Document text
Principal Investigator: Sarah E. Millar
Organization: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
Fiscal Year: 2024
Award: $731,611
Funding agency: National Institute on Deafness and Other Communication Disorders
Project Summary/Abstract
Infection of the olfactory epithelium in COVID-19 patients is thought to underlie loss of smell (anosmia), a
pathognomonic symptom that can be long-term in some patients, significantly affecting quality of life. The
olfactory epithelium is also believed to be a major entry point for systemic SARS-CoV-2 infection, which can
result in neurological as well as respiratory symptoms. Wild-type SARS-CoV-2 cannot bind the mouse ACE2
receptor, and existing human ACE2 (hACE2)-expressing mouse models either do not permit conditional
analysis or do not confer severe illness after infection. Due to the lack of genetically manipulable models that
display severe disease, the infected cell types responsible for acute and long-term anosmia, and the route(s)
by which the virus penetrates the brain, have not been definitively identified. To address these gaps in
knowledge and test cell type-specific requirements for COVID-19-related pathologies we generated conditional
hACE2fl knockin mice that express hACE2 in similar cell types to humans. hACE2fl mice nasally inoculated with
a high dose of wild-type SARS-CoV-2 display initial infection of olfactory epithelium and rapidly develop
anosmia. This is followed by infection of neurons in the olfactory bulb and brain, which is associated with
lethality and requires neuronal hACE2 expression. Importantly, specific destruction of olfactory epithelium via
methimazole treatment prevents olfactory bulb and brain infection and lethality, identifying the olfactory
epithelium as an essential gateway to CNS infection. hACE2fl mice inoculated with a low dose of wild-type
SARS-CoV-2 show reversible disease and survive, but a subset displays a long-term decrease in odor
sensitivity (hyposmia) like that observed in humans. We propose to use hACE2fl mice to provide definitive
genetic evidence for cellular mechanisms of short- and long-term loss of smell and identify the pathways for
brain infection during COVID-19. These studies are expected to complement existing descriptive human
studies to identify causal pathogenic mechanisms and preventative and therapeutic targets. Three specific
aims will be pursued: (i) define the cellular requirements for acute loss of smell; (ii) determine the mechanisms
of long-term hyposmia; and (iii) uncover the cellular mechanisms of olfactory bulb and brain infection.
Terms: <1,3-dihydro-1-methyl-2H-imidazole-2-thione><1-Methyl-2-mercaptoimidazole><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><ACTL6B><ACTL6B gene><ATAC sequencing><ATAC-seq><ATACseq><Ablation><Acute><Address><Affect><Anosmia><Assay><Assay for Transposase-Accessible Chromatin using sequencing><Autopsy><B.1.1.529><BAF53B><Binding><Bioassay><Biological Assay><Brain><Brain Nervous System><CNS infection><COVID infected patient><COVID patient><COVID positive patient><COVID-19><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 predisposition><COVID-19 susceptibility><COVID-19 virus><COVID-19 virus infection><COVID-19 vulnerability><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cell Body><Cells><Central Nervous System Infections><Central Nervous System Infectious Disease><Central Nervous System Infectious Disorder><Cerebrospinal Fluid><Chromatin><CoV-2><CoV2><Complement><Complement Proteins><Coronavirus Infectious Disease 2019><Coronavirus disease 2019 predisposition><Coronavirus disease 2019 susceptibility><Coronavirus disease 2019 vulnerability><Cranial Nerves><Cricetinae><Data><Defect><Dexamethasone><Diffuse><Disease><Disorder><Dose><Dysfunction><Encephalon><Expression Signature><Functional disorder><Gene Expression Profile><Genetic><Hamsters><Hamsters Mammals><Human><Impairment><Infection><Infiltration><Inflammation><Inflammatory><Invaded><K-18><K-18 conjugate><K18><K18 combination><KI mice><Knock-in Mouse><Knowledge><Maintenance><Mercasolyl><Mercazolyl><Merkazolil><Methimazole><Methylmercaptoimidazole><Mice><Mice Mammals><Modeling><Modern Man><Molecular Interaction><Murine><Mus><Nasal><Nasal Passages Nose><Natural regeneration><Nerve Cells><Nerve Unit><Neural Cell><Neurocyte><Neurologic><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological><Neurological Manifestations><Neurological Signs and Symptoms><Neurons><Nose><Odors><Olfactory Epithelium><Omicron variant><Pathogenicity><Pathology><Patients><Pattern><Penetration><Phenotype><Physiopathology><Population><Predisposed to COVID-19><Predisposed to SARS-CoV-2><Predisposed to Severe acute respiratory syndrome coronavirus 2><Progenitor Cells><Publishing><QOL><Quality of life><Receptor Protein><Regeneration><Respiratory Signs and Symptoms><Respiratory System, Nose, Nasal Passages><Route><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 B.1.1.529><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 omicron><SARS-CoV-2 omicron variant><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 predisposition><SARS-CoV-2 susceptibility><SARS-CoV-2 vulnerability><SARS-CoV2><SARS-CoV2 infection><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 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-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 predisposition><Severe acute respiratory syndrome coronavirus 2 susceptibility><Severe acute respiratory syndrome coronavirus 2 vulnerability><Severe acute respiratory syndrome related corona virus 2><Symptoms><Tapazole><Testing><Thiamazole><Time><Travel><Viral><Virus><Visualization><Wuhan coronavirus><actin-like 6B><airway symptom><angiotensin converting enzyme 2><angiotensin converting enzyme II><anosphrasia><assay for transposase accessible chromatin followed by sequencing><assay for transposase accessible chromatin seq><assay for transposase accessible chromatin sequencing><assay for transposase-accessible chromatin with sequencing><brain pathway><cell type><cerebral spinal fluid><complementation><coronavirus disease 2019><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><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><cribriform plate><gene expression pattern><gene expression signature><hCoV19><human data><hyposmia><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><interest><knockin mice><loss of smell><lymph channel><lymph vessel><lymphatic channel><lymphatic vessel><mouse model><murine model><nCoV2><necropsy><neural><neural manifestation><neuronal><olfactory bulb><olfactory loss><omicron variant of COVID-19><omicron variant of SARS-CoV-2><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><postmortem><predisposed to Coronavirus disease 2019><prevent><preventing><receptor><reduced smell><regenerate><respiratory symptom><scRNA-seq><secondary infection><severe acute respiratory syndrome coronavirus 2 B.1.1.529><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><spinal fluid><stem cells><susceptible to COVID-19><susceptible to Coronavirus disease 2019><susceptible to SARS-CoV-2><susceptible to Severe acute respiratory syndrome coronavirus 2><sustentacular cell><therapeutic target><transcriptional profile><transcriptional signature><vulnerable to COVID-19><vulnerable to Coronavirus disease 2019><vulnerable to SARS-CoV-2><vulnerable to Severe acute respiratory syndrome coronavirus 2>