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Principal Investigator: TIONE BURANDA
Organization: TULANE UNIVERSITY OF LOUISIANA
Fiscal Year: 2023
Award: $2,254,100
Funding agency: National Institute on Aging
ABSTRACT
Rapidly emerging evidence has characterized the association between vascular dementia (VaD) and increased
COVID-19 incidence, morbidity, and post-COVID cognitive decline. We theorize that brain vascular pathology in
VaD and additional pathophysiologic features such as blood-brain barrier (BBB) disruption and reduced cerebral
blood flow may directly contribute to both VaD and COVID-19. Several lines of evidence support this hypothesis.
First, we have demonstrated that SARS-CoV-2 binds to the vascular integrin α5β1 receptor to infect cells, the
same receptor we have also linked to BBB disruption in brain ischemia (stroke) models and chronic bilateral
carotid artery stenosis (BCAS), which models pathophysiological aspects of VaD such as reduced cerebral blood
flow, BBB disruption, neuroinflammation, white matter damage, and cognitive decline. Second, integrin α5β1 is
substantially upregulated in an age-dependent fashion (aged>young) in the brain vasculature after stroke and
BCAS, and inhibition of this receptor with the clinically-validated integrin α5β1 pentapeptide inhibitor ATN-161
lessens BBB disruption and cognitive impairment in these models. Third, SARS-CoV-2 infection also increases
integrin α5β1 expression in vivo and disrupts the BBB. Forth, preliminary results suggest that SARS-CoV-2
infection after BCAS further increases morbidity vs. BCAS or infection alone and accelerates brain vascular
integrin α5β1 upregulation. Fifth, ATN-161 inhibits SARS-CoV-2 infection in vitro and in vivo and prevents SARS-
CoV-2-induced increased expression of α5β1 integrin. Finally, although angiotensin-converting enzyme 2
(ACE2) is the canonical receptor for viral entry (internalization and fusion) into host cells, its ectodomain binds
the viral spike protein (S-protein) on the surface to facilitate virus attachment and access into host cells through
receptor-mediated endocytosis using an RGD motif. As many cell-surface integrins also bind RGD, we and
others have provided compelling evidence that integrins are co-receptors of the virus. Additionally, we have
shown that talin-dependent integrin activation is required for SARS-CoV-2 infectivity. Consistent with our results,
previous studies have shown that α5β1 and ACE2 engage in signaling crosstalk likely driven by mutual
interaction at their cytoplasmic tails. Building on these findings, we hypothesize that (i) integrin α5β1 plays an
important age-dependent pathogenic role in the association between SARS-CoV-2 infection and VaD by
worsening pre-existing VaD after COVID-19, (ii) ATN-161 treatment before, during, or after COVID-19 infection
will stabilize BBB integrity to improve COVID-19 neurocognitive outcomes in the context of pre-existing vascular
dementia, and (iii) integrin α5β1 signaling regulates infectivity, and its upregulation potentiates dysregulation of
the BBB. To investigate these hypotheses, we propose to 1). Demonstrate that experimental VaD worsens
COVID-19 morbidity and subsequent cognitive decline, 2). Determine the therapeutic potential of integrin α5β1
inhibition in improving VaD post-COVID morbidity and cognitive decline, 3). Determine the signaling mechanism
of integrin α5β1 required for SARS-CoV-2 productive infection and dysregulation of cell barrier function.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV variant><2019-nCoV variant forms><2019-nCoV variant strains><ACE2><Acceleration><Acute><Address><Amentia><Animals><Apoplexy><Arg-Gly-Asp><Arginine-Glycine-Aspartic Acid Cell Adhesion Domain><Arteriosclerotic Dementia><BALB C Mouse><BALB/c><BBB disruption><Band 2 Protein><Bilateral><Binding><Blood - brain barrier anatomy><Blood Serum><Blood Vessels><Blood-Brain Barrier><Brain><Brain Ischemia><Brain Nervous System><Brain Pathology><Brain Vascular Accident><COVID associated morbidity><COVID induced morbidity><COVID morbidity><COVID related morbidity><COVID-19><COVID-19 associated morbidity><COVID-19 induced morbidity><COVID-19 infection><COVID-19 morbidity><COVID-19 related morbidity><COVID-19 related risk><COVID-19 risk><COVID-19 risk factor><COVID-19 variant><COVID-19 variant forms><COVID-19 variant strains><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 infection><COVID19 virus><CV-19><CV19><Carotid Artery Narrowing><Carotid Artery Stenosis><Carotid Stenosis><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Signaling><Cell membrane><Cell surface><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Circulation><Cerebrovascular Stroke><Cerebrovascular system><Chemotactic Cytokines><Chronic><Clinical><Clinical Research><Clinical Study><CoV-2><CoV2><Cognitive><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive function abnormal><Complex><Contracting Opportunities><Contracts><Cytoplasmic Domain><Cytoplasmic Membrane><Cytoplasmic Tail><Data><Dementia><Disturbance in cognition><Dysfunction><Elderly><Encephalon><Endothelial Cells><Exposure to><Female><Functional disorder><Gel><Hemato-Encephalic Barrier><Homologous Chemotactic Cytokines><Hypoxia><Hypoxic><Immunofluorescence><Immunofluorescence Immunologic><Impaired cognition><In Vitro><Inbred BALB C Mice><Incidence><Individual><Infection><Integrin Inhibition><Integrin alpha-5 beta-1><Integrin alpha5beta1><Integrin α5β1><Integrins><Integrins Extracellular Matrix><Intercrines><Interphase Cell><Intracellular Communication and Signaling><Ischemic Encephalopathy><Label><Link><Measurement><Mice><Mice Mammals><Modeling><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Neurocognitive><Non-dividing Cell><Nondividing Cell><Outcome><Oxygen Deficiency><Pathogenicity><Pathologic><Pathology><Patients><Physiopathology><Plasma Membrane><Platelet Glycoprotein Ic/IIa><Play><Predisposition><Prevalence><Productivity><Proteins><RGD (sequence)><RGD Cell Adhesion Domain><RGD Domain><RGD Motif><RGD Tripeptide Sequence><RGD peptide><RGD tripeptide><Receptor Inhibition><Receptor Protein><Resting Cell><Risk><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 infection><SARS-CoV-2 inhibitor><SARS-CoV-2 variant><SARS-CoV-2 variant forms><SARS-CoV-2 variant strains><SARS-CoV2><SARS-CoV2 infection><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><SIS cytokines><Serum><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 inhibitor><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Stroke><Surface><Susceptibility><Talin><Therapeutic><Therapeutic Studies><Therapy Research><Up-Regulation><Upregulation><VLA-5><VLA-5 Receptors><Vascular Dementia><Viral><Viral Receptor><Virus><Virus Receptors><Wuhan coronavirus><advanced age><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after infection by SARS-CoV-2><after severe acute respiratory distress syndrome CoV-2 infection><after stroke><age dependent><age related><aged><aged population><aging population><angiotensin converting enzyme 2><angiotensin converting enzyme II><arginyl-glycyl-aspartic acid><base><bases><behavior test><behavioral test><biological signal transduction><block SARS-CoV-2><block severe acute respiratory syndrome coronavirus 2><blood vessels in the brain><blood-brain barrier 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disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><male><monolayer><mortality><nCoV2><neural inflammation><neuroinflammation><neuroinflammatory><non-demented><nondemented><novel><older adult><older person><pathophysiology><plasmalemma><population aging><post SARS-CoV-2 infection><post stroke><post-COVID><post-COVID-19><post-coronavirus disease 2019><poststroke><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><receptor><receptor mediated endocytosis><rho G-Proteins><rho GTP-Binding Proteins><rho GTPases><rho Protein P21><rho Small GTP-Binding Proteins><risk associated with COVID-19><risk factor associated with COVID-19><risk factor related to 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