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Principal Investigator: Anil Prasad
Organization: BETH ISRAEL DEACONESS MEDICAL CENTER
Fiscal Year: 2021
Award: $78,750
Funding agency: National Institute on Drug Abuse
Abstract:
Endothelial injury is hypothesized to importantly contribute to the respiratory failure and thromboemboli seen in
COVID-19. Yet, how SARS- CoV-2 may injure pulmonary endothelium has not been well elucidated. Though
viral components of SARS-CoV-2 were reported to be occasionally detected in pulmonary endothelial cells of
patient samples, it’s still not clearly understood whether the virus actively replicates in these cells. We
hypothesize that circulating mediators released from neighboring infected lung epithelial cells such as
extracellular vesicles (EVs) harboring Spike-proteins or soluble Spike protein subunits may mediate inflammation
and dysfunction of the vascular system.
In addition, we propose that methamphetamine (Meth), one of the most commonly used illicit drugs known
to be associated with an acute vascular syndrome, further exacerbates the SARS-CoV-2 induced endothelial
disease by activating pro-coagulative pathways in endothelial cells.
The overall objective of this proposal is to study the effects or Spike harboring EVs (Spike-EVs) or soluble
Spike proteins derived from Spike expressing lung epithelial cells on elicitation of inflammation and endothelial
injury and dysfunction. Further we will explore how Meth augments Spike protein-induced endothelial
pathobiology.
Specific points of innovation include: (i) Characterizing the EVs released from SARS-CoV-2 Spike protein
expressing primary lung epithelial cells, (ii)Analyzing the effects of Spike-EVs or soluble Spike proteins on the
release of pro-inflammatory cytokines in the presence or absence of Meth and studying the effects of Meth alone
and Meth in combination with Spike-EVs or soluble Spike proteins on modulating the ACE2/Ang II/AT1R
pathway in Human Lung Microvascular Endothelial Cells (HMVEC-L), (iii) Addressing whether Meth enhances
Spike-EVs or soluble Spike proteins induced alteration of HMVEC-L monolayer integrity and permeability, (iv)
Studying the effects of Meth on Spike-EVs or soluble Spike protein-induced expression of endothelial injury
markers and pro-coagulative molecules, and (v) Exploring whether blocking TNF-α receptors in the cell
membrane inhibits Meth and Spike-EVs or soluble Spike protein- induced endothelial injury.
We set out three specific aims to: (i) Explore the effects of Spike-EVs derived from lung epithelial cells or soluble
spike proteins on elicitation of inflammation in HMVEC-Ls and further study their role in inducing endothelial
dysfunction and impairing monolayer integrity in the presence or absence of Meth, and (ii) Evaluate whether
Spike-EVs or soluble Spike proteins augment Meth-enhanced expression of tissue factor (TF) and impairment
of tissue factor pathway inhibitor, which contribute to an acute vascular syndrome.
Deciphering the role of Spike-EVs and Meth in the pathogenesis of EC injury and dysfunction may provide
insights into developing novel therapeutic strategies against severe COVID-19 complications in Meth using
SARS-CoV-2 infected hosts.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><ACE2><Acute><Address><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Beta Proprotein Interleukin 1><Blood Coagulation Factor III><Blood Vessels><Blood leukocyte><CD 120a Antigen><CD106><CD106 Antigens><CD120a Antigens><CD142 Antigens><CD54 Antigens><COVID associated ARDS><COVID associated acute respiratory distress syndrome><COVID induced ARDS><COVID induced acute respiratory distress syndrome><COVID related ARDS><COVID related acute respiratory distress syndrome><COVID-19><COVID-19 S protein><COVID-19 associated ARDS><COVID-19 associated acute respiratory distress syndrome><COVID-19 induced ARDS><COVID-19 induced acute respiratory distress syndrome><COVID-19 infection><COVID-19 related ARDS><COVID-19 related acute respiratory distress syndrome><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 virus><COVID-19/ARDS><COVID-19/acute respiratory distress syndrome><COVID/ARDS><COVID/acute respiratory distress syndrome><COVID19><COVID19 S protein><COVID19 associated ARDS><COVID19 associated acute respiratory distress syndrome><COVID19 induced ARDS><COVID19 induced acute respiratory distress syndrome><COVID19 infection><COVID19 related ARDS><COVID19 related acute respiratory distress syndrome><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><COVID19/ARDS><COVID19/acute respiratory distress syndrome><CV-19><CV19><Cachectin><Cell Body><Cell membrane><Cells><Clinical><CoV-2><CoV2><Coagulation Factor III><Coagulin><Cocaine><Crystal Meth><Cytoplasmic Membrane><Deoxyephedrine><Desoxyephedrine><Development><Disease><Disorder><Dysfunction><Endothelial Cells><Endothelium><Epithelial Cells><F8VWF><Factor III><Functional disorder><Glomerular Procoagulant Activity><HPGF><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><ICAM-1><IFN-beta 2><IFNB2><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-6><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL6 Protein><INCAM-110><Impairment><Inducible Cell Adhesion Molecule 110><Infiltration><Inflammation><Inflammatory><Injury><Intercellular adhesion molecule 1><Interleukin 1beta><Interleukin-1 beta><Interleukin-1β><Interleukin-6><Leukocytes><Leukocytes Reticuloendothelial System><Lung><Lung Respiratory System><METH effect><METH use><METH using><MGI-2><Macrophage-Derived TNF><Marrow leukocyte><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Methamphetamine><Methylamphetamine><Modern Man><Monocyte-Derived TNF><Myeloid Differentiation-Inducing Protein><N-Methylamphetamine><Outcome><PAI-1><PAI1><PLANH1><Pathogenesis><Pathway interactions><Patients><Permeability><Physiopathology><Plasma Membrane><Plasmacytoma Growth Factor><Plasminogen Activator Inhibitor 1><Preinterleukin 1 Beta><Production><Protein C><Protein Subunits><Proteins><Prothrombinase><Public Health><Reporting><Research><Respiratory Failure><Role><SARS corona virus 2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 associated ARDS><SARS-CoV-2 associated acute respiratory distress syndrome><SARS-CoV-2 induced ARDS><SARS-CoV-2 induced acute respiratory distress syndrome><SARS-CoV-2 infection><SARS-CoV-2 related ARDS><SARS-CoV-2 related acute respiratory distress syndrome><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2/ARDS><SARS-CoV-2/acute respiratory distress syndrome><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Serine or Cysteine Proteinase Inhibitor Clade E Member 1><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-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><Syndrome><TFPI><TNF><TNF A><TNF Alpha><TNF Receptor p55><TNF gene><TNF-sR55><TNF-α><TNF-α receptor><TNFA><TNFAR><TNFBR><TNFR p60><TNFR, 55-kD><TNFR, 60-kD><TNFR-I><TNFR1><TNFR2><TNFR55><TNFR60><TNFR80><TNFRSF1A><TNFRSF1A Receptor><TNFRSF1A gene><TNFRSF1B><TNFRSF1B gene><TNFalpha receptor><TNFα><TNFα receptor><Therapeutic><Thromboplastin><Tissue Factor><Tissue Factor Procoagulant><Tissue Thromboplastin><Tumor Necrosis Factor><Tumor Necrosis Factor Beta Receptor><Tumor Necrosis Factor Receptor 1><Tumor Necrosis Factor Receptor 55><Tumor Necrosis Factor-alpha><Type 1 Plasminogen Activator Inhibitor><Urothromboplastin><VCAM><VCAM-1><VWF gene><Vascular Cell Adhesion Molecule><Vascular Cell Adhesion Molecule-1><Vascular Diseases><Vascular Disorder><Vascular System><Viral><Virus><Virus Replication><White Blood Cells><White Cell><Wuhan coronavirus><airway epithelium><angiotensin converting enzyme 2><angiotensin converting enzyme II><base><blood vessel disorder><cofactor><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 associated ARDS><coronavirus disease 2019 associated acute respiratory distress syndrome><coronavirus disease 2019 induced ARDS><coronavirus disease 2019 induced acute respiratory distress syndrome><coronavirus disease 2019 infection><coronavirus disease 2019 related ARDS><coronavirus disease 2019 related acute respiratory distress syndrome><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease 2019/ARDS><coronavirus disease 2019/acute respiratory distress syndrome><coronavirus disease associated ARDS><coronavirus disease associated acute respiratory distress syndrome><coronavirus disease induced ARDS><coronavirus disease induced acute respiratory distress syndrome><coronavirus disease related ARDS><coronavirus disease related acute respiratory distress syndrome><coronavirus disease/ARDS><coronavirus disease/acute respiratory distress syndrome><cytokine><design><designing><developmental><endothelial dysfunction><extracellular vesicles><hCoV19><high risk group><high risk population><illicit drug use><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><injuries><innovate><innovation><innovative><insight><interferon beta 2><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><lung failure><meth user><methamphetamine effect><methamphetamine use><methamphetamine user><methamphetamine using><monolayer><nCoV2><neuroinflammation><neuroinflammatory><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pathophysiology><pathway><plasmalemma><prevent><preventing><pulmonary><pulmonary failure><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 associated ARDS><severe acute respiratory syndrome coronavirus 2 associated acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 induced ARDS><severe acute respiratory syndrome coronavirus 2 induced acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2 related ARDS><severe acute respiratory syndrome coronavirus 2 related acute respiratory distress syndrome><severe acute respiratory syndrome coronavirus 2/ARDS><severe acute respiratory syndrome coronavirus 2/acute respiratory distress syndrome><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><tissue factor pathway inhibitor><tumor necrosis factor alpha receptor><tumor necrosis factor receptor 1A><tumor necrosis factor receptor superfamily, member 1B><tumor necrosis factor α receptor><vWF><vascular><vascular dysfunction><vasculopathy><vesicle release><vesicular release><viral multiplication><viral replication><virus multiplication><white blood cell><white blood corpuscle>