Abstract
Current SARS-CoV-2 vaccines take advantage of the viral spike protein required for infection in humans. Considering that spike proteins may contain both “self” and “nonself” sequences (sequences that exist in the human proteome and those that do not, respectively), nonself sequences are likely to be better candidate epitopes than self sequences for vaccines to efficiently eliminate pathogenic proteins and to reduce the potential long-term risks of autoimmune diseases. This viewpoint is likely important when one considers that various autoantibodies are produced in COVID-19 patients. Here, we comprehensively identified self and nonself short constituent sequences (SCSs) of 5 amino acid residues in the proteome of SARS-CoV-2. Self and nonself SCSs comprised 91.2% and 8.8% of the SARS-CoV-2 proteome, respectively. We identified potentially important nonself SCS clusters in the receptor-binding domain of the spike protein that overlap with previously identified epitopes of neutralizing antibodies. These nonself SCS clusters may serve as functional epitopes for effective, safe, and long-term vaccines against SARS-CoV-2 infection. Additionally, analyses of self/nonself status changes in mutants revealed that the SARS-CoV-2 proteome may be evolving to mimic the human proteome. Further SCS-based proteome analyses may provide useful information to predict epidemiological dynamics of the current COVID-19 pandemic.
Highlights
The current COVID-19 pandemic caused by a novel coronavirus, SARS-CoV-2, started in December 2019 in Wuhan, China [1,2,3,4]
Proteomes that were not aligned exactly with the reference proteome due to insertion or deletion were excluded for simplicity; we focused on point mutations that changed amino acids and ignored insertions and deletions, resulting in 68 proteomes that were analyzed (Supplementary Materials and Methods; Additional Data 3 at GitHub)
We focused on the spike protein of SARS-CoV-2, which has a key role in establishing infection by binding to its receptor, angiotensin-converting enzyme 2 (ACE2) [38,41,42]
Summary
The current COVID-19 pandemic caused by a novel coronavirus, SARS-CoV-2, started in December 2019 in Wuhan, China [1,2,3,4]. The human immune system efficiently recognizes and eliminates foreign proteins but does not attack its own human proteins. This self/nonself discrimination is critical for immunological tolerance to avoid the development of autoimmune diseases, and it is antigen presentation by MHC (major histocompatibility complex) or HLA (human leukocyte antigen) class I and class II molecules that realizes this discrimination process [5,6,7]. An integrated strategy to overcome COVID-19 is to promote both efficient production of neutralizing antibodies and activation of CTLs against SARS-CoV-2 proteins and to repress the production of self-targeted antibodies and CTLs to avoid potential side effects
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