Antigenic Evolution on a Global Scale Reveals the Potential Natural Selection of Severe Acute Respiratory Syndrome-Coronavirus 2 by Pre-existing Cross-Reactive T-Cell Immunity.

Chengdong Zhang,Li Qiu,Qibin Leng,Xianyang Chen,Xuanxuan Jin,Tianyi Qiu

doi:10.3389/fmicb.2021.599562

Abstract

The mutation pattern of severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) has changed constantly during worldwide community transmission of this virus. However, the reasons for the changes in mutation patterns are still unclear. Accordingly, in this study, we present a comprehensive analysis of over 300 million peptides derived from 13,432 SARS-CoV-2 strains harboring 4,420 amino acid mutations to analyze the potential selective pressure of the host immune system and reveal the driver of mutations in circulating SARS-CoV-2 isolates. The results showed that the nonstructural protein ORF1ab and the structural protein Spike were most susceptible to mutations. Furthermore, mutations in cross-reactive T-cell epitopes between SARS-CoV-2 and seasonal human coronavirus may help SARS-CoV-2 to escape cellular immunity under long-term and large-scale community transmission. Additionally, through homology modeling and protein docking, mutations in Spike protein may enhance the ability of SARS-CoV-2 to invade host cells and escape antibody-mediated B-cell immunity. Our research provided insights into the potential mutation patterns of SARS-CoV-2 under natural selection, improved our understanding of the evolution of the virus, and established important guidance for potential vaccine design.

Highlights

The coronavirus disease 2019 (COVID-19) epidemic caused by severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) is a worldwide pandemic (Lu et al, 2020; Tang et al, 2020)
In this study, we conducted a comprehensive analysis, including mapping amino acid mutations on the wholegenome sequence of SARS-CoV-2 and screening all potential T-cell epitopes (PTEs) involving mutation sites (Figures 1A,B); analyzing the immunogenicity of potential peptides based on the circulating regions of viruses worldwide and local dominant alleles (Figure 1C); analyzing the selective pressure of human leukocyte antigen (HLA) through cross-reactive epitopes (CREs) between seasonal human coronaviruses (HCoVs) and SARS-CoV-2 (Figure 1D); and evaluating the binding affinity of S protein mutants against human angiotensin-converting enzyme 2 (ACE2) and binding antibodies (Figure 1E)
The results indicated that long-term and largescale community transmission in continents such as North America and Europe led to a high mutation frequency in both ORF1ab and S proteins

Summary

INTRODUCTION

The coronavirus disease 2019 (COVID-19) epidemic caused by severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) is a worldwide pandemic (Lu et al, 2020; Tang et al, 2020). In this study, we conducted a comprehensive analysis, including mapping amino acid mutations on the wholegenome sequence of SARS-CoV-2 and screening all potential T-cell epitopes (PTEs) involving mutation sites (Figures 1A,B); analyzing the immunogenicity of potential peptides based on the circulating regions of viruses worldwide and local dominant alleles (Figure 1C); analyzing the selective pressure of HLA through cross-reactive epitopes (CREs) between seasonal HCoVs and SARS-CoV-2 (Figure 1D); and evaluating the binding affinity of S protein mutants against human angiotensin-converting enzyme 2 (ACE2) and binding antibodies (Figure 1E). We detected 13 cross-reactive HLA-II WSPs in data from South Asia; this was higher than the number of SWPs, possibly because of the lack of sequence data submitted from South Asia These results indicated that the natural selective pressure caused by pre-existing cross-reactive T-cell immunity may have driven the evolutionary direction of SARS-CoV-2 and allowed the virus to escape immune monitoring. The linear epitopes in the RBD domain could induce T-cell immunity and the mutations in RBDs could change the ability to induce T-cell immunity and alter the T-cell responses

DISCUSSION

Findings

DATA AVAILABILITY STATEMENT