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Principal Investigator: Tuoqi Wu
Organization: UT SOUTHWESTERN MEDICAL CENTER
Fiscal Year: 2024
Award: $246,000
Funding agency: National Institute on Aging
Summary
Immunosenescence increases morbidity and mortality after infection and reduces vaccine efficacy. Most deaths
associated with infections by influenza virus, SARS-CoV, or SARS-CoV-2 occurred in people older than 65. Thus,
understanding the mechanism of age-associated decline in antiviral immunity is critical to the development of
strategies to protect the elderly from viral pathogens. Despite its critical role in protection against infections, T-
cell immunity declines with age. During aging, the prevalence of naïve T cells decreases, whereas the frequency
of terminally differentiated CD8 T cells increases. In addition, aging reduces the responsiveness of naïve T cells
to antigen. However, the molecular mechanism underlying age-associated decline in antiviral T cell immunity
remains poorly defined. Using a mouse model of murine hepatitis virus (MHV) infection, we found that aging
increased mortality and decreased antiviral CD4 and CD8 T cell responses. Surprisingly, although aging
increased terminally differentiated CD8 T cells at baseline, there was a profound reduction in terminally
differentiated effector CD8 T cells and an elevated gene-signature of T-cell exhaustion in aged mice after MHV
infection. In addition, we showed that age-associated decline in T-cell expansion was primarily caused by TCR-
triggered apoptosis and necroptosis pathways and was rescued by rebalancing TCR and IL2 signaling. We also
found that aging reduced the metabolic rate of T cells at baseline and impaired metabolic adaptation of T cells
after activation. Here, we hypothesize that age-associated exhaustion-prone epigenetic state and defective
metabolic adaptation impair effector CD8 T cell response in viral infection. In this study, we will define the
epigenetic and metabolic pathways in antiviral CD8 T cells altered by aging before and after infection, while
accounting for age-associated changes in differentiation. We will also evaluate strategies that harness IL2 and
TCR pathways to rescue age-related defects in antiviral CD8 T cells.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><ATAC><Age><Aged 65 and Over><Aging><Aldesleukin Gene><Antigens><Apoptosis><Apoptosis Pathway><Assay><Basal Transcription Factor><Basal transcription factor genes><Binding><Binding Sites><Bioassay><Biological Assay><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 virus><COVID19 virus><Cell Body><Cell Communication and Signaling><Cell Lineage><Cell Signaling><Cells><Cellular Metabolic Process><Cessation of life><Chromatin><Chronic><CoV-2><CoV2><Combining Site><Communicable Diseases><Coronaviridae Infections><Coronavirus Infections><Data><Death><Defect><Development><Elderly><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Equilibrium><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Frequencies><Future><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genes><Genetic Transcription><IL-2 Gene><IL2><IL2 gene><Immune><Immune response><Immunes><Immunity><Immunological response><Impairment><In Vitro><Individual><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Interleukin 2 Precursor Gene><Interleukin-2 Gene><Intermediary Metabolism><Intracellular Communication and Signaling><LPTN><Metabolic><Metabolic Pathway><Metabolic Processes><Metabolism><Mice><Mice Mammals><Modeling><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Mouse Hepatitis Coronavirus><Mouse Hepatitis Virus><Murine><Murine Gastroenteritis Virus><Murine hepatitis virus><Mus><Older Population><PD 1><PD-1><PD1><Pathway interactions><Prevalence><Programmed Cell Death><RNA Expression><RNA Seq><RNA sequencing><RNAseq><Reactive Site><Role><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><SCM-1><SCM-1a><SCM1><SCYC1><Severe Acute Respiratory Coronavirus><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 Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><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 related corona virus 2><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Stimulus><T cell differentiation><T cell response><T-Cell Growth Factor Gene><T-Cell Subsets><T-Cells><T-Lymphocyte><T-Lymphocyte Subsets><T8 Cells><T8 Lymphocytes><TCGF Gene><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Viral><Viral Diseases><Viral hepatitis><Virus><Virus Diseases><Wuhan coronavirus><XCL1><XCL1 gene><aberrant aging><abnormal aging><above age 65><advanced age><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated><age associated alterations><age associated changes><age associated decline><age correlated><age correlated alterations><age correlated changes><age dependent><age dependent alterations><age dependent changes><age dependent decline><age linked><age of 65 years onward><age related><age related alterations><age related changes><age related decline><age specific><age specific alterations><age specific changes><aged><aged 65 and greater><aged 65+><aged mice><aged mouse><aged ≥65><ages><alterations with age><anti-viral immunity><antiviral immunity><balance><balance function><biological signal transduction><cell metabolism><cellular metabaolism><changes with age><coronavirus disease 2019 virus><coronavirus disease-19 virus><decline with age><developmental><dysfunctional age related change><dysfunctional aging><elderly mice><epigenetically><exhaust><exhaustion><experiment><experimental research><experimental study><experiments><flow cytophotometry><flu infection><flu virus infection><gene signatures><genetic signature><geriatric><global gene expression><global transcription profile><hCoV19><hepatitis virus infection><host response><human old age (65+)><immune senescence><immune system response><immunogen><immunoresponse><immunosenescence><impaired aging><improved><infected with flu><infected with flu virus><infected with influenza><infected with influenza virus><influenza infection><influenza virus infection><maladaptive aging><metabolic rate><mortality><mouse model><murine hepatitis coronavirus><murine model><nCoV2><old age><old mice><older groups><older individuals><older person><over 65 years><pathogenic virus><pathological age related changes><pathological aging><pathway><programmed cell death 1><programmed cell death protein 1><programmed death 1><programs><scRNA-seq><senior citizen><severe acute respiratory syndrome-CoV><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><sle2><social role><systemic lupus erythematosus susceptibility 2><thymus derived lymphocyte><transcription factor><transcriptome><transcriptome sequencing><transcriptomic sequencing><vaccine efficacy><viral infection><viral pathogen><virus infection><virus pathogen><virus-induced disease><≥65 years>