Document text
Principal Investigator: Roy A Mariuzza
Organization: UNIV OF MARYLAND, COLLEGE PARK
Fiscal Year: 2024
Award: $193,671
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the virus responsible for the global
coronavirus disease 2019 (COVID-19) pandemic. Elucidating the mechanisms underlying the adaptive immune
response to SARS-CoV-2 is crucial for predicting vaccine efficacy and assessing the risk of reinfection.
Neutralizing antibodies against SARS-CoV-2 have been studied extensively and are clearly protective, but may
be short-lived and are not elicited in all infected individuals. Mounting evidence indicates that T cells play a vital
role in the clearance of SARS-CoV-2 and in formation of long-term memory responses to this virus. Extensive
structural information is now available on neutralizing antibodies from COVID-19 convalescent patients (CPs)
bound to the SARS-CoV-2 spike trimer or RBD (>330 PDB entries), resulting in a comprehensive picture of the
B cell response to this virus. By contrast, very little structural information is available for SARS-CoV-2-specific
TCRs bound to their peptide–MHC (pMHC) targets (4 PDB entries), despite the increasingly appreciated role of
T cell-mediated immunity in combatting COVID-19. Our goal is to address this major unmet need by obtaining
atomic-level information on SARS-CoV-2 recognition by MHC class I-restricted TCRs from COVID-19 CPs. We
will focus on CD8+ T cell epitopes because cytotoxic CD8+ T cells participate directly in viral clearance. Our
Specific Aims are:
Aim 1: Determine crystal structures of TCR–pMHC complexes. We will target for X-ray
crystallographic analysis TCRs specific for epitopes that elicit high levels of TCR expansion in COVID-19 CPs,
as well as TCRs associated with protection. To demonstrate feasibility, we have already determined structures
of a public and a private TCR from COVID-19 CPs in complex with HLA-A2 and two SARS-CoV-2 spike (S)
epitopes, YLQ and RLQ. We will extend these studies to three additional S epitopes (FVF, FQF, RLN) and three
nucleocapsid (N) epitopes (LLL, LQL, SPR), which elicit strong T cell responses, and are presented by HLA-A2
or HLA-B7 MHCs. We have diverse panels of TCRs targeting each of these CD8+ T cell epitopes.
Aim 2: Analysis of TCR–pMHC structures. TCR–pMHC complex structures determined in Aim 1 will
be analyzed using advanced computational structural biology tools to delineate key features of their recognition,
as well as the predicted targeting of epitope variants from SARS-CoV-2 and related coronaviruses.
These studies will yield foundational knowledge about TCR recognition of SARS-CoV-2 epitopes, about
the generation of clonal diversity in epitope-specific TCR repertoires, and about the ways mutations in these
epitopes may enable the virus to escape immune surveillance.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><2019-nCoV vaccine><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><3-D structure><3-dimensional structure><3D structure><Address><Agammaglobulinemia><Antibodies><Antibody Response><Antigenic Determinants><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 S protein><COVID-19 antibody><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 spike><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 vaccine><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 years><COVID19 virus><CV-19><Cell Mediated Immunology><Cell-Mediated Immunity><Cellular Immunity><Class I Genes><CoV-2><CoV2><Complex><Computational toolkit><Coronaviridae><Coronavirus><Coronavirus Infectious Disease 2019><Data Bases><Databases><Deposit><Deposition><Disease><Disorder><Epitopes><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Genetics-Mutagenesis><Goals><Grant><HLA Class I Histocompatibility Antigen, A-2 Alpha Chain><HLA-A><HLA-A Class I Antigen 2><HLA-A Histocompatibility Type Antigen 2><HLA-A gene><HLA-A2><HLA-A2 Antigen><HLA-B><HLA-B Antigens><HLA-B7><HLA-B7 Antigen><HLAA><Immune><Immune Surveillance><Immunes><Immunity><Immunologic Surveillance><Immunologic Surveillances><Immunological Surveillance><Immunological Surveillances><Immunosurveillance><Individual><Infection><Influenza A><Influenza A virus><Influenza Viruses Type A><Influenzavirus A><Knowledge><Lymphocytopenia><Lymphopenia><MHC Class I><MHC Class I Genes><MHC Receptor><Major Histocompatibility Complex Receptor><Major Histocompatibility Complex, Class I, A2 Antigen><Mediating><Modeling><Molecular><Molecular Interaction><Mutagenesis><Mutagenesis Molecular Biology><Mutation><Nucleocapsid><Orthomyxovirus Type A><Patients><Peptide-MHC><Peptide-Major Histocompatibility Protein Complex><Peptide/MHC Complex><Pharmaceutical Agent><Pharmaceuticals><Pharmacologic Substance><Pharmacological Substance><Play><Privatization><Pulmonary Body System><Pulmonary Organ System><Recovery><Resolution><Respiratory System><Respiratory Tracts><Respiratory syncytial virus><Respiratory tract structure><Risk Assessment><Roentgen Rays><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S><SARS-CoV-2 S protein><SARS-CoV-2 antibody><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 vaccine><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Single Crystal Diffraction><Structure><T cell response><T memory cell><T-Cell Activation><T-Cell Antigen Receptors><T-Cell Epitopes><T-Cell Receptor><T-Cells><T-Lymphocyte><T-Lymphocyte Epitopes><T-cell receptor repertoire><T8 Cells><T8 Lymphocytes><TCR repertoire><Testing><Time><Type A Influenza><Vaccine Design><Variant><Variation><Viral><Viral Respiratory Tract Infection><Virus><Wuhan coronavirus><X Ray Crystallographies><X-Radiation><X-Ray Crystallography><X-Ray Diffraction Crystallography><X-Ray Radiation><X-Ray/Neutron Crystallography><X-ray><Xray><Xray Crystallography><activate T cells><adaptive immune response><antibody against COVID-19><antibody against SARS-CoV-2><antibody against coronavirus disease 2019><antibody against severe acute respiratory syndrome coronavirus 2><antibody to COVID-19><antibody to SARS-CoV-2><antibody to coronavirus disease 2019><antibody to severe acute respiratory syndrome coronavirus 2><computational toolbox><computational tools><computational toolset><computerized tools><corona virus><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 antibody><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 vaccine><coronavirus disease 2019 variant><coronavirus disease 2019 variant forms><coronavirus disease 2019 variant strains><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><cross reactivity><cytotoxic CD8 T cells><cytotoxic CD8 T lymphocyte><data base><design><designing><disease severity><experience><genome mutation><hCoV19><insight><long term memory><longterm memory><memory T lymphocyte><molecular sequence database><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><nCoV2><neutralizing antibody><novel><pMHC><pan CoV vaccine><pan coronavirus vaccine><panCoV vaccine><pancoronavirus vaccine><pharmaceutical><receptor binding><receptor bound><resolutions><response><sequence database><sequencing database><severe acute respiratory syndrome coronavirus 2 antibody><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 variant><severe acute respiratory syndrome coronavirus 2 variant forms><severe acute respiratory syndrome coronavirus 2 variant strains><social role><spike proteins on SARS-CoV-2><structural biology><three dimensional structure><thymus derived lymphocyte><tool><universal CoV vaccine><universal coronavirus vaccine><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidates against SARS-CoV-2><vaccine efficacy><vaccine for novel coronavirus><vaccines preventing COVID><vaccines to prevent COVID><viral respiratory infection>