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Principal Investigator: GILL DIAMOND
Organization: UNIVERSITY OF MISSISSIPPI MED CTR
Fiscal Year: 2022
Award: $822,036
Funding agency: National Institute of Dental and Craniofacial Research
Abstract
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019
(COVID-19), a life-threatening illness with multi-system involvement in a subset of infected individuals. Oral and
nasopharyngeal (NP) epithelial cells express the SARS-CoV-2 receptor ACE2, and infection of the
oral/nasopharyngeal cavity (ONP) is likely an obligate step in the development of COVID-19. Immune responses
first generated in the ONP are almost certainly crucial for viral clearance but may also play a central role in the
development of hyperinflammatory injury observed in many infected individuals. We have used single cell (sc)-
RNA sequencing from a racially diverse prospective cohort of COVID-19 patients to identify distinct subsets of
ciliated epithelial cells within the NP that are direct targets for SARS-CoV-2 infection and have described innate
anti-viral responses generated by those cells within both directly infected as well as non-infected bystander cells.
Interestingly this analysis demonstrates that increased mortality is linked to blunted anti-viral gene response in
the NP, suggesting that a successful innate response to viral infection in the nose is a critical component of a
successful anti-viral response. In addition to the nose, there is strong evidence that SARS-CoV-2 can infect the
oral epithelium. While there are several anatomic sites within the mouth that are likely involved in anti-viral
responses, the gingival sulcus is a unique immunologically active location that is crucial for maintaining oral
health. The gingival epithelium expresses both the SARS-CoV-2 receptor ACE2 as well as the host protease
TMPRSS2 necessary for viral entry, but exhibits important immunological differences compared to the nasal
epithelium including a bias towards IL-17 associated neutrophil responses. Thus, our overall hypothesis is that
identifying and enhancing successful innate and adaptive cellular immune responses of the nasal and gingival
epithelium will lead to novel therapeutic avenues for COVID-19. To address this hypothesis, propose the
following aims: 1. Stratify cell states and viral dynamics across mucosal surfaces following SARS-CoV-2
infection and vaccination; 2. Compare memory T cell responses within the nose and gingiva that are associated
with successful or pathogenic responses to SARS-CoV-2; and 3. Characterize the regulation of host innate
immune defense mechanisms that are essential to limit propagation of SARS-CoV-2 infection within ONP
epithelial cells. To accomplish these aims, we will analyze human ONP samples from individuals with COVID-
19, recovered from COVID-19, and vaccinated for COVID-19 using sc-RNA-seq, flow cytometry, and other
molecular biology techniques. At completion, the project will define the protective innate and adaptive immune
mechanisms operating in the ONP of patients infected with SARS-CoV-2, improve our overall understanding of
viral induced immunity in the ONP, and provide insight into how these pathways influence disease pathogenesis.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><3-D><3-Dimensional><3D><ACE2><Acute><Address><Aero-digestive Tract><Aerodigestive Tract><Affect><Anatomic><Anatomic Sites><Anatomic structures><Anatomical Sciences><Anatomy><Angiotensin AT2 Receptor><Angiotensin Receptor 2><Anti-Viral Response><Antiviral Response><Area><Bio-Informatics><Bioinformatics><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Body Tissues><Buccal Cavity><Buccal Cavity Head and Neck><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19><COVID19 S protein><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CTLA-8><CTLA8><CV-19><CV19><Cavitas Oris><Cell Body><Cell to Cell Communication and Signaling><Cell-Cell Signaling><Cells><Cessation of life><Clinical><CoV-2><CoV2><Complement><Complement Proteins><Congestive><Coughing><Cytotoxic T-Lymphocyte-Associated Antigen 8><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8><Death><Defect><Defense Mechanisms><Development><Disease><Disorder><Dysfunction><Enrollment><Epithelial><Epithelial Cells><Epitheliasin Gene><Esteroproteases><Exhibits><Fever><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Future><Gene Expression><Generations><Genes><Gingiva><Gingival><Goals><Host Defense><Human><IFN><IL-17><IL-17A><IL17 Protein><IL17A><IMiD><Immune><Immune modulatory therapeutic><Immune response><Immunes><Immunity><Immunization><Immunochemical Immunologic><Immunologic><Immunologic Sensitization><Immunologic Stimulation><Immunological><Immunological Sensitization><Immunological Stimulation><Immunological response><Immunologically><Immunologics><Immunology><Immunomodulators><Immunostimulation><Individual><Infection><Inflammatory><Inflammatory Response><Injury><Interdisciplinary Research><Interdisciplinary Study><Interferons><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8)><Interleukin 17 Precursor><Interleukin-17><Knowledge><Life><Link><Location><MHC Receptor><Major Histocompatibility Complex Receptor><Marrow Neutrophil><Metadata><Modern Man><Molecular Biology Techniques><Morbidity><Morbidity - disease rate><Mouth><Mucosa><Mucosal Tissue><Mucous Membrane><Multidisciplinary Collaboration><Multidisciplinary Research><Nasal><Nasal Epithelium><Nasal Passages Nose><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nose><Oral><Oral cavity><Oral health><PRSS10><Pathogenesis><Pathogenicity><Pathway interactions><Peptidases><Peptide Hydrolases><Peptides><Pharyngeal structure><Pharynx><Phenotype><Physiopathology><Play><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Preventive><Production><Prospective cohort><Protease Gene><Proteases><Proteinases><Proteolytic Enzymes><Pyrexia><Receptor Protein><Receptor, Angiotensin, Type 2><Regulation><Respiratory Signs and Symptoms><Respiratory System, Nose, Nasal Passages><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 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><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><Sampling><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><Severity of illness><Site><Sore Throat><Structure of gingival sulcus><Surface><System><Systemic disease><T cell receptor repertoire sequencing><T cell receptor sequencing><T cell response><T memory cell><T-Cell Antigen Receptors><T-Cell Receptor><T-Cells><T-Lymphocyte><T-cell receptor repertoire><TCR repertoire><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><TMPRSS2><TMPRSS2 gene><Talents><Therapeutic><Throat><Tissues><Type 2 Angiotensin II Receptor><Vaccinated><Vaccination><Vaccinee><Vaccines><Viral><Viral Diseases><Viral Genes><Virus><Virus Diseases><Wuhan coronavirus><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after severe acute respiratory distress syndrome CoV-2 infection><airway symptom><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral immunity><antiviral immunity><base><cohort><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><density><dental health><developmental><disease severity><enroll><ethnic diversity><ethnically diverse><exhaustion><febrile><febris><flow cytophotometry><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following severe acute respiratory distress syndrome CoV-2 infection><gingival sulcus><hCoV19><host response><immune modulating agents><immune modulating drug><immune modulating therapeutics><immune modulators><immune modulatory agents><immune modulatory drugs><immune system response><immunomodulating agents><immunomodulatory agents><immunomodulatory drugs><immunomodulatory therapeutics><immunoresponse><improved><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><infection mouth><injuries><insight><intercellular communication><memory T lymphocyte><meta data><mitochondrial dysfunction><mortality><nCoV2><neutrophil><new drug treatments><new drugs><new therapeutics><new therapy><next generation><next generation therapeutics><novel drug treatments><novel drugs><novel therapeutics><novel therapy><oral biology><oral cavity epithelium><oral epithelia><oral epithelium><oral infection><oral infectious><pathogen><pathophysiology><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with 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coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome-CoV><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><social role><three dimensional><thymus derived lymphocyte><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><viral infection><virology><virus infection><virus-induced disease>