID-19 infections, hospitalizations, and deaths. Despite these efforts, emerging SARS-CoV-2 variants that prevent antibody neutralization against previous lineages have threatened the efficacy of current vaccines.
A new study published on the prepress server bioRxiv * explores the mechanism by which the lambda variant of SARS-CoV-2 has acquired higher immune escape capabilities than the wild-type. This seems to involve shortening the epitopes of the spike viral protein, as well as acquiring additional sites that may be N-glycosylated.
To study: Cut out epitopes to survive: the case of the lambda variant. Image credit: manaemedia / Shutterstock.com
Background
The SARS-CoV-2 lambda variant was first identified in Peru, but has spread rapidly to other parts of South America and the United States. The peak SARS-CoV-2 protein, which contains the viral receptor binding domain (RBD), binds to the angiotensin converting enzyme 2 (ACE2) receptor in the host cell.
Although the data have shown how SARS-CoV-2 RBD mediates the entry of this virus into the cell, its precise interaction with the host cell is not fully understood. Mutations in both peak protein and RBD are key to the increased resistance of new SARS-CoV-2 variants to antibody-mediated neutralization and infectivity.
About the study
In the current study, the scientists compared the genetic sequence of the spike of the lambda variant and the Wuhan reference sequence. The mutations observed in the RBD were modeled on the crystal structure using appropriate software.
After incorporating the point mutations observed in this variant, computational modeling predicted its effect on spike structure and glycosylation sites.
Study results
The results showed that two of the lambda mutations, G75V and T76I, were located in an exposed loop between two antiparallel β chains. Both mutations were found to stabilize the peak glycoprotein. In addition, these two mutations appear to ensure that the loop remains in contact with another loop between positions 246-280, which is a binding site for virus-specific monoclonal antibodies (MAbs).
The 246-252 suppression mutation is also found in this loop. This suppression may affect the N-terminal domain binding affinity (NTD) of the ear to human MAbs.
To confirm the role of this deletion mutation in NTD, a Mab spike-4A8 complex was studied in detail. The mutant NTD overlapped with the wild-type domain of the ear-antibody complex.
All in all, that in silico The experiment showed that MAb interacts less strongly with the loop when there is partial suppression, thus causing a weaker binding affinity as a result of the loss of several potential interactions. This key suppression of NTD in the lambda strain results in the loss of interactions between L249 and F60 and Y54 of the 4A8 MAb light chain.
A) Map of lambda mutations in the spike structure of Spike. Only one mutation per monomer has been indicated. B) NTD-4A8 interface. The mutant NTD has been modeled via SwissModel and superimposed on the wild-type domain of the complex. Interface interactions and energies calculated by PRODIGY have been compared. Comparison of interfaces between wild type (green drawing) and lambda NTD (gray drawing) and mAb 48A in the suppression region. The red and blue patterns indicate the heavy and light chain respectively. The side chains of the deleted loop and the residues that interact are indicated with stick models and labeled. Sequence numbering refers to the wild-type spike.
Other mutations
The L452Q and F400S point mutations in the RBD of the SARS-CoV-2 lambda variant do not appear to significantly affect domain stability; however, these mutations convert the hydrophobic residue here into a hydrophilic one. The result is a highly hydrophilic surface of the RBD.
These sites are susceptible to solvation near RBD-ACE2 binding, with both the wild-type and mutant RBD showing almost the same binding affinity. The D614G mutation of the S1 domain emerged early and was responsible for the rapid rise of the lineage to the global domain.
In the S2 subunit of the ear protein, T859N is expressed near the G614 mutant of the neighboring subunit. In general, this mutation is not expected to affect the stability of the molecule.
Interestingly, as a result of this change, a new hydrogen bond to H487 occurs. The researchers suggest that the two mutations of D614G and T859N together can cause a long-range allosteric effect that affects the structural flexibility of the complex.
Implications
This prototype modeling analysis of the RBD receptor complex appears to dissociate the mutations defining the lambda variant from any effect on RBD-ACE2 binding affinity. The mechanism by which the former affects virus transmission is still uncertain.
One explanation is that mutations in the S2 domain exert a long-range allosteric effect, which changes the flexibility of protein conformation and its affinity for the ACE2 receptor. A better suggestion is that suppression 246-252 in the lambda variant is likely to be responsible for its functional change that allows this variant to escape the host’s immune response.
The ability of the lambda variant to escape the immune response is probably achieved in two possible ways. One explanation is the shortening of the antibody binding sites to the ear protein loops, while the other is by changing the level of glycosylation upward. These factors have already been shown to occur during viral transmission and protect the virus from antibody recognition.
In another recent prepress study, a suppression of seven residues in the NTD of the lambda variant was observed. This suppression could make this variant resistant to antiviral immunity, according to the findings of the current study.
“Biophysical and bioinformatics data suggest that a combination of shortening of immunogenic epitope loops and the generation of potential N-glycosylation sites may be a viable adaptation strategy that allows this emerging viral variant to escape immune immunity. host“.
* Important news
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice / health-related behavior, or treated as established information.