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Principal Investigator: David M Koelle
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2020
Award: $563,301
Funding agency: National Institute on Aging
Project Summary:
The waning of immunity has a major impact on morbidity and mortality in the aged.
Antigen-specific, acquired, and especially T-cellular is important in host defense against
chronic intracellular pathogens and cancer. Infections with these microbes and skin
cancers with high mutational burdens and neoepitope loads, are disproportionally high
in the elderly. In this application, the investigative team uses an established tetramer
and TCR toolkit for the study of T-cell responses to varicella zoster virus infections
(VZV) in humans to determine the mechanisms of age-related susceptibility to shingles,
and the mechanisms of action of a uniquely successful vaccine that retains efficacy in
the elderly.
Recently, it has been appreciated that host defense against many localized infections
is mediated by special populations of tissue resident memory cells, abbreviated TRM. As
murine and human studies have advanced, the lineage of TRM, TRM subsets, and the
transcriptional and metabolic signature of TRM in various tissues have begun to come
into focus. TRM are locally mobile, patrol tissue for antigen, and can proliferate upon
antigen re-exposure, yet do not re-enter the blood and are out of reach of blood-based
studies. Notably, studies of human antigen-specific TRM are rare, such that assays of
overall TRM populations may overlook the complexity of TRM.
Here, we use VZV infection and vaccination as related probes of TRM T-cells across
the age spectrum. Aim 1 focuses on endogenous reactivation of VZV and uses biopsies
of healed shingles and control skin to, for the first time, fully characterize helpful human
virus-specific TRM at the single cell level. Aim 2 uses the new RZV vaccine for shingles
prevention, which retains efficacy even in aged adults, to determine if the vaccine leads
to TRM seeding in the skin, improvement in the pool of homing-committed cells in the
blood, or both. Taken together, these studies will increase our understanding of age-
related changes in vital effector T-cells and strategies that may be useful to overcome
immune senescence.
Terms: <21+ years old><Adult><Adult Human><Age><Aging><Animals><Antigens><Assay><Bioassay><Biologic Assays><Biological><Biological Assay><Biopsy><Blood><Blood Reticuloendothelial System><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><CD8><CD8B><CD8B1><CD8B1 gene><Cancers><Cell Body><Cell Mobility><Cells><Cellular Mobility><Chickenpox Virus><Chronic><Clinical><Contralateral><Cranial Nerves><Cutaneous><Data><Deposit><Deposition><Elderly><Exanthem><Exanthema><Expression Signature><Focal Infection><Ganglia><Gene Expression Profile><Gene Transcription><Genetic Alteration><Genetic Change><Genetic Transcription><Genetic defect><HHV-3><HHV3><HSV><Herpes Simplex Virus><Herpes Zoster><Herpes labialis Virus><Herpes zoster Virus><Herpes zoster disease><Herpesvirus Type 3><Herpesvirus varicellae><Home><Home environment><Homing><Host Defense><Human><Immune><Immunes><Immunity><Immunology><Infection><Innate Immunity><Intramuscular><Intramuscular Injections><LYT3><Life><Malignant Neoplasms><Malignant Skin Neoplasm><Malignant Tumor><Measurement><Measures><Mediating><Memory><Metabolic><Methods><Mice><Mice Mammals><Microbe><Modern Man><Molecular Fingerprinting><Molecular Profiling><Morbidity><Morbidity - disease rate><Murine><Mus><Mutation><NIAID><NIDCR><NIDR><National Institute of Allergy and Infectious Disease><National Institute of Dental Research><National Institute of Dental and Craniofacial Research><Native Immunity><Natural Immunity><Nerve Cells><Nerve Unit><Neural Cell><Neural Ganglion><Neurocyte><Neurons><Non-Polyadenylated RNA><Non-Specific Immunity><Nonspecific Immunity><Ocular Herpes zoster Virus><PBMC><Peripheral Blood Mononuclear Cell><Persons><Phenotype><Physiologic><Physiological><Population><Position><Positioning Attribute><Predisposition><Prevention><Primary Infection><Proliferating><Proteins><RNA><RNA Expression><RNA Gene Products><Rash><Recovery><Rejuvenation><Research><Ribonucleic Acid><Risk><Risk Factors><Route><Shingles><Simplexvirus><Site><Skin><Skin Cancer><Skin Rash><Special Population><Specificity><Subgroup><Susceptibility><T cell response><T memory cell><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Time><Tissues><Transcription><Twin Multiple Birth><Twins><VZ Virus><VZV vaccine><Vaccination><Vaccines><Varicella-Zoster Virus><Viral><Viral Diseases><Virus><Virus Diseases><Zona><Zoster><acquired immunity><adulthood><advanced age><age dependent><age effect><age related><aged><ages><aging effect><base><circulating biomarkers><circulating markers><craniofacial><craniofacies><develop a vaccine><development of a vaccine><effector T cell><elders><gene expression pattern><gene expression signature><genome mutation><geriatric><healing><herpes zona><immunogen><infection localized><infection recurrence><interest><intramuscular drug administration><late life><later life><local infection><mRNA Expression><malignancy><malignant skin tumor><memory T lymphocyte><molecular profile><molecular signature><mortality><named group><neo-antigen><neo-epitopes><neoantigens><neoepitopes><neoplasm/cancer><neuronal><older adult><older person><pathogen><prevent><preventing><recurrent infection><senescence><senescent><senior citizen><thymus derived lymphocyte><tool><transcriptional signature><vaccine development><vaccine discovery><vaccine formulation><vaccinology><varicella zoster virus vaccine><viral infection><virus infection><virus-induced disease>