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Principal Investigator: CHRISTOPHER C. W. HUGHES
Organization: UNIVERSITY OF CALIFORNIA-IRVINE
Fiscal Year: 2020
Award: $179,153
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
COVID19 is caused by SARS-CoV-2, a novel member of the human coronavirus family that includes the closely
related SARS-CoV (SARS) and MERS-CoV (MERS) viruses. SARS-CoV-2 viral spike protein binds to human
angiotensin converting enzyme-2 (ACE2) on the surface of cells and is then primed by the serine/threonine
protease TMPRS22, whereupon the entire complex is internalized by the target cell. ACE2 is expressed by
multiple cell types of the body, including lung and gut epithelium (likely the primary sites of initial infection) and
vascular endothelial cells (EC) of multiple organs. In addition to the well-described pneumonia-like disease
characterized by compromised lung function with subsequent depressed pO2 levels in blood, patients often also
show signs of multi-organ involvement, which can include gut, kidney, liver, heart, and brain. Most recently,
numerous pediatric patients have been showing signs of Kawasaki disease, a systemic vascular inflammation.
Over 30% of COVID19 ICU patients also show signs of thrombosis and 25% suffer venous embolism. Cerebral
ischemia, likely due to clot formation, has also been reported. What is not clear is whether this multi-organ
involvement is due to secondary infection of these tissues or whether these are all a consequence of systemic
hyperinflammation. The sequence of events that could drive systemic hyperinflammation stems from the SARS-
CoV-2 mechanism of infection. Angiotensin II (AngII) is an important vasoconstrictor and under normal
physiological conditions its level is closely controlled through rapid degradation by ACE2, however, SARS-CoV-
2 entry into cells clears ACE2 from the cell surface, potentially prolonging the action of AngII. Primary
consequences of this would be two-fold: prolonged vasoconstriction in the lung (exacerbating poor oxygenation
of the blood by the already compromised lungs) and a shift toward a pro-inflammatory state, as it is well
established that AngII can drive local vascular inflammation, in large part through the induction of IL-6 in EC and
smooth muscle cells (SMC). IL-6 is one of the major drivers of systemic hyperinflammation, and in its most
severe form, a so-called “cytokine storm”. IL-6 is also strongly correlated with thrombosis, likely through
upregulation of tissue factor on EC and macrophages, and by downregulation of thrombomodulin on EC.
Through the parent award we have generated Vascularized Micro-Organs (VMOs), comprised of perfused
human vasculature and a surrounding stroma, and have further developed these into Vascularized Micro-Brains
(VMBs) incorporating a Blood-Brain Barrier, and Vascularized Micro-Livers (VMLs). Additional cells, including
macrophages and SMC have also been incorporated into the VMO. Using these platforms we will address three
hypotheses: 1) That the VMO can be used to assess the ability of convalescent serum, soluble ACE2 or small
molecule inhibitors to block entry of a SARS-CoV-2 pseudotyped virus; 2) That sustained AngII expression can
trigger a hyperinflammatory response from EC and macrophages; and 3) That hyperinflammation can
compromise peripheral and BBB vasculature as well as liver function.
Terms: <2019 novel coronavirus><2019-nCoV><7S Gamma Globulin><Address><AngII><Angiotensin Converting Enzyme><Angiotensin I-Converting Enzyme><Angiotensin II><Antibodies><Award><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><Binding Proteins><Blood><Blood - brain barrier anatomy><Blood Coagulation Factor III><Blood Reticuloendothelial System><Blood Serum><Blood Vessels><Blood monocyte><Blood-Brain Barrier><Body Build><Body Tissues><Body Types><Brain><Brain Nervous System><CD142 Antigens><CD143 Antigens><COVID-19><COVID19><Carboxycathepsin><Cell Body><Cell Surface Receptors><Cell surface><Cells><Cerebral Ischemia><Chronic><Clotting><CoV emergence><Coagulation><Coagulation Factor III><Coagulation Process><Coagulin><Complex><Coronaviridae><Coronavirus><Depressed mood><Dipeptidyl Peptidase A><Disease><Disorder><Down-Regulation><Downregulation><Drug Targeting><Embolism><Embolus><Encephalon><Endothelial Cell Inhibitor><Endothelial Cells><Enzyme Gene><Enzymes><Esteroproteases><Event><Factor III><Family><Funding><Genes><Glomerular Procoagulant Activity><Gut Epithelium><HCoV><HPGF><Heart><Hemato-Encephalic Barrier><Hepatic Cells><Hepatic Parenchymal Cell><Hepatocyte><Hepatocyte-Stimulating Factor><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><IgG><Immunoglobulin G><Infection><Infection prevention><Inflammation><Inflammatory><Interleukin-6><Kawasaki Disease><Kidney><Kidney Urinary System><Kininase A><Kininase II><L-Serine><L-Threonine><Lead><Leiomyocyte><Ligand Binding Protein><Ligand Binding Protein Gene><Liver><Liver Cells><Lung><Lung Respiratory System><MERS corona virus><MERS coronavirus><MERS virus><MERS-CoV><MGI-2><Macrophage Activation><Marrow monocyte><Mediating><Middle East Respiratory Syndrome Corona Virus><Middle East Respiratory Syndrome Coronavirus><Middle East Respiratory Syndrome Virus><Middle East Respiratory Syndrome-CoV><Middle Eastern Respiratory Syndrome Corona virus><Middle Eastern Respiratory Syndrome Coronavirus><Middle Eastern Respiratory Syndrome Virus><Middle Eastern Respiratory Syndrome-CoV><Modeling><Modern Man><Mucocutaneous Lymph Node Syndrome><Myeloid Differentiation-Inducing Protein><Organ><Parents><Partner in relationship><Patients><Pb element><Peptidases><Peptide Hydrolases><Peptidyl-Dipeptidase A><Peripheral><Physiologic><Physiological><Plasmacytoma Growth Factor><Pneumonia><Position><Positioning Attribute><Prevent infection><Primary Infection><Protease Gene><Proteases><Protein Binding><Proteinases><Proteolytic Enzymes><Prothrombinase><Receptor Cell><Receptor Protein><Regulation><Renin-Angiotensin System><Reporting><Respiratory physiology><SARS><SARS Virus><SARS corona virus><SARS coronavirus><SARS coronavirus disease><SARS-Associated Coronavirus><SARS-CoV><SARS-CoV disease><SARS-CoV-2><SARS-CoV2><SARS-Related Coronavirus><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related coronavirus 2><Secondary to><Serine><Serum><Severe Acute Respiratory Syndrome><Severe Acute Respiratory Syndrome CoV disease><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome coronavirus disease><Severe acute respiratory syndrome coronavirus 2><Site><Smooth Muscle Cells><Smooth Muscle Myocytes><Smooth Muscle Tissue Cell><Somatotype><Surface><Technology><Testing><Threonine><Thrombomodulin><Thromboplastin><Thrombosis><Tissue Arrays><Tissue Chip><Tissue Factor><Tissue Factor Procoagulant><Tissue Microarray><Tissue Thromboplastin><Tissues><Up-Regulation><Upregulation><Urothromboplastin><Vascular Endothelial Cell><Vasoactive Agonists><Vasoconstrictor Agents><Vasoconstrictor Drugs><Vasoconstrictors><Vasopressor Agents><Venous><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Viral Receptor><Virus><Virus Diseases><Virus Receptors><Wuhan coronavirus><bloodbrain barrier><bound protein><cell type><child patients><corona virus><corona virus disease 2019><coronavirus disease 2019><coronavirus emergence><cytokine><cytokine release syndrome><cytokine storm><depressed><emergent CoV><emergent coronavirus><emerging CoV><emerging coronavirus><gastrointestinal epithelium><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><human CoV><human corona virus><human coronavirus><interferon beta 2><knock-down><knockdown><liver function><lung function><macrophage><malformation><mate><member><microphysiologic model><microphysiologic platform><microphysiologic system><microphysiology model><microphysiology platform><microphysiology system><monocyte><nCoV><new CoV><new coronavirus><novel><novel CoV><novel coronavirus><pandemic><pandemic disease><pediatric patients><pulmonary><receptor><renal><renin hypertension><respiratory function><response><sadness><secondary infection><severe acute respiratory syndrome-CoV><side effect><small molecule inhibitor><stem><therapeutic target><thrombotic disease><thrombotic disorder><tool><vascular><vascular constriction><vascular inflammation><vasoconstriction><vasopressor><viral infection><virus infection><virus protein><virus-induced disease>