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Principal Investigator: Thomas M McIntyre
Organization: CLEVELAND CLINIC LERNER COM-CWRU
Fiscal Year: 2021
Award: $572,341
Funding agency: National Heart Lung and Blood Institute
Hypertension, for unknown reasons, is a primary co-morbidity risk factor for poor COVID-19 outcomes. SARS-
Cov-2 breaches the lung blood-air barrier to spread among organs inducing endothelial cell dysfunction and
multi-organ thromboembolism. ACE2 is the high affinity receptor for SARS-Cov-2 with TMPRSS2 cleavage then
enabling fusion. However, ACE2 and TMPRSS are not co-expressed by all SARS-Cov-2 infected organs.
We discovered human platelets express ACE2 and TMPRSS, bind SARS-Cov-2 spike protein, and
internalize ACE2-spike protein complexes. SARS-Cov-2 RNA accumulates within platelets.
Platelets are activated in essential hypertension, transgenic renin expression stimulates fibrosis and
coagulation, and inhibition of coagulation blocks renin fibrosis. The direct renin inhibitor Aliskiren blocks
thrombosis in hypertensive animals, so renin intercalates into coagulation to initiate thromboembolic disease.
We discovered cells releasing prorenin stimulate explosive platelet activation, but in a unique way; the onset
of activation was very delayed, and activation was always maximal. Mechanistically, prorenin interacted with
quiescent platelets promoting escape of intracellular phosphatidylserine onto the platelet surface.
Phosphatidylserine organizes tenase and prothrombinase coagulation complexes, forming factor Xa and then
thrombin that explosively activated the platelet PAR1 thrombin receptor. Aliskiren abolished phosphatidylserine
expression, thrombin formation, and thrombosis. This establishes renin as a novel, direct platelet agonist.
Platelets displaying surface phosphatidylserine are rapidly cleared by engulfment by endothelial cells and
perivascular macrophages of the reticuloendothelial system of liver, lung, and spleen. We postulate
hypertension and renin expression promotes phosphatidylserine display on platelets, initiating coagulation and
platelet activation, but also promoting rapid platelet clearance. This, we postulate, internalizes SARS-Cov-2 into
cells that need not express ACE2 or TMPRSS2, themselves.
Aim 1. Test the hypothesis that renin-activated platelets are entry vectors for SARS-Cov-2 into
endothelial cells and macrophages of the reticuloendothelial system.
Aim 2. Test the hypothesis renin-stimulated platelet turnover in vivo introduces SARS-Cov-2
pseudotyped lentivirus-platelet complexes into diverse organs.
This project will establish a functional connection between hypertension and SARS-Cov-2 infection, identify
renin activated platelets as novel SARS-Cov-2 entry vectors, and define a basis for altered platelet clearance in
renin-clamped hypertensive mice. This provides a translational basis for Aliskiren use to normalize hypertension
risk in COVID-19, elucidates novel approaches to suppress SARS-Cov-2 organ infection and damage, and
establish circulating platelet ACE2 expression as a measure of risk for COVID-19 multi-organ damage.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><Activated Blood Coagulation Factor X><Activated Factor X><Acute><Affinity><Age><Agonist><Aldosterone><Alveolocapillary Membrane><Angiotensin-Forming Enzyme><Angiotensinogen><Angiotensinogenase><Animals><Autoprothrombin C><Autopsy><Big Renin><Binding><Blood><Blood Circulation><Blood Clotting><Blood Coagulation Disorders><Blood Coagulation Factor III><Blood Plasma><Blood Platelets><Blood Reticuloendothelial System><Blood coagulation><Blood megakaryocyte><Blood-Air Barrier><Bloodstream><Body Tissues><CD142 Antigens><CF2R><COVID crisis><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID-19><COVID-19 S protein><COVID-19 crisis><COVID-19 epidemic><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 prognosis><COVID-19 public health crisis><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID19><COVID19 S protein><COVID19 crisis><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 prognosis><COVID19 public health crisis><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CV-19><CV19><Cardiovascular><Cardiovascular Body System><Cardiovascular Organ System><Cardiovascular system><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular injury><Circulation><Clampings><Cleaved cell><Closure by clamp><Clotting><CoV-2><CoV2><Coagulation><Coagulation Disorder><Coagulation Factor III><Coagulation Factor Xa><Coagulation Process><Coagulin><Coagulopathy><Common Rat Strains><Complex><Consumption><Cryorenin><Denervation><Deposit><Deposition><Disease><Disorder><Drugs><Dysfunction><Eating><Endothelial Cells><Endothelium><Epitheliasin Gene><Essential Hypertension><Esteroproteases><F2R><F2R gene><FDA approved><Factor III><Factor Xa><Fibrin><Fibrosis><Food Intake><Functional disorder><Genetic><German><German population><Glomerular Procoagulant Activity><Heart Injuries><Heart Vascular><Human><Hypertensinogen><Hypertension><Inactive Renin><Incidence><Infection><Inflammation><Injury to Liver><Intracellular Communication and Signaling><Kidney><Kidney Urinary System><Lentivirinae><Lentivirus><Liver><Lung><Lung Respiratory System><Lung damage><Lung diseases><Marrow platelet><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Mediating><Medication><Megakaryocytes><Megalokaryocyte><Membrane><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><Mφ><Nervous System Injuries><Nervous System Trauma><Nervous System damage><Neurological Damage><Neurological Injury><Neurological trauma><Non-Polyadenylated RNA><Organ><Outcome><PAR1><PRSS10><Pathway interactions><Patients><Pattern><Pepstatins><Peptidases><Peptide Hydrolases><Pharmaceutic Preparations><Pharmaceutical Preparations><Phosphatidylserines><Physiopathology><Plasma><Plasma Serum><Platelet Activation><Platelet aggregation><Platelets><Proangiotensin><Prorenin><Protease Gene><Proteases><Protein Cleavage><Proteinases><Proteins><Proteolysis><Proteolytic Enzymes><Prothrombinase><Pulmonary Diseases><Pulmonary Disorder><RNA><RNA Gene Products><Rat><Rats Mammals><Rattus><Receptor Protein><Renin><Renin-Substrate><Reporter><Respiratory Disease><Respiratory System Disease><Respiratory System Disorder><Reticuloendothelial System><Reticuloendothelial System, Serum, Plasma><Ribonucleic Acid><Risk><Risk Factors><Role><Route><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 S protein><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 prognosis><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 epidemic><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><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><Serine Phosphoglycerides><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><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome coronavirus disease><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 epidemic><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><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><Site><Spleen><Spleen Reticuloendothelial System><Surface><System><TMPRSS2><TMPRSS2 gene><Testing><Therapeutic><Thrombase><Thrombin><Thrombin Receptor><Thrombocytes><Thrombocytopenia><Thromboembolism><Thrombokinase><Thrombopenia><Thromboplastin><Thrombosis><Thrombus><Tissue Factor><Tissue Factor Procoagulant><Tissue Thromboplastin><Tissues><Transgenic Animals><Transgenic Organisms><Tropism><Urothromboplastin><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viral><Virus><Virus-Lenti><Wuhan coronavirus><ages><ahpatinin C><aliskiren><angiotensin converting enzyme 2><angiotensin converting enzyme II><biological signal transduction><bleeding disorder><cardiac damage><cardiac injury><cell damage><cell injury><cellular damage><circulatory system><cleaved><clotting disorder><co-morbid><co-morbidity><comorbidity><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 S protein><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 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 prognosis><coronavirus disease 2019 public health crisis><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><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 patient><damage to cells><damage to kidney><disease of the lung><disorder of the lung><drug/agent><factor IXa-factor VIIIa><fibrinogenase><hCoV19><heart damage><hepatic body system><hepatic damage><hepatic injury><hepatic organ system><high blood pressure><hyperpiesia><hyperpiesis><hypertensive disease><idiopathic hypertension><in vivo><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><inhibitor><inhibitor/antagonist><injury to cells><innovate><innovation><innovative><intrinsic tenase><kidney damage><liver damage><liver injury><lung disorder><lung injury><macrophage><membrane structure><multiorgan damage><nCoV2><necropsy><neurotrauma><new approaches><novel><novel approaches><novel strategies><novel strategy><particle><pathophysiology><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><postmortem><primary hypertension><prognosis in COVID-19><prognosis in COVID19><prognosis in SARS-COV-2><prognosis in coronavirus disease 2019><prophylactic><prorenin receptor><protein complex><prothrombase><pulmonary><receptor><renal><renal damage><respiratory><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 prognosis><social role><tenase><thromboembolic complications><thrombosis complications><thrombotic><thrombotic complications><thrombotic disease><thrombotic disorder><transgenic><uptake><vector>