In a recent study published on the bioRxiv* preprint server, researchers investigate the relationship between the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant and the human immune system by developing a simple approach for predicting antigenicity based on self/nonself short constituent sequences (SCSs).
The SARS-CoV-2 Omicron variant has the most significant number of unique mutations compared to any other variant of this virus. As a result, these mutations have caused the Omicron variant to also be more infectious and transmissible than prior variants, thus posing a serious public health risk.
Study: Nonself Mutations in the Spike Protein Suggest an Increase in the Antigenicity and a Decrease in the Virulence of the Omicron Variant of SARS-CoV-2. Image Credit: MedMoMedia / Shutterstock.com
Overview of self/nonself SCSs
Major histocompatibility complex (MHC) molecules present short amino acid sequences as peptides to the human immune system, which allow it to recognize foreign proteins. An SCS is a segment of an amino acid sequence that exists as part of a protein.
All conceivable SCSs from the human proteome are stored in the immune system's memory, which is referred to as self SCSs here. A collection of self SCSs is used to collate every peptide offered by MHC molecules.
When a sequence of a certain peptide presented by MHC molecules is discovered in the dataset, it is identified as "self," or a component of the human body. Comparatively, when a peptide sequence is not discovered in the dataset, it is classified as "nonself," or a foreign entity that the immune system must destroy.
About the study
In the current study, SCSs consisting of five amino acids were recovered from SARS-CoV-2 proteomes by sliding one amino acid residue from the N-terminus to the C-terminus at a time. The SARS-CoV-2 SCSs were divided into two categories including self, which are found in the human reference proteome, and nonself, which are not found in the human reference proteome.
At the initial position of each amino acid in a protein sequence, the researchers assigned a 0 (self; invisible to the host immune system) or 1 (nonself; visible to the host immune system) to each SCS in the SARS-CoV-2 proteome. The number of nonself SCSs was manually counted and assigned in sequence maps based on the program's self (0) or nonself (1) assignments.
In this study, a nonself mutation produces a shift in SCS status from self to nonself. A nonself SCS is created as a result of such a mutation. A self-mutation, on the other hand, is a mutation that causes a nonself-to-self SCS status change, resulting in a self SCS. In a protein or a proteome, an increase in nonself SCSs equals a decrease in self SCSs and vice versa.
Self/nonself mapping of the SARS-CoV-2 spike protein of the Delta variant. The first amino acids of nonself SCSs are indicated by green (present in RefSeq) or red (new in this variant) shading. Other SCSs with no such indications are self SCSs. The receptor-binding domain (RBD)  is boxed in pink lines. The receptor-binding motif (RBM) is shaded in pink. The nonself SCSs in the RBM are boxed in black lines. A potentially important nonself SCS region for vaccine development in the RBD is underlined in blue. For self/nonself mapping of RefSeq, see Otaki et al. (2021)
At the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein, the researchers discovered that the Omicron variant has acquired self-to-nonself status change mutations. In the RBD, the Omicron variant has seven new nonself SCSs as compared to only two in the Delta variant.
In the Omicron variant, the net increase in nonself SCSs within the RBD was +4, which is comparable to the +2 in the Delta variant. As the RBD is easily accessible to other proteins including the angiotensin-converting enzyme 2 (ACE2) receptor, antibodies, and T-cell receptors, this increase is likely immunologically significant.
In both the Omicron and Delta variants, there were only two newly added nonself SCSs in the non-RBD regions. However, the Omicron variant introduced more new self SCSs in the non-RBD regions than that in the non-RBD regions of the Delta variant and the RBD regions of the Omicron variant.
In the Omicron variant, the increase in self SCSs in non-RBD regions may compensate for the rise in nonself SCSs in the RBD, thereby resulting in a small net nonself SCS increase and lower antigenicity. Indeed, in the Omicron and Delta variants, the differences in nonself SCS modifications between the RBD and non-RBD regions (ΔN) were +7 and +3, respectively. The Omicron variant is most likely the result of offensive evolution with a high antigenicity compromise.
Within the receptor-binding motif (RBM) of the reference sequence (RefSeq) spike protein, the researchers identified a prospective stretch of amino acids containing nonself SCSs, which could be used to develop a vaccine to prevent vaccination-induced autoimmunity. Three additional nonself SCSs were present at the N-terminal side of the potential epitope region in the Omicron variant but not in the Delta variant, and two additional nonself SCSs were present at the C-terminal side, despite the absence of one nonself SCS in RefSeq.
Both the N-terminal and C-terminal sides of the putative epitope region in RefSeq have been extended. Since this area of the RBM is critical for ACE2 binding, it was likely inevitable to expand this nonself SCS epitope region to increase ACE2 binding affinity at the expense of antigenicity.
Since the evolution of SARS-CoV-2 may have been influenced by selection pressure imposed by worldwide vaccination, vaccine-focused techniques targeting the Omicron variant could improve the current mode of evolution. Alternatives to vaccination-based strategies could also be beneficial.
“It appears that the Omicron variant increased its infectivity and transmissibility at the expense of higher antigenicity and lower virulence.”
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.