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Principal Investigator: Sarah E. Millar
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2022
Award: $748,027
Funding agency: National Institute of Dental and Craniofacial Research
Project Summary/Abstract
The COVID-19 pandemic has produced a global health and economic crisis. While the pandemic is gradually
being lessened by mass vaccinations, full control of this disaster is hampered by several ongoing problems
including: (i) resistance or poor access to vaccination; (ii) emergence of new more infectious viral variants; (iii)
“long COVID” symptoms in some patients; and (iv) incomplete understanding of the mechanisms of viral entry.
Thus, it remains important to identify additional methods of blocking infection and to improve understanding of
long-lasting symptoms so that these can be prevented and/or treated more effectively. SARS-CoV-2 infection
is transmitted via airborne droplets, and loss or alterations of taste and smell appear early in disease
progression, can occur in the absence of other symptoms, and serve as a diagnostic tool for COVID-19,
suggesting oral and nasal epithelia as primary viral targets. However, functional evidence for these epithelia as
primary infection sites is lacking, and the basis for chemosensory symptoms, and why these can persist after
disease recovery, remains poorly understood. In particular, whether COVID-19-associated taste abnormalities
are secondary to anosmia, infection of associated oral epithelia, and/or altered salivary secretion, or result from
direct or secondary infection of taste buds or nerves, is currently unclear. Addressing these questions in vivo at
the mechanistic level requires robust and genetically manipulable model systems. Mice provide an excellent
genetic system for human disease modeling, but cannot be robustly infected by wild-type SARS-CoV-2
because its spike protein does not efficiently bind the mouse ACE2 receptor. Existing human (h)ACE2-
expressing mice either express hACE2 in a transgenic, non-endogenous manner, or exhibit relatively weak
expression of hACE2 following knockin to the mouse Ace2 allele resulting in absence of clinical disease after
SARS-CoV-2 infection, limiting their use in mechanistic studies. The proposed studies will utilize powerful new
hACE2 conditional knockin mouse lines that support lethal SARS-CoV-2 infection and permit tissue-specific
Cre-mediated loss and gain of hACE2 function. Using these tools, we will: (i) determine whether hACE2
expression in oral and nasal epithelia is required and/or sufficient for lethal COVID-19 disease; and (ii)
elucidate the oral and nasal cellular mechanisms underlying taste dysfunction in COVID-19 disease. Combined
with human tissue validation, these studies will define the role of oral and nasal cells in COVID-19 disease and
reveal strategies to prevent or treat the disease by targeting these cells.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Address><Affect><Ageusia><Airway infections><Alleles><Allelomorphs><Altered Taste><Animals><Anosmia><Assay><BF1><Binding><Bioassay><Biologic Assays><Biologic Models><Biological Assay><Biological Models><Body Tissues><Body Weight decreased><Brain Factor 1><Buccal Cavity><Buccal Cavity Head and Neck><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID survivors><COVID-19><COVID-19 assay><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 infection survivors><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 survivors><COVID-19 virus><COVID19><COVID19 assay><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 virus><CV-19><CV19><Cavitas Oris><Cell Body><Cells><Clinical><CoV-2><CoV2><Complement><Complement Proteins><Conchae Nasales><Detection><Disasters><Disease><Disease Progression><Disease model><Disorder><Dysfunction><Epithelial><Epithelial Cells><Exhibits><FKHL1><FOXG1><FOXG1B gene><Food><Food or Food Product><Forkhead Box G1><Forkhead Box G1B><Forkhead Protein G1B><Forkhead-Like 1><Functional disorder><Genetic><Goals><Gustation><Histologic><Histologically><Human><IRES><Immune><Immunes><Infection><Internal Ribosome Entry Segment><Internal Ribosome Entry Site><Investigation><K-18><K-18 conjugate><K18><K18 combination><KI mice><Knock-in><Knock-in Mouse><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Mass Vaccinations><Mediating><Methods><Mice><Mice Mammals><Model System><Modeling><Modern Man><Molecular Interaction><Mouth><Murine><Mus><Nasal><Nasal Epithelium><Nasal Passages Nose><Nasal cavity><Nasal turbinate bone structure><Nerve><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurons><Nose><Olfaction><Olfactory Epithelium><Oncogene QIN><Oral><Oral cavity><Patients><Phenotype><Physiopathology><Primary Infection><Progenitor Cells><Proteins><QOL><Quality of life><Receptor Protein><Recovery><Resistance><Respiratory Epithelium><Respiratory Infections><Respiratory System, Nose, Nasal Passages><Respiratory Tract Infections><Ribosome Entry Site><Role><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 assay><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 survivors><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Salivary Glands><Salivary Glands Head and Neck><Salivation><Sampling><Secondary to><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 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Site><Smell><Smell Perception><Structure of parenchyma of lung><Structure of respiratory epithelium><Supporting Cell><Swelling><Symptoms><System><Taste><Taste Buds><Taste Perception><Testing><Therapeutic><Time><Tissues><Transgenic Organisms><Turbinates><Type II Pneumocyte><Variant><Variation><Viral><Weight Loss><Weight Reduction><Wuhan coronavirus><access to vaccination><access to vaccines><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after severe acute respiratory distress syndrome CoV-2 infection><airway epithelium><alveolar type II cell><angiotensin converting enzyme 2><angiotensin converting enzyme II><anosphrasia><body weight loss><cell type><chronic COVID><chronic COVID-19><chronic novel coronavirus disease 2019><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 assay><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><diagnostic tool><disorder model><experiment><experimental research><experimental study><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following severe acute respiratory distress syndrome CoV-2 infection><gene manipulation><genetic manipulation><genetically manipulate><genetically perturb><global health><gustatory perception><gustatory processing><gustatory response><hCoV19><health economics><human disease><human tissue><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><knockin><knockin mice><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><loss of function><loss of smell><nCoV2><neuronal><new approaches><novel approaches><novel strategies><novel strategy><odor perception><olfactory loss><olfactory perception><olfactory receptor><oral cavity epithelium><oral epithelia><oral epithelium><oral infection><oral infectious><pandemic><pandemic disease><pathophysiology><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><post COVID syndrome><post COVID-19 syndrome><post SARS-CoV-2 infection><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-acute phases of COVID-19><prevent><preventing><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><pulmonary><receptor><regenerate new tissue><regenerate tissue><regenerating damaged tissue><regenerating tissue><resistant><saliva secretion><salivary acinar cell><salivary secretion><secondary infection><sensory input><severe acute respiratory syndrome coronavirus 2 assay><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><social><social role><stem cells><survive COVID-19><survive SARS-CoV-2><sustentacular cell><taste loss><taste processing><taste receptor><taste response><tissue regeneration><tissue regrowth><tissue renewal><tissue specific regeneration><tool><transgenic><vaccination access><vaccination availability><vaccine access><vaccine availability><validation studies><wt-loss>