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Principal Investigator: Shelli Farhadian
Organization: YALE UNIVERSITY
Fiscal Year: 2022
Award: $70,603
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
The COVID-19 pandemic has rampantly affected the population of the world and created lasting effects on the
economy, health and psyche of the global community. Although it shares similarities with SARS-CoV-1, the full
extent of the pathophysiology caused by SARS-CoV-2 is unclear. In particular, extrapulmonary manifestations
effects of SARS-CoV-2 infection remain poorly understood. Case series from China and Europe suggest that
the central nervous system is involved in the disease process in at least a subset of patients, with some reports
estimating up to 30% of COVID-19 patients having neurological symptoms, including seizure, intractable
headache, and impaired smell and taste. Although there are reports of neurological disease in in COVID-19
patients, it is unclear if SARS-CoV-2 invades the central nervous system (CNS). Studies of other
coronaviruses, including SARS-CoV-1, demonstrate clear neurotropism as well as neuroinflammation
associated with other members of this family of viruses. These studies raise the possibility that SARS-CoV-2
may cause neurological symptoms either through invasion of the CNS or through an increase in inflammatory
cytokines within the CNS. We hypothesize that SARS-CoV-2 infections have neuroinvasive potential and lead
to altered and hyperinflammatory immune states within the CNS of infected individuals. We further hypothesize
that infection of the CNS exacerbates respiratory dysfunction through direct toxicity of ACE2 expressing
neurons that are critical regulators of cardiopulmonary function. Our investigations will combine the power of
human studies with those utilizing mouse models in which we can readily administer virus and assess for
pathophysiology. Aim 1, we will determine the CNS immune responses in COVID-19 patients with
neurological symptoms. Using a combination of single cell RNA-sequencing, cytokine profiling, viral
sequencing and antibody validations, we will fully dissect out the inflammatory responses within the CNS
compartment compared to the systemic circulation in COVID-19 patients. Using mouse models, in Aim 2, we
will investigate the encephalitic potential of SARS-CoV-2. Using several complementary approaches to
infect mice with SARS-CoV-2, we will introduce the virus into the central nervous system of mice. Using
depletion antibodies and various knockout mice, we will identify which immune cells are required for
neuropathology in these mice through survival studies, flow cytometry and immunofluorescent staining. Finally,
in Aim 3, we will evaluate the effects of CNS infection on respiratory outcomes. Because of the known
expression of ACE2 in the brainstem, and the brainstem’s critical role in regulating cardiopulmonary functions,
we suspect that CNS infection with SARS-CoV-2 will exacerbate SARS-CoV-2 respiratory disease.
These three aims will help support our hypotheses of how SARS-CoV-2 infections can affect the CNS and
respiratory compartments. We expect that our findings will uncover new strategies to treat patients diagnosed
with COVID-19 and help gain new insight to understanding the biology of SARS-CoV-2 pathophysiology.
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diagnosis><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 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Cardiopulmonary><Case Series><Cell Body><Cells><Central Nervous System><Central Nervous System Infections><Central Nervous System Infectious Disease><Central Nervous System Infectious Disorder><Cephalalgia><Cephalgia><Cephalodynia><Cerebrospinal Fluid><China><Circulation><CoV disease><CoV-2><CoV2><Communities><Coordination Impairment><Cor pulmonale><Coronaviridae><Coronavirus><Cranial Pain><Data><Disease><Disorder><Dose><Dysfunction><Dyssynergia><Encephalon><Encephalopathies><Enrollment><Europe><Evaluation><Family member><Fever><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Functional disorder><Genomics><Goals><Gustation><Head Pain><Headache><Health><Heart><Heart Hypertrophy><Histology><Histopathology><Human><Hypertension><Hypogeusia><Hypoxemia><IRB><IRBs><Immune><Immune infiltrates><Immune reaction><Immune response><Immunes><Immunological response><Impairment><Individual><Infection><Inflammatory><Inflammatory Response><Influenza Virus><Institutional Review Boards><Intractable Headaches><Invaded><Investigation><KO mice><Knock-out Mice><Knockout Mice><Lead><Lumbar Puncture><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lung infections><Mainland China><Maps><Marrow monocyte><Measurement><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Monitor><Murine><Mus><Nerve Cells><Nerve Unit><Nervous System><Nervous System Diseases><Nervous System Injuries><Nervous System Trauma><Nervous System damage><Nervous system structure><Neural Cell><Neuraxis><Neurocyte><Neurologic><Neurologic Body System><Neurologic Disorders><Neurologic Effect><Neurologic Manifestations><Neurologic Models><Neurologic Organ System><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological><Neurological Damage><Neurological Disorders><Neurological Injury><Neurological Manifestations><Neurological Models><Neurological Signs and Symptoms><Neurological trauma><Neurons><Neurotropism><Null Mouse><Olfaction><Olfactory dysfunction><Outcome><Pathogenicity><Pathology><Pathway interactions><Patients><Pb element><Physiologic><Physiological><Physiopathology><Plaque Assay><Plasma Cells><Plasmacytes><Pneumonia><Population><Process><Production><Protocol><Protocols documentation><Pulmonary Heart Disease><Pulmonary Heart Disorder><Pulmonary Pathology><Pyrexia><Receptor Protein><Reporting><Respiration Disorders><Respiratory Disease><Respiratory Disorder><Respiratory Failure><Respiratory Infections><Respiratory System Disease><Respiratory System Disorder><Respiratory Tract Infections><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 diagnosis><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 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-Related Coronavirus><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><Sampling><Secondary to><Seizures><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 CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><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 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Smell><Smell Perception><Spinal Puncture><Staining method><Stains><Structure of parenchyma of lung><Study models><Supporting Cell><Symptoms><T cell infiltration><T cell tumor trafficking><Taste><Taste Perception><Tissues><Toxic effect><Toxicities><Tumor-infiltrating immune cells><Validation><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viral><Virus><Wild Type Mouse><Wuhan coronavirus><adeno-associated viral vector><adeno-associated virus vector><angiotensin converting enzyme 2><angiotensin converting enzyme II><anosphrasia><antigen based detection><antigen detection><associated symptom><biobank><biorepository><brain tissue><breathing disorder><cardiac hypertrophy><cardiopulmonary disease><cardiopulmonary disorder><central nervous system injury><cerebral spinal fluid><co-morbid symptom><co-occuring symptom><common symptom><comorbid symptom><concurrent symptom><cooccuring symptom><corona virus><corona virus disease><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 consequence><coronavirus disease 2019 crisis><coronavirus disease 2019 diagnosis><coronavirus disease 2019 effect><coronavirus disease 2019 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assay><diagnosed with COVID-19><diagnosed with COVID19><diagnosed with SARS-CoV-2><diagnosed with coronavirus 2019><diagnosed with coronavirus disease 2019><enroll><febrile><febris><flow cytophotometry><gustatory perception><gustatory processing><gustatory response><hCoV19><head ache><heavy metal Pb><heavy metal lead><high blood pressure><host response><human tissue><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><hypoxemic><immune cell infiltrate><immune infiltration><immune system response><immunoreaction><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><influenzavirus><injured CNS><insight><interest><intratumoral immune cell><loss of smell><lung failure><lung pathology><monocyte><mortality><mouse model><murine model><nCoV2><necropsy><nerve cell death><nerve cell loss><nervous system 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SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><tumor immune cell><viral detection><virus detection><wildtype mouse>