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Principal Investigator: HARRIS A GELBARD
Organization: UNIVERSITY OF ROCHESTER
Fiscal Year: 2022
Award: $423,500
Funding agency: National Institute of Neurological Disorders and Stroke
PROJECT SUMMARY/ABSTRACT
Public/health/relevance: Chronic, or recurring, neurological deficits in 60% of recovered COVID-19 patients
are now an unmet medical need to treat the aftermath of SARS-CoV-2 infection of the central nervous system
(CNS). A recent study from Germany suggests that these symptoms persist beyond a year, similarly to patients
suffering from chronic symptoms due to SARS-CoV-1 infection. Thus, there is clear need for interventions
against chronic neurologic symptoms after COVID. Elucidating the mechanism for SARS-CoV-2 impact on the
CNS is essential to inform the design of such interventions.
Objective: This proposal aims to identify a pathway for SARS-CoV-2’s effects on the CNS through a
dysregulated blood-brain barrier (BBB) mediated by a neutrophil-dependent “storm” of bradykinin (BK). We
hypothesize that this storm induces neuroinflammation that ultimately disrupts normal neuronal signaling,
providing the substrate for enduring neurological symptoms.
Research Plan: Recent studies have reported altered integrity of the BBB in response to the spike (S) protein
of SARS-CoV-2, thereby suggesting a neuroinvasive pathway for SARS-CoV-2 or inflammatory immune cells
through the BBB. In line with these observations, this proposal will investigate how pro-inflammatory mediators
associated with COVID infection activate neutrophil-mediated upregulation of BK; this leads to an increased
permeability through paracellular gaps across the BBB due to dysregulated tight junctions (TJs). Such a model
aligns with the upregulated levels of BK observed in bronchoalveolar fluid taken from COVID-19 patients coupled
with the ability of neutrophils to engage the kinin system to remodel endothelial barriers in acute inflammation.
As a proxy for native SARS-CoV-2, we will construct S protein coated quantum dots as high fidelity biomimetics
of SARS-CoV-2 to investigate the size and structural constraints regulating SARS-CoV-2 permeability across
the BBB. These constructs will be used to bias neutrophils to a pro-inflammatory state in the presence of relevant
kallikrein-kinin factors to increase the permeability of cultured bEnd.3 monolayers, a high-fidelity in vitro model
system for murine BBB. A leakier BBB will be indicated by increased permeability of our fluorescent SARS-CoV-2 biomimetic and corroborated with complementary measurements of global barrier health, as measured by
transendothelial electrical resistance (TEER). Lastly, we will construct a correlated scanning ion conductance
and confocal microscope system to examine the heterogeneity of dysregulated barrier function and the specific
nanoscale changes in TJ expression and localization that regulate it.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><Acute><Alveolar><Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg><Assay><BBB permeabilization><BBB permeable><Behavior><Bioassay><Biologic Assays><Biologic Models><Biological Assay><Biological Mimetics><Biological Models><Biomimetics><Blood - brain barrier anatomy><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood-Brain Barrier><Bradykinin><Bradykinin B2 Receptor><Bradykinin Type 2 Receptor><Bronchoalveolar Lavage Fluid><CNS Nervous System><CNS infection><COVID><COVID complications><COVID infected patient><COVID patient><COVID positive patient><COVID related complications><COVID-19><COVID-19 S protein><COVID-19 complications><COVID-19 infected patient><COVID-19 infection><COVID-19 long hauler><COVID-19 patient><COVID-19 positive patient><COVID-19 related complications><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19><COVID19 S protein><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CV-19><CV19><Callicrein><Capsid Proteins><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Central Nervous System><Central Nervous System Infections><Central Nervous System Infectious Disease><Central Nervous System Infectious Disorder><Chronic><CoV disease><CoV-2><CoV2><Coat Proteins><Complement><Complement Proteins><Coupled><Data><Diffuse><Dilatation><Dilatation - action><Disease><Disorder><Electric Resistance><Electrical Resistance><Encapsulated><Endothelium><Event><Exhibits><Future><Gene Expression><Germany><Health><Hemato-Encephalic Barrier><Heterogeneity><Image><Immune><Immune Cell Activation><Immunes><Incubated><Individual><Infection><Inflammation><Inflammation Mediators><Inflammatory><Inflammatory Response><Intervention><Intervention Strategies><Intracellular Communication and Signaling><Ions><KLK family><KLKs><Kallidinogenase><Kalliginogenase><Kallikrein-Kinin System><Kallikreins><Kinin-Forming Enzyme><Kininogen Cystatins><Kininogenase><Kininogens><Kinins><Label><Lead><Ligands><Liquid substance><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Maps><Marrow Neutrophil><Measurement><Measures><Mediating><Medical><Mice><Mice Mammals><Micelles><Microscope><Model System><Modeling><Murine><Mus><Nature><Nerve Impulse Transmission><Nerve Transmission><Nervous System Diseases><Neuraxis><Neurologic Deficit><Neurologic Disorders><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological Disorders><Neurological Manifestations><Neurological Signs and Symptoms><Neuronal Transmission><Neutrophil Activation><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Occluding Junctions><Particle Size><Pathway interactions><Patients><Pb element><Permeability><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Prekinins><Prokinins><Proteins><Proxy><Q-Dot><QOL><Quality of life><Quantum Dots><Receptor Protein><Renin-Angiotensin System><Reporting><Research><Resolution><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 S protein><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Scanning><Scheme><Seminal><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 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 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Structure><Symptoms><System><Testing><Tight Junctions><Tracer><Up-Regulation><Upregulation><Viral Coat Proteins><Viral Outer Coat Protein><Virion><Virus Particle><Visualization><Wuhan coronavirus><Zonula Occludens><antagonist><axon signaling><axon-glial signaling><axonal signaling><biological signal transduction><blood damage><blood-brain barrier permeabilization><blood-brain barrier permeable><bloodbrain barrier><bloodbrain barrier permeabilization><bloodbrain barrier permeable><brain endothelial cell><brain microvascular endothelial cell><brain vascular endothelial cell><cerebral endothelial cell><cerebral microvascular endothelial cell><cerebral vascular endothelial cell><chronic COVID><chronic COVID-19><chronic novel coronavirus disease 2019><chronic symptom><complications due to COVID-19><confocal imaging><corona virus disease><corona virus disease 2019><coronavirus disease><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 long hauler><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><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><cytokine><design><designing><experiment><experimental research><experimental study><fluid><fluorescence imaging><fluorescent imaging><glia signaling><glial signaling><hCoV19><heavy metal Pb><heavy metal lead><imaging><immune activation><in vitro Model><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><inflammatory mediator><inhibitor><innovative technologies><intervention design><interventional strategy><kallidin 9><kallidin I><kininogenin><liquid><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long hauler><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><monolayer><nCoV2><nano crystal><nano meter scale><nano meter sized><nano scale><nanocrystal><nanometer scale><nanometer sized><nanoscale><nerve signaling><nervous system disorder><neural manifestation><neural signaling><neuro-vascular unit><neuroinflammation><neuroinflammatory><neurological disease><neuronal signaling><neurotransmission><neurovascular unit><neutrophil><pathway><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><persistent symptom><post COVID syndrome><post COVID-19 syndrome><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><public health relevance><receptor><response><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome-CoV><social role><therapy design><transcytosis><treatment design><virus development>