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Principal Investigator: Ann Venables Griffith
Organization: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
Fiscal Year: 2022
Award: $232,500
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
The novel coronavirus, SARS-CoV-2, and the resulting Coronavirus Infectious Disease 2019 (COVID-19) has
caused more than 500,000 deaths in the US. COVID-19 causes increased mortality and morbidity in patients
over 65 years of age relative to younger patients. This is consistent with well-characterized age-associated
decreases in responsiveness to viral infections such as SARS-1, MERS, and West Nile Virus. Likewise,
responsiveness to vaccines for these viruses decline in the elderly. Therefore, approaches to enhance vaccine
responsiveness in the elderly are critical to protect the most vulnerable population. A major contributor to the
loss of immunocompetence with age is the atrophy of the thymus, the primary site of T cell maturation. Production
of new naïve T cells depends on the availability of lymphopoietic niches within the thymic microenvironment.
Since each T cell generally has one TCR specificity, the narrowing of the naïve T cell repertoire that results from
thymic atrophy restricts the magnitude of the T cell response to new infections by reducing the number of naïve
T cells capable of mounting a robust response against a given antigen. A well-known example is the loss of CD8
T cells recognizing an immunodominant influenza in the spleen and lungs during aging in mice. Likewise, recent
work suggests loss of naïve T cells increases COVID-19 severity in elderly patients. Loss of naïve T cells specific
for immunodominant epitopes may be exacerbated by dysfunction of the aged naïve T cells that do persist in
older animals. For example, dysfunctional NP366-374-specific tissue-resident memory T cell (Trm) responses, which
were suggested to arise as a result of thymus atrophy, were recently shown to promote persistent lung
inflammation and exacerbate lung damage during viral pneumonia at 60 days post infection (d.p.i.) in aged mice.
The thymus retains a remarkable capacity to regenerate, and regeneration increases the number of flu-specific
T cells in aged spleen, however, it is not known whether thymic regeneration affects T cell responses in the lung,
survival, or vaccine efficacy for flu, or other viral pathogens. Given the recently revealed role for Trm in age-
associated viral pneumonia, and their potential role mediating vaccine responses, it is also important to
understand whether thymic regeneration impacts the Trm population in aged lungs. We will evaluate the effect of
thymus regeneration (mediated by Growth Hormone (GH) administration, an approach currently used in ongoing
human clinical trials) on vaccine-mediated protection from viral pneumonia and secondary CD8 T cell responses
using the well-characterized mouse-adapted flu model. As a second model, we have generated an experimental
vaccine based on MVA (Modified Vaccinia Ankara) to be used for immunization ahead of infection with mouse-
adapted SARS-CoV-2.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><65+ years old><Abscission><Acute><Affect><Age><Age-Years><Aged 65 and Over><Aging><Animals><Antigenic Determinants><Antigens><Atrophic><Atrophy><Binding Determinants><Body Tissues><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><COVID-19 S protein><COVID-19 infection><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19 S protein><COVID19 infection><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><Cell Maturation><Cessation of life><Clinical Trials><CoV emergence><CoV-2><CoV2><Communicable Diseases><Complementary DNA><Coronaviridae><Coronavirus><Data><Death><Dysfunction><Egypt 101 virus><Elderly><Epitopes><Excision><Extirpation><Functional disorder><Generations><Grippe><Growth Hormone><Growth Hormone 1><Human><IFN><Immunization><Immunize><Immunocompetence><Immunodominant Antigenic Determinants><Immunodominant Determinants><Immunodominant Domains><Immunodominant Epitopes><Immunodominant Regions><Immunodominant Sites><Immunologic Competence><Immunologic Sensitization><Immunologic Stimulation><Immunological Competence><Immunological Sensitization><Immunological Stimulation><Immunostimulation><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Influenza><Interferons><Lung><Lung Inflammation><Lung Respiratory System><Lung Tissue Fibrosis><Lung damage><Lung infections><MERS><MERS coronavirus disease><MERS-CoV disease><Measures><Mediating><Mice><Mice Mammals><Middle East Respiratory Syndrome><Middle East Respiratory Syndrome CoV disease><Middle East Respiratory Syndrome coronavirus disease><Middle Eastern Respiratory Syndrome><Middle Eastern Respiratory Syndrome CoV disease><Middle Eastern Respiratory Syndrome coronavirus disease><Modeling><Modern Man><Modified Vaccinia Ankara><Modified Vaccinia Virus Ankara><Morbidity><Morbidity - disease rate><Murine><Mus><Natural regeneration><Patients><Peptides><Phenotype><Physiopathology><Pituitary Growth Hormone><Pneumonitis><Population><Production><Pulmonary Fibrosis><Pulmonary Inflammation><Regeneration><Removal><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-CoV-2 S protein><SARS-CoV-2 infection><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><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><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 corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Severities><Site><Somatotropin><Specificity><Spleen><Spleen Reticuloendothelial System><Stimulus><Surgical Removal><T cell response><T memory cell><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Testing><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><Tissues><Vaccination><Vaccines><Viral><Viral Diseases><Viral Pathogenesis><Viral Pneumonia><Viral Vaccines><Virus><Virus Diseases><Vulnerable Populations><WNV><Weights and Measures><West Nile><West Nile virus><Work><Wuhan coronavirus><advanced age><age 65 and greater><age 65 and older><aged><aged 65 and greater><aged ≥65><ages><base><cDNA><clinical relevance><clinically relevant><corona virus><corona virus emergence><coronavirus disease 2019 S protein><coronavirus disease 2019 infection><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease-19 virus><coronavirus emergence><elderly patient><elders><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><fibrosis in the lung><flu><geriatric><hCoV19><human old age (65+)><immunogen><improved><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><late life><later life><lung fibrosis><lung injury><lung vaccination><memory T lymphocyte><mortality><nCoV><nCoV2><new CoV><new corona virus><new coronavirus><novel CoV><novel corona virus><novel coronavirus><old age><older adult><older patient><older person><pathogen><pathogenic virus><pathophysiology><prevent><preventing><pulmonary><pulmonary damage><pulmonary infections><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><pulmonary vaccination><regenerate><resection><response><senior citizen><severe acute respiratory syndrome-CoV><social role><somatotropic hormone><thymic regeneration><thymus derived lymphocyte><thymus regeneration><vaccine efficacy><vaccine response><vaccine responsiveness><vaccine-induced response><viral infection><viral pathogen><virus infection><virus pathogen><virus pathogenesis><virus-induced disease><vulnerable group><vulnerable people>