Document text
Principal Investigator: David M Koelle
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2022
Award: $220,624
Funding agency: National Institute of Allergy and Infectious Diseases
Summary
The acquired, antigen-specific immune response to SARS-CoV-2-infection is likely central to
determining the outcome of COVID-19 and the efficacy and durability of vaccination. CD4 T cell
help is required for lasting, avid antibody responses. The leading vaccine candidates include
some formats that can also induce CD8 T cells, such as viral vectors and nucleic acids, and
other formats such as adjuvanted protein that cannot. Compelling evidence for an antiviral
effects of virus-specific CD8 T cells could tilt the balance in favor of CD8-eliciting vaccine
platforms. Aim 1 and Aim 2 of this exploratory R21 on the T cell response to SARS-CoV-2
concern CD8- and CD4 T cell responses, respectively. Upper and lower airway respiratory
epithelium are the primary target tissues for SARS-CoV-2. The nasal epithelium is particularly
rich in expression of ACE2 and TMPRSS2, host molecules required for viral entry. We leverage
Co-Investigator Abuzeid’s experience in harvesting nasal cells and expanding primary nasal
epithelial cells (HNEpC) and Collaborator Greninger’s expertise in BSL3 virology and
quantitative RNA measurement to create systems to study T cell-infected epithelial cell
interactions in vitro. We use our large COVID-19 biobank, in-lab experience, and other NIAID
resources to generate functionally unlimited amounts of highly avid SARS-CoV-2-specific CD8
and CD4 T cells with precisely known HLA restriction and defined peptide targets. Infection of
HNEpC will be carefully characterized and optimized. We will then measure T cell effector
functions including the killing of infected cells, reduction of viral progeny output, and cytokine
release. In follow-up studies, we hope to leverage SARS-CoV-2 genetic systems to make
defined mutants in candidate immune evasion genes and extend our studies to lower respiratory
tract cells and organoids. Overall, we strive to model important interactions between immune
cells and the SARS-CoV-2 infected respiratory tract.
Relevance
Vaccines may need to elicit SARS-CoV-2 specific T cells that can quickly recognize SARS-CoV-
2-specific infected upper respiratory tract epithelial cells and shut down their production of
progeny virus, to both limit the progression of infection and symptoms within patients, and
reduce the shedding of infectious virus that may infect other persons. In this R21 grant
application, we will use established, working methods to isolate large quantities of pure SARS-
CoV-2-specific T cells from recovered persons and study their ability to exert anti-viral effects
using cell cultures of the cells that line the nasal cavity that are normally infected during COVID-
19.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV vaccine><ACE2><ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adjuvant><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><Anatomic><Anatomic Sites><Anatomic structures><Anatomical Sciences><Anatomy><Anti-Viral Response><Antibody Response><Antigenic Determinants><Antigens><Antiviral Response><Applications Grants><Area><Attenuated><Avidity><Binding Determinants><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><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><COVID-19><COVID-19 infection><COVID-19 vaccine><COVID-19 virus><COVID19><COVID19 infection><COVID19 vaccine><COVID19 virus><CV-19><CV19><Cell Body><Cell Communication><Cell Culture Techniques><Cell Death><Cell Interaction><Cell Line><Cell-to-Cell Interaction><CellLine><Cells><CoV-2><CoV2><Complex><Containment><Curette><Da Nang Lung><Data><Daughter><Disease><Disorder><Environment><Epithelial><Epithelial Cells><Epitheliasin Gene><Epitopes><Equilibrium><Flu vaccination><Follow-Up Studies><Followup Studies><Genes><Genetic><Grant Proposals><Harvest><Home><Human><Immune><Immune Evasion><Immune response><Immunes><Immunological response><In Vitro><Infection><Inferior Turbinate><Inferior nasal concha><Inflammatory><Influenza immunization><Influenza vaccination><Investigators><LYT3><Lower respiratory tract structure><Lytotoxicity><Measurement><Measures><Medical><Methods><Modeling><Modern Man><NIAID><Nasal><Nasal Epithelium><Nasal Passages Nose><Nasal cavity><National Institute of Allergy and Infectious Disease><Non-Polyadenylated RNA><Nose><Nucleic Acids><Organ><Organoids><Outcome><Output><PBMC><PRSS10><Patients><Peptides><Peripheral Blood Mononuclear Cell><Persons><Physiologic><Physiological><Pneumonia><Production><Prophylactic vaccination against influenza><Proteins><Pulmonary Body System><Pulmonary Organ System><RNA><RNA Gene Products><Reagent><Research Personnel><Research Resources><Researchers><Resources><Respiratory Epithelium><Respiratory System><Respiratory System, Nose, Nasal Passages><Respiratory Tracts><Respiratory tract structure><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 infection><SARS-CoV-2 vaccine><SARS-CoV2><SARS-CoV2 infection><SARS-CoV2 vaccine><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 vaccine><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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 CoV 2 vaccine><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 infection><Severe acute respiratory syndrome coronavirus 2 vaccine><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Site><Specificity><Speed><Stiff lung><Strains Cell Lines><Structure of respiratory epithelium><Symptoms><System><T cell response><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><T8 Cells><T8 Lymphocytes><TMPRSS2><TMPRSS2 gene><Technology><Teff cell><Time><Tissues><Triad><Triad Acrylic Resin><Triad resin><Upper respiratory tract><Vaccination><Vaccines><Viral><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Viral Vector><Virus><Virus Replication><Work><Wuhan coronavirus><acquired immunity><airway epithelium><angiotensin converting enzyme 2><angiotensin converting enzyme II><balance><balance function><biobank><biorepository><cell culture><cell cultures><cohort><corona virus disease 2019><corona virus disease 2019 vaccine><coronavirus disease 2019><coronavirus disease 2019 infection><coronavirus disease 2019 vaccine><coronavirus disease 2019 virus><coronavirus disease-19><coronavirus disease-19 vaccine><coronavirus disease-19 virus><coronavirus infectious disease-19><cultured cell line><cytokine><cytotoxicity><effector T cell><experience><flu immunisation><hCoV19><host response><immune system response><immunogen><immunoresponse><in vivo><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><influenza virus vaccination><lab experience><lab training><laboratory experience><laboratory training><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lower respiratory tract><mutant><nCoV2><necrocytosis><neutralizing antibody><pathogen><response><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><thymus derived lymphocyte><tool><upper airway tract><vaccination against influenza><vaccine against 2019-nCov><vaccine against SARS-CoV-2><vaccine against SARS-CoV2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine candidate><vaccine for novel coronavirus><vaccine platform><viral multiplication><viral replication><virology><virus multiplication><virus protein><wet lung>