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Principal Investigator: John T Chang
Organization: VA SAN DIEGO HEALTHCARE SYSTEM
Fiscal Year: 2020
Funding agency: Veterans Affairs
DESCRIPTION (provided by applicant):
Mortality from chronic infectious diseases, including Hepatitis C, HIV, and tuberculosis, remains a major problem among Veterans, making the development of new vaccines an important priority of biomedical research. Immunologic memory is a cardinal feature of adaptive immunity and an important goal of vaccination strategies. Traditional vaccination strategies are very effective at generating neutralizing antibodies against bacteria and viruses. However, a vaccine capable of generating robust T cell memory is still beyond our research, due, in part, to an incomplete understanding of the molecular basis for memory lymphocyte fate specification. Moreover, the molecular mechanisms underlying immune `exhaustion,' a state in which T cells are rendered ineffective during many chronic viral infections, remain incompletely understood. Thus, a fundamental understanding of how memory lymphocyte fate is specified, as well as what goes awry in the exhausted state, is a crucial first step in rational vaccine design for infectious diseases such as HIV, HCV, malaria, and tuberculosis. Our underlying hypothesis is that previously unappreciated molecular determinants control the specification of terminal effector and memory (TCM, TEM, and TRM) cell fates as well as the exhausted CD8+ T cell state. Our goal is to identify and validate these determinants using innovative multi-disciplinary approaches that include single-cell RNA sequencing, computational analyses, and immunological techniques.
Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Acute><Bacteria><Biomedical Research><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cancers><Cell Body><Cells><Chronic><Communicable Diseases><Computer Analysis><Data><Data Set><Dataset><Development><Exhibits><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Gene Transcription><Genetic Transcription><Goals><Gut Mucosa><HCV><HCV infection><HIV><HIV/Mtb><HIV/TB><HIV/mycobacterium tuberculosis><HIV/tuberculosis><Hepatitis C><Hepatitis C virus><Hepatitis C virus infection><Hepatitis, Viral, Non-A, Non-B, Parenterally-Transmitted><Hepatitus C><Heterogeneity><Human Immunodeficiency Viruses><Immune><Immune memory><Immune system><Immunes><Immunologic Memory><Immunologic Technics><Immunologic Techniques><Immunological Memory><Immunological Technics><Immunological Techniques><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><LAV-HTLV-III><LCM Viruses><LCMV><LYT3><Lymphadenopathy-Associated Virus><Lymphocyte><Lymphocytic><Lymphocytic choriomeningitis virus><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M. tuberculosis/HIV><M.tb infection><M.tuberculosis infection><MTB infection><Malaria><Malignant Neoplasms><Malignant Tumor><Memory><Modeling><Molecular><Morbidity><Morbidity - disease rate><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Paludism><Pathway interactions><Plasmodium Infections><Population><RNA Computations><RNA Expression><Research><SCmRNAseq><Specific qualifier value><Specified><Supervision><T memory cell><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><TB infection><Transcript Expression Analyses><Transcript Expression Analysis><Transcription><Transcription Regulation><Transcriptional Control><Transcriptional Regulation><Tuberculosis><Vaccine Design><Vaccines><Veterans><Viral Diseases><Virus><Virus Diseases><Virus-HIV><adaptive immune response><adaptive immunity><allergic/immunologic body system><allergic/immunologic organ system><anamnestic reaction><base><computational analyses><computational analysis><computer analyses><design><designing><developmental><disseminated TB><disseminated tuberculosis><exhaust><exhaustion><gene expression analysis><gene expression assay><global gene expression><global transcription profile><hep C><hepatitis non A non B><improved><in vivo><infection due to Mycobacterium tuberculosis><innovate><innovation><innovative><insight><interdisciplinary approach><lymph cell><malignancy><memory T lymphocyte><microbial><microbial pathogen><mortality><multidisciplinary approach><neoplasm/cancer><neutralizing antibody><new vaccines><next generation vaccines><non A, non B hepatitis><non-A, non-B hepatitis><novel><novel vaccines><pathogenic microbe><pathway><public health relevance><response><scRNA-seq><secondary immune response><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell mRNA sequencing><single-cell RNA sequencing><thymus derived lymphocyte><transcriptional profiling><transcriptome><transcriptomics><tuberculosis infection><tuberculous spondyloarthropathy><vaccination strategy><viral infection><virus infection><virus-induced disease>