grant

ACE2-independent alternative receptors for SARS-CoV-2 at the oral mucosa

Organization RUTGERS BIOMEDICAL AND HEALTH SCIENCESLocation Newark, UNITED STATESPosted 1 Aug 2024Deadline 31 Jul 2027
NIHUS FederalResearch GrantFY20252019 novel corona virus2019 novel coronavirus2019-nCoV2019-nCoV S protein2019-nCoV spike glycoprotein2019-nCoV spike protein2019-nCoV vaccine2019-nCoV variant2019-nCoV variant forms2019-nCoV variant strainsACE2After CareAfter-TreatmentAftercareAnti-viral AgentsAntibodiesB.1.1.529BindingBody TissuesBuccal CavityBuccal Cavity Head and NeckBuccal MucosaCOVID-19COVID-19 S proteinCOVID-19 infectionCOVID-19 predispositionCOVID-19 spikeCOVID-19 spike glycoproteinCOVID-19 spike proteinCOVID-19 susceptibilityCOVID-19 vaccineCOVID-19 variantCOVID-19 variant formsCOVID-19 variant strainsCOVID-19 virusCOVID-19 virus infectionCOVID-19 vulnerabilityCOVID19 infectionCOVID19 virusCV-19Cavitas OrisCell BodyCellsCenters for Disease ControlCenters for Disease Control and PreventionCenters for Disease Control and Prevention (U.S.)ClinicalClinical Treatment MoabCoV diseaseCoV-2CoV2Coronavirus Infectious Disease 2019Coronavirus disease 2019 predispositionCoronavirus disease 2019 susceptibilityCoronavirus disease 2019 vulnerabilityDataDiseaseDisease OutcomeDisorderEpithelial CellsExhibitsGenesGingivaGingivalGoalsHumanImmuneImmune Cell ActivationImmune DiseasesImmune DisordersImmune DysfunctionImmune System DiseasesImmune System DisorderImmune System DysfunctionImmune System and Related DisordersImmune responseImmunesImmunologic DiseasesImmunological DiseasesImmunological DysfunctionImmunological System DysfunctionIndividualInfectionInfection preventionInflammationKnowledgeLaboratoriesLocationMapsMediatingMembraneModern ManMolecular InteractionMonoclonal AntibodiesMouthMouth MucosaMucosaMucosal TissueMucous MembraneNon-Polyadenylated RNAOmicron variantOralOral MucosaOral cavityOral mucous membrane structureOrganPlayPredisposed to COVID-19Predisposed to SARS-CoV-2Predisposed to Severe acute respiratory syndrome coronavirus 2PredispositionPrevent infectionPreventative strategyPrevention strategyPreventive strategyProteinsPublic HealthRNARNA Gene ProductsReceptor ProteinReportingResearchResistanceRibonucleic AcidRoleSARS corona virus 2SARS-CO-V2SARS-COVID-2SARS-CoV-2SARS-CoV-2 B.1.1.529SARS-CoV-2 SSARS-CoV-2 S proteinSARS-CoV-2 infectionSARS-CoV-2 omicronSARS-CoV-2 omicron variantSARS-CoV-2 pathogenesisSARS-CoV-2 predispositionSARS-CoV-2 spikeSARS-CoV-2 spike glycoproteinSARS-CoV-2 spike proteinSARS-CoV-2 susceptibilitySARS-CoV-2 vaccineSARS-CoV-2 variantSARS-CoV-2 variant formsSARS-CoV-2 variant strainsSARS-CoV-2 vulnerabilitySARS-CoV2SARS-CoV2 infectionSARS-associated corona virus 2SARS-associated coronavirus 2SARS-coronavirus-2SARS-coronavirus-2 vaccineSARS-related corona virus 2SARS-related coronavirus 2SARSCoV2SalivaSalivarySalivary DuctsSalivary GlandsSalivary duct structureSerine EndopeptidasesSerine ProteaseSerine Protein HydrolasesSerine ProteinasesSevere Acute Respiratory Coronavirus 2Severe Acute Respiratory Distress Syndrome CoV 2Severe Acute Respiratory Distress Syndrome Corona Virus 2Severe Acute Respiratory Distress Syndrome Coronavirus 2Severe Acute Respiratory Syndrome CoV 2Severe Acute Respiratory Syndrome CoV 2 vaccineSevere Acute Respiratory Syndrome-associated coronavirus 2Severe Acute Respiratory Syndrome-related coronavirus 2Severe acute respiratory syndrome associated corona virus 2Severe acute respiratory syndrome coronavirus 2Severe acute respiratory syndrome coronavirus 2 S proteinSevere acute respiratory syndrome coronavirus 2 infectionSevere acute respiratory syndrome coronavirus 2 predispositionSevere acute respiratory syndrome coronavirus 2 spike glycoproteinSevere acute respiratory syndrome coronavirus 2 spike proteinSevere acute respiratory syndrome coronavirus 2 susceptibilitySevere acute respiratory syndrome coronavirus 2 vaccineSevere acute respiratory syndrome coronavirus 2 vulnerabilitySevere acute respiratory syndrome related corona virus 2Supporting CellSusceptibilityTestingTissuesTongueTonsilTransmissionUnited States Centers for Disease ControlUnited States Centers for Disease Control and PreventionVaccineeVariantVariationViralVirusVirus ReplicationWorld Health OrganizationWuhan coronavirusangiotensin converting enzyme 2angiotensin converting enzyme IIanti-viral compoundanti-viral developmentanti-viral drug developmentanti-viral drugsanti-viral medicationanti-viral therapeuticanti-viral therapeutic developmentanti-viral therapy developmentanti-viralsantiviral developmentantiviral drug developmentantiviral therapeutic developmentantiviral therapy developmentcorona virus diseasecoronavirus diseasecoronavirus disease 2019coronavirus disease 2019 S proteincoronavirus disease 2019 infectioncoronavirus disease 2019 spike glycoproteincoronavirus disease 2019 spike proteincoronavirus disease 2019 vaccinecoronavirus disease 2019 variantcoronavirus disease 2019 variant formscoronavirus disease 2019 variant strainscoronavirus disease 2019 viruscoronavirus disease-19coronavirus disease-19 vaccinecoronavirus disease-19 viruscoronavirus infectious disease-19defined contributiondeveloping anti-viral agentdeveloping anti-viral drugdeveloping anti-viral therapeuticdeveloping anti-viral therapydeveloping antiviral agentdeveloping antiviral drugdeveloping antiviral therapeuticdeveloping antiviral therapyhCoV19host responseimmune activationimmune system responseimmunoresponseinfected with COVID-19infected with COVID19infected with SARS-CoV-2infected with SARS-CoV2infected with coronavirus disease 2019infected with severe acute respiratory syndrome coronavirus 2infection mouthinfection riskknock-downknockdownmAbsmembrane structuremonoclonal AbsnCoV vaccinenCoV-19 vaccinenCoV19 vaccinenCoV2neutralizing antibodynew vaccinesnext generation vaccinesnovel vaccinesomicron variant of COVID-19omicron variant of SARS-CoV-2oral cavity epitheliumoral epitheliaoral epitheliumoral infectionoral infectiousoral mucosaeoral mucosaloral tissuepost treatmentpredisposed to Coronavirus disease 2019public health emergencyreceptorreceptor bindingreceptor boundreceptor expressionresistantrespiratorysevere acute respiratory syndrome coronavirus 2 B.1.1.529severe acute respiratory syndrome coronavirus 2 pathogenesissevere acute respiratory syndrome coronavirus 2 variantsevere acute respiratory syndrome coronavirus 2 variant formssevere acute respiratory syndrome coronavirus 2 variant strainssocial rolespike proteins on SARS-CoV-2susceptible to COVID-19susceptible to Coronavirus disease 2019susceptible to SARS-CoV-2susceptible to Severe acute respiratory syndrome coronavirus 2tonsillartransmission processvaccinated individualvaccinated participantvaccinated patientvaccinated personvaccinated subjectvaccine against 2019-nCovvaccine against COVID-19vaccine against SARS-CoV-2vaccine against SARS-coronavirus-2vaccine against Severe Acute Respiratory Syndrome CoV 2vaccine against Severe acute respiratory syndrome coronavirus 2vaccine candidates against SARS-CoV-2vaccine for novel coronavirusvaccines preventing COVIDvaccines to prevent COVIDviral multiplicationviral replicationvirus multiplicationvulnerable to COVID-19vulnerable to Coronavirus disease 2019vulnerable to SARS-CoV-2vulnerable to Severe acute respiratory syndrome coronavirus 2
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Full Description

PROJECT SUMMARY
Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2
(SARS-CoV-2), has been a major challenge for public health since the first case was reported in December
2019. In May 2023, the WHO and CDC marked the end of the COVID-19 public health emergency. However,
COVID-19 remains a threat due to continuously evolving new variants, and fully vaccinated people remain
susceptible to infection by the newer variants of the virus. SARS-CoV-2 entry is primarily mediated by binding
of the SARS-CoV-2 spike protein (receptor-binding domain, RBD) to the human angiotensin-converting
enzyme 2 (ACE2) receptor. Although ACE2-expressing cells support robust SARS-CoV-2 viral replication,
ACE2 expression profiles are not completely associated with clinical manifestations or immune responses.
Furthermore, SARS-CoV-2 infects organs or cells that do not express ACE2, suggesting the involvement of
alternative receptors for SARS-CoV-2. Our and other laboratories have identified ACE2-independent
alternative receptors for SARS-CoV-2, and infection via alternative receptors (e.g. CD147) is resistant to
monoclonal antibodies against spike RBD, which is the target for several SARS-CoV-2 vaccines to block ACE2
binding. Our preliminary data show that oral epithelial, salivary gland, and gingival epithelial cells are
susceptible to the replication-competent SARS-CoV-2 and pseudotyped SARS-CoV-2 Omicron variant
despite low or undetectable expression of ACE2. These oral epithelial cells do however express high levels of
alternative receptors CD147 or AXL, suggesting the role of alternative receptors in SARS-CoV-2 infection of
oral epithelial cells. We hypothesize that these alternative receptors play a critical role in SARS-CoV-2 infection
and virus-mediated immune activation in region-specific oral epithelial cells. In Aim 1, we will determine
repertories of receptors for SARS-CoV-2 and infection profiles in region-specific oral epithelial cells and tissues
from healthy subjects and subjects with oral inflammation pre- and post-treatment. In Aim 2, we will determine
the contribution of specific receptors to SARS-CoV-2 infection and virus-mediated immune activation in oral
epithelial cells. Considering that the virus will continue to infect humans regularly, it is critical to understand the
role of alternative receptors for SARS-CoV-2 in the oral mucosa, the potential portal of SARS-CoV-2 entry, to
develop anti-viral therapeutics and strategies to dampen virus-mediated immune activation and disease
outcomes, especially as regards emerging variants.

Grant Number: 5R21DE033170-02
NIH Institute/Center: NIH
Principal Investigator: Theresa Chang

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