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Principal Investigator: Chiara Giannarelli
Organization: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
Fiscal Year: 2023
Award: $783,846
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus
2 (SARS-CoV-2), remains a global health concern and despite the fast-track development of vaccines and the
imminent prospective of new antiviral drugs, is expected to become endemic. COVID-19 is associated with
atherosclerotic cardiovascular (CV) complications like acute coronary syndrome (ACS), Myocardial Infarction
(MI) and stroke, a risk that remains high for up to one year following recovery, but the underlying mechanisms
are poorly understood. In preliminary work using atherosclerotic tissue from COVID-19 patients at autopsy and
subjects who recovered from COVID-19, along with an ex-vivo SARS-CoV-2 model of human vascular explants,
we identified SARS-CoV-2 viral material in human plaques that persists in plaques of patients who recovered
from COVID-19. Single cell RNA sequencing (scRNAseq) of human atherosclerotic plaques identified high levels
of neuropilin-1 (NRP1), a receptor for SARS-CoV-2 entry, in plaque macrophages and foam cells. NRP-1
blockade abrogated the accumulation of viral material in SARS-CoV-2 treated human plaques. These data
suggest that SARS-COV-2 or its viral components can accumulate in human plaques, where they exacerbate
inflammation and disease progression by engaging NRP-1. Using the Syrian Golden hamster model, that
faithfully mimics human SARS-CoV2 infection, we found that viral replication in the heart, lungs and olfactory
bulb of infected hamsters did not correlate with expression levels of Ace2, supporting a role for alternative
mechanisms of viral entry such as NRP-1. Moreover, this model revealed acute and sustained tissue-specific
inflammatory responses (i.e. Nfkb1, Il6, Il1b) in several tissues due to the persistence in the circulation of
noninfectious viral RNA debris (vRNA) for up to several weeks following viral clearance. Based on these exciting
preliminary data, we propose two independent aims to study how SARS-CoV-2 aggravates plaque inflammation
and atherosclerosis and to determine the molecular basis for the increased risk of acute and long-term CV events
in COVID-19 patients. In Aim 1 we will identify the role of NRP-1 in SARS-CoV-2-induced atherosclerotic plaque
inflammation and atherosclerosis progression. Aim 2 will identify the contribution of SARS-CoV-2 vRNA debris
to inflammation and atherosclerosis. We will also determine the effect of persistent vRNA on inflammation and
atherogenesis following viral clearance and recovery from COVID-19. These studies will address important gaps
in knowledge on the effect of SARS-CoV-2 infection on plaque inflammation and atherosclerosis, and will tackle
the molecular basis for the increased CV in patients with COVID-19. We foresee that this information will help
guide the future design of precise therapies to prevent CV outcomes in patients with COVID-19.
Terms: <18-FDG><18F- FDG><18FDG><2 Fluoro 2 deoxy D glucose><2-Fluoro-2-deoxyglucose><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><A5 Antigen><ACE2><Acute><Adverse effects><Affect><Antiviral Agents><Antiviral Drugs><Antivirals><Apoplexy><Arterial Fatty Streak><Arterial Fatty Streaks><Assay><Atheroma><Atheromatous><Atheromatous degeneration><Atheromatous plaque><Atheroscleroses><Atherosclerosis><Atherosclerotic Cardiovascular Disease><Autopsy><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B220><BCDF><BSF-2><BSF2><Bioassay><Biologic Assays><Biological Assay><Blood><Blood Reticuloendothelial System><Blood Vessels><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Brain Vascular Accident><CAT scan><CD45><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 affected><COVID-19 consequence><COVID-19 crisis><COVID-19 effect><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 impact><COVID-19 impacted><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 crisis><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><CT X Ray><CT Xray><CT imaging><CT scan><CV-19><CV19><Cardiac infarction><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cells><Cerebral Stroke><Cerebrovascular Apoplexy><Cerebrovascular Stroke><Circulation><Clinical Sciences><CoV-2><CoV2><Computed Tomography><Cricetinae><Data><Detection><Disease Progression><Event><Exposure to><Foam Cells><Future><GP180><Gene Transfer><Goals><Golden Hamsters><Golden Syrian Hamsters><HPGF><Hamsters><Hamsters Mammals><Heart><Heart Vascular><Hematopoietic><Hepatocyte-Stimulating Factor><Histologic><Histologically><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune><Immune response><Immunes><Immunofluorescence><Immunofluorescence Immunologic><Immunological response><Infection><Inflammation><Inflammatory><Inflammatory Response><Interleukin-6><Knowledge><LY5><Lung><Lung Respiratory System><MGI-2><Macrophage><Measures><Mediating><Medical center><Mesocricetus auratus><Modeling><Modern Man><Molecular><Monitor><Myeloid Differentiation-Inducing Protein><Myocardial Infarct><Myocardial Infarction><Mφ><NIH><NRP1 Protein><National Institutes of Health><Neuropilin-1><New York City><Npn-1 Protein><Nucleocapsid><Organ><Outcome><PASC><PET/CT><PET/CT scan><PTPRC><PTPRC gene><Patients><Plasmacytoma Growth Factor><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><Proteins><Public Health><Receptor Protein><Recovery><Resolution><Risk><Role><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 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-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><Sema III Receptor><Semaphorin III Receptor><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><Spleen><Spleen Reticuloendothelial System><Stroke><Syrian Hamsters><T200><Testing><Tissues><Tomodensitometry><United States National Institutes of Health><Vascular Endothelial Cell Growth Factor 165 Receptor><Viral><Virus><Virus Replication><Work><Wuhan coronavirus><X-Ray CAT Scan><X-Ray Computed Tomography><X-Ray Computerized Tomography><Xray CAT scan><Xray Computed Tomography><Xray computerized tomography><acute coronary syndrome><acute infection><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><angiotensin converting enzyme 2><angiotensin converting enzyme II><anti-viral agents><anti-viral compound><anti-viral drugs><anti-viral medication><anti-viral therapeutic><anti-virals><antiviral compound><antiviral medication><antiviral therapeutic><atherogenesis><atheromatosis><atherosclerosis plaque><atherosclerotic disease><atherosclerotic lesions><atherosclerotic plaque><atherosclerotic vascular disease><biobank><biorepository><brain attack><cardiac infarct><cardiovascular risk><cardiovascular risk factor><catscan><cerebral vascular accident><cerebrovascular accident><chronic COVID-19 sequelae><circulatory system><clinical relevance><clinically relevant><computed axial tomography><computer tomography><computerized axial tomography><computerized tomography><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronary attack><coronary infarct><coronary infarction><coronavirus disease 2019><coronavirus disease 2019 consequence><coronavirus disease 2019 crisis><coronavirus disease 2019 effect><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 impact><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 impact><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><customized therapy><customized treatment><cytokine><design><designing><develop a vaccine><develop vaccines><development of a vaccine><fat metabolism><fluorodeoxyglucose><global gene expression><global health><global transcription profile><hCoV19><heart attack><heart infarct><heart infarction><hemopoietic><host response><human RNA sequencing><human RNA-seq><human data><human model><immune system response><immunoresponse><indexing><individualized medicine><individualized patient treatment><individualized therapeutic strategy><individualized therapy><individualized treatment><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><interferon beta 2><lipid metabolism><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><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><model of human><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><molnupiravir><nCoV2><necropsy><non-contrast CT><noncontrast CT><noncontrast computed tomography><olfactory bulb><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 specific therapies><patient specific treatment><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><positron emission computed tomography><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><prevent><preventing><prospective><pulmonary><receptor><resolutions><scRNA-seq><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><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 coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><single cell RNA-seq><single cell RNAseq><single cell analysis><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><small molecule inhibitor><social role><stroked><strokes><systemic inflammation><systemic inflammatory response><tailored medical treatment><tailored therapy><tailored treatment><transcriptome><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><unique treatment><vaccine development><vascular><viral RNA><viral multiplication><viral replication><virus RNA><virus multiplication><vulnerable plaque><western diet><western-style diet><western-type diet>