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Principal Investigator: Stanley Perlman
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2024
Award: $656,039
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract
SARS-CoV-2, the cause of COVID-19, continues to cause widespread infection and morbidity, but death rates
have decreased as most of the world has either been infected or vaccinated or both. However, at the same time,
it has become clear that many patients have developed long term sequelae. These sequelae, called PASC (Post
Acute Sequelae of COVID-19), affect many organ systems even though virus is found at autopsy in nearly all
studies only in the respiratory and gastrointestinal tracts. One common symptom of acute COVID-19 is anosmia.
Recovery of olfactory function is often incomplete in patients. However, only supporting (sustentacular) cells and
not olfactory sensory neurons are infected in patients, raising the question of how infection of a supporting cell
could have such profound effects on olfaction. In addition, neurological disease is also present in many patients
with PASC. Many of these manifestations reflect ongoing inflammation (usually observed on autopsy), but the
basis of these inflammatory changes is unclear since virus cannot be detected. We have isolated a mouse-
adapted virus that causes severe acute respiratory disease in infected mice, as well as persistent signs of
disease is the lungs and brains months after the acute infection has resolved. Infected mice develop anosmia,
as well as long term behavioral abnormalities and defects in neurotransmitter expression, but virus is not present
in the brain. Our central hypothesis is that ongoing inflammation is a major contributory factor in the observed
dysfunction in the olfactory and neurological systems. This hypothesis will be addressed in the following specific
aims: Specific Aim 1: To understand the relationship between sustentacular cell infection and olfactory
dysfunction and to understand the basis of chronic changes in the brains of SARS-CoV-2-infected mice. Acute
and chronic changes in olfactory pathways will be probed using electrophysiological and olfactory
measurements. These changes will be related to sustentacular function and gene expression. Parts of the brain,
such as the substantia nigra, which are affected in neurodegenerative diseases such as Parkinson’s disease will
be studied. Our preliminary results show changes in neurotransmitter expression in the substantia nigra several
months after infection, supporting this hypothesis. Specific Aim 2: To examine the role of viral macromolecular
products and infiltrating inflammatory cells in the brains of mice infected with SARS-CoV-2 in the development
of PASC. Using molecular and immunological approaches, we will assess whether inflammation results from
extrapulmonary SARS-CoV-2 infection and rapid clearance within the first days of infection (‘hit and run’). Using
a mouse in which infiltrating myeloid cells can be readily identified, we will analyze localization, function and
gene expression of these infiltrating myeloid cells, as well as of T cells that infect the brain chronically. The
ultimate goal is to relate these changes in inflammation to the neurological/olfactory dysfunction that we
characterize in Aim 1.
Terms: <1918 H1N1 pandemic><1918 flu pandemic><1918 influenza pandemic><1918 pandemic><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><Acute><Address><Affect><Alimentary Canal><Animal Experiments><Anosmia><Assay><Autopsy><Behavioral><Bioassay><Biological Assay><Body System><Body Tissues><Brain><Brain Nervous System><COVID crisis><COVID epidemic><COVID pandemic><COVID-19><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infection><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 virus><COVID-19 virus infection><COVID-19 years><COVID19 infection><COVID19 virus><CV-19><Cell Body><Cell Communication and Signaling><Cell Function><Cell Physiology><Cell Process><Cell Signaling><Cells><Cellular Function><Cellular Physiology><Cellular Process><Chronic><Clinical><CoV-2><CoV2><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Coronavirus Infectious Disease 2019><Death Rate><Defect><Degenerative Neurologic Disorders><Development><Digestive Tract><Disease><Disorder><Disturbance in cognition><Dysfunction><Electrophysiology><Electrophysiology (science)><Encephalitis Lethargica><Encephalon><Functional disorder><GI Tract><Gastrointestinal Tract><Gastrointestinal tract structure><Gene Expression><Goals><Health><Hematogenous><Human><Immune response><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Impaired cognition><Individual><Infection><Infiltration><Inflammation><Inflammatory><Inflammatory Infiltrate><Intracellular Communication and Signaling><Label><Long-Term Effects><Longterm Effects><Lung><Lung Respiratory System><Measurement><Mice><Mice Mammals><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Nasal cavity><Nerve Cells><Nerve Transmitter Substances><Nerve Unit><Nervous System Degenerative Diseases><Nervous System Diseases><Nervous System Disorder><Nervous System Physiology><Neural Cell><Neural Degenerative Diseases><Neural degenerative Disorders><Neurocyte><Neurodegenerative Diseases><Neurodegenerative Disorders><Neurologic><Neurologic Degenerative Conditions><Neurologic Disorders><Neurologic Dysfunctions><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurologic function><Neurological><Neurological Disorders><Neurological Manifestations><Neurological Signs and Symptoms><Neurological function><Neurons><Neurophysiology / Electrophysiology><Neurotransmitters><Olfaction><Olfactory Epithelium><Olfactory Pathways><Olfactory dysfunction><Olfactory system><Operative Procedures><Operative Surgical Procedures><Organ><Organ System><PASC><Paralysis Agitans><Paraosmias><Parkinson><Parkinson Disease><Patients><Persons><Physiopathology><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Primary Parkinsonism><Pulmonary Body System><Pulmonary Organ System><Recovery><Residual><Residual state><Resolution><Respiration Disorders><Respiratory Disease><Respiratory Disorder><Respiratory System><Respiratory System Disease><Respiratory System Disorder><Respiratory Tracts><Respiratory tract structure><Role><Running><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV2><SARS-CoV2 infection><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><Sensory><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 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><Signal Transduction><Signal Transduction Systems><Signaling><Site><Smell><Smell Perception><Spanish flu pandemic><Spanish influenza pandemic><Subcellular Process><Substantia Nigra><Substantia nigra structure><Supporting Cell><Surgical><Surgical Interventions><Surgical Procedure><Survivors><System><T-Cells><T-Lymphocyte><Time><Tissues><Transmission><Vaccinated><Vaccination><Viral><Viral Antigens><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Wuhan coronavirus><acute COVID-19><acute SARS-CoV-2 infection><acute infection><acute phase of COVID-19><acute phase of SARS-CoV-2 infection><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><alimentary tract><animal experiment><anosphrasia><behavior test><behavioral test><biological signal transduction><brain fog><breathing disorder><chronic COVID-19 sequelae><cognitive dysfunction><cognitive loss><common symptom><coronavirus disease 2019><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 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 virus><coronavirus infectious disease-19><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><developmental><digestive canal><electrophysiological><experiment><experimental animal><experimental animals><experimental research><experimental study><experiments><gene function><hCoV19><host response><hyposmia><immune system response><immunoresponse><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><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-term sequelae><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><loss of smell><mortality><mortality rate><mortality ratio><nCoV2><necropsy><nervous system function><neural manifestation><neurodegenerative illness><neurological disease><neurological dysfunction><neuronal><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><odor perception><olfactory bulb><olfactory circuitry><olfactory circuits><olfactory impairment><olfactory loss><olfactory perception><olfactory sensory neurons><parosmia><pathophysiology><post COVID-19 sequelae><post acute sequelae following COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><postmortem><pulmonary><reduced smell><resolutions><respiratory dysfunction><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><social role><surgery><sustentacular cell><thymus derived lymphocyte><transmission process><viral RNA><virus RNA><virus antigen><virus protein>