Research On Immune Characteristic And Applications In COVID-19 Based On Multi-omics Data

The coronavirus disease 2019(COVID-19),caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),is a type of acute respiratory disease.As of17 July 2022,over 550 million confirmed cases including more than 6.3 million COVID-19-related deaths were reported worldwide according to the World Health Organization.The rapid expansion of COVID-19 brings a great threat to human health and public safety,causing serious damage to the global economy.As a new pathogen,we know little about infection mechanism,prevention,and treatment of COVID-19.Hence,we conducte a joint analysis using single cell multi-omics data to elucidate the immunological characteristics of COVID-19,identify its potential vaccine antigen target,and screen monoclonal antibodies.Along with the emergence of the mutant strains,we further evaluate the effect of mutations in SARS-CoV-2 protein on the viral fitness(including viral infectivity and neutralizing antibody effectiveness)of SARS-CoV-2.To elucidate the immunological characteristics of COVID-19,we identify the COVID-19-specific changes in the composition and function of immune cells on the basis of 140 956 single-cell expression data from 12 convalescent covid-19 patients and 8 healthy controls.Firstly,SARS-CoV-2 increases the proportion of cytotoxic CD8+ T cells in all T cells and activates antigen recognition and killing function of cytotoxic CD8+ T cells.Secondly,plasma cells in convalescent covid-19 patients gained an increase of more than three folds compared with that in healthy controls,and the antibody synthesis of plasma cells is also significantly enhanced.Thirdly,both the number and phagocytosis function of classical monocytes are increased.What’s more,the number of ADCC monocytes is also increased,which suggests the antibody-dependent cell-mediated cytotoxicity activity of monocytes is enhanced.To identify the potential vaccine antigen target of COVID-19,we systematically characterize clonally expanded T cells in COVID-19 patients by integrating singlecell RNA sequencing,single-cell TCR sequencing,deep TCR repertoire sequencing,and HLA typing data from 16 convalescent covid-19 patients,and identify 916COVID-19-specific TCR groups.Then according to the "HLA-pipetide-TCR" molecular basis of the T cell-mediated adaptive immune response,we identify 114 candidate antigenic epitopes from SARS-CoV-2.Our findings provide guidance for efficient SARS-CoV-2 vaccine design.To screen the monoclonal antibody from plasma of early-stage convalescent covid-19 patients,we integrate single-cell RNA sequencing,single-cell BCR sequencing,and deep BCR repertoire sequencing data to systematically characterize clonally expanded B cells in 16 COVID-19 patients and identify COVID-19 specific BCR groups.On the biological basis of antibody maturation,we combine the bioinformatics prediction approach with experimental evidence and identify 3 human monoclonal antibodies with potent neutralizing activity and natural heavy and light chain pairing.Our results provide a valuable SARSCoV-2 neutralizing monoclonal antibody for the prevention and treatment of COVID-19.More importantly,we also provide an additional promising reagent for future medicines against the rapidly evolving SARS-CoV-2 virus.To evaluate the effect of mutations in SARS-CoV-2 protein on viral fitness,we characterize the spatiotemporal evolution of common mutations in SARS-COV-2spike protein on the basis of 1 750 995 genomic sequences from different times and regions.Then we develop a software named Mut Cov to evaluate the effect of mutations in spike protein on infectivity and antigenicity of SARS-CoV-2 utilizing homology modeling,molecular dynamics simulations,and binding free energy calculation methods.Mut Cov is used to evaluate the effect of novel mutations,the results show the N439 K mutation confers the SARS-CoV-2 more infectious than the original strain.Meanwhile,the N439K-mutated strain shows resistance to some neutralizing antibodies,especially for neutralizing antibody REGN10987.Our findings reveal the structural mechanism under viral fitness of N439 K,and also provide guidance on the assessment of the infection efficiency and antigenicity effect of continuing mutations in SARS-CoV-2.In conclusion,we integrate single cell multi-omics data from the COVID-19 patients and healthy controls.Firstly,our findings reveal the immunological characteristics of COVID-19 and deeply analyze the molecular basis under the change of lymphocyte subsets.Secondly,on the basis of T lymphocyte immunological characteristics,we identify candidate antigenic epitopes from the virus proteins,and provide guidance for efficient SARS-CoV-2 vaccine design.Thirdly,we identify the COVID-19 antigen-specific BCR with potent neutralizing activity,and also provide a valuable SARSCoV-2 neutralizing monoclonal antibody for the prevention and treatment of COVID-19.Finally,we develop the Mut Cov,which is a rapid and accurate pipeline for evaluating the effect of mutations in spike protein on SARSCoV-2 infectivity and antigenicity.Those findings not only will be of value for the current epidemic prevention,but also provide guidance on the possible future epidemics.