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Principal Investigator: Mark Morris Davis
Organization: STANFORD UNIVERSITY
Fiscal Year: 2024
Award: $187,843
Funding agency: National Cancer Institute
PROJECT 3: SUMMARY
COVID-19 is currently a global pandemic, but human T cell responses contributing to the quantity and quality of
SARS-CoV-2 specific antibodies, or acting by cytotoxic mechanisms on infected cells, remain poorly understood.
In this U54 Project, we will study virus-specific T cell immunity in the blood as well as the respiratory mucosal
tissues where the virus is likely to initiate infection. We will also compare responses to natural infection with
those generated by a peptide-based vaccine in early clinical trials, and in other vaccines approved during this 5-
year study. Our groups have previously developed a suite of innovative, high-throughput technologies and
computational algorithms to enable the analysis of TCR alpha beta sequences, transcriptional profiles, and
epigenetic states in primary T cells from human samples, providing a comprehensive view of T cell specificity
and molecular phenotype. We hypothesize that a critical component of immunity to SARS-CoV-2 is the antigen-
specificity, phenotype, and epigenetic durability of the T cell response, and the goal of this study is to measure
these components using high-throughput genomic tools to inform clinical profiles of protective immunity and the
design of effective vaccination strategies. In the first aim, we will build a comprehensive database of TCRs
specific for SARS-CoV-2 and its variants to identify private and shared TCR specificities associated with disease
response and immunity. In the second aim, we will pair TCR specificities with transcriptional and epigenetic
phenotypes in SARS-CoV-2-specific T cells to identify immunotypes of the virus-specific T cell response. In the
third aim, we will investigate the role of epigenetic changes due to X chromosome inactivation in lymphocytes in
sex bias in COVID-19 immunity. We will pursue these aims in the context of several large patient cohorts of
COVID-19 patients, convalescent donors, and healthy subjects developed by the Clinical Virology Core, and all
T cell response data will be integrated with serology and B cell measurements in collaboration with Projects 1
and 2. Altogether, our studies will guide efforts to understand: (1) the diversity and specificity of antigen-specific
T cell responses in COVID-19 patients, (2) the phenotypes and durability of T cell memory in recovered
individuals, (3) relationships between T and B cell responses to SARS-CoV-2, and (4) T cell responses
stimulated by vaccination compared to natural infection.
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virus><CV-19><Cell Body><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Characteristics><Chromatin><Clinical><Clinical Data><Clinical Virology><CoV-2><CoV2><Collaborations><Communities><Computational algorithm><Coronavirus Infectious Disease 2019><Data><Data Analyses><Data Analysis><Data Bases><Data Set><Databases><Disease><Disorder><Ensure><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epitopes><Expression Signature><Female><Gender Bias><Gene Expression Profile><Gene Transcription><Genetic><Genetic Transcription><Genome><Genomics><Goals><HCoV><HLA testing><HLA typing><Human><Immune Cell Activation><Immunity><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Individual><Infection><Link><Lymphatic cell><Lymphocyte><Lymphocytic><Lyonization><Measurement><Measures><Modeling><Modern Man><Molecular Analysis><Mucosa><Mucosal Tissue><Mucous Membrane><NGS Method><NGS system><Patients><Peptides><Peripheral Blood Cell><Phenotype><Privatization><Process><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Receptors, Antigen, T-Cell, alpha-beta><Respiratory Mucosa><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 antigen><SARS-CoV-2 immunity><SARS-CoV-2 infected patient><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Serology><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-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 immunity><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Sex Bias><Site><Specificity><Subcellular Process><T Cell Specificity><T cell receptor repertoire sequencing><T cell receptor sequencing><T cell response><T memory cell><T-Cell Immunologic Specificity><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><TcR alpha-beta><TcR αβ><Technology><Testing><Tissues><Transcription><Transposase><Vaccination><Vaccines><Variant><Variation><Viral><Viral Antigens><Virus><Work><Wuhan coronavirus><X Inactivation><X-Chromosome Inactivation><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><alpha-beta T-Cell Receptor><antigen-specific T cells><cohort><computer algorithm><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 antigen><coronavirus disease 2019 immunity><coronavirus disease 2019 infected patient><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytotoxic><data base><data integration><data interpretation><design><designing><driving><early clinical trial><early phase clinical trial><epigenetically><female outcomes><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following infection by SARS-CoV-2><following severe acute respiratory distress syndrome CoV-2 infection><gene expression pattern><gene expression signature><genome scale><genome-wide><genomewide><genomic tools><global gene expression><global transcription profile><hCoV19><high throughput technology><human CoV><human corona virus><human coronavirus><human leukocyte antigen testing><human leukocyte antigen typing><immune activation><immunity against COVID-19><immunity against SARS-CoV-2><immunity against Severe acute respiratory syndrome coronavirus 2><immunity against coronavirus disease 2019><immunity to COVID-19><immunity to SARS-CoV-2><immunity to Severe acute respiratory syndrome coronavirus 2><immunity to coronavirus disease 2019><immunization strategy><immunogen><improved outcome><innovate><innovation><innovative><interest><lymph cell><memory T lymphocyte><molecular phenotype><nCoV2><next gen sequencing><next generation sequencing><nextgen sequencing><novel><outcomes among females><outcomes among women><outcomes in females><outcomes in women><pandemic><pandemic disease><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><peptide based vaccine><post SARS-CoV-2 infection><pre-pandemic><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><programs><response><severe acute respiratory syndrome coronavirus 2 antigen><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><social role><spike proteins on SARS-CoV-2><thymus derived lymphocyte><tool><transcriptional profile><transcriptional signature><transcriptome><transcriptome sequencing><transcriptomic sequencing><vaccination strategy><virus antigen><women's outcomes><αβ T-Cell Receptor>