Document text
Principal Investigator: Sanjana Dayal
Organization: UNIVERSITY OF IOWA
Fiscal Year: 2024
Award: $673,720
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary
Infection with severe acute respiratory syndrome novel corona virus (SARS-CoV-2) causes COVID-19. In
severe cases, COVID-19 leads to profound inflammation (“cytokine storm”) followed by coagulopathy and a
prothrombotic-state with progression to multiple organ failure. Several cytokines, including IL6 are elevated.
Further, a proinflammatory galectin, Galectin-3 (Gal-3) is also found elevated. Gal-3 upregulates IL6 and other
cytokines, can directly activate platelets, neutrophils, and endothelial cells, and is known to mediate venous
thrombosis via IL6 in a mouse model. A growing body of literature has implicated neutrophil, platelet and
endothelial cell activation as potential drivers of thrombotic complications in COVID-19 patients. However,
there are no direct mechanistic links established between inflammation, vascular cell activation, and
thrombosis during SARS-CoV-2 infection. Our objective is to define the mediators that cause activation of
neutrophils, platelets and/or endothelial cells during SARS-CoV-2 infection and their mechanistic roles in
promoting thrombin generation and thrombosis. At the University of Iowa, we led a multicenter randomized
clinical trial (RCT) comparing standard prophylactic dose to intermediate dose enoxaparin in hospitalized
patients with COVID-19 (NCT04360824) and collected plasma samples for biomarkers and mechanistic
studies. Given the upsurge in late thrombotic complications of COVID-19, we now propose to recruit additional
patients to collect serial samples every week during hospitalization and thereafter every 3 months for up to 3
years. We hypothesize that thrombogenicity in COVID-19 is mediated by IL6- and Gal-3-driven activation of
hematopoietic and endothelial cells and that the prothrombotic state persists even after recovery from viral
infection. Our team has a unique combination of expertise and resources that will address the hypothesis in 2
well integrated but independent aims. In Aim 1, using serially collected patient’s samples, we will determine
the mechanistic role of IL6, Gal-3, and NETs in mediating cellular activation and enhancing thrombin
generation and thrombosis in COVID-19. Aim 2 will utilize a novel transgenic mouse model of SARS-CoV-2
infection to determine if targeting IL6, Gal-3, or NETs in vivo protects against cellular activation, thrombin
generation and thrombosis. A strength of this proposal is in utilizing clinical samples and a novel preclinical
model to identify critical mechanistic pathways for cellular activation, thrombin generation and in vivo
thrombosis in COVID-19. Thus, the overall impact of the proposed research agenda is very high and is likely to
provide therapeutic targets for decreasing thrombotic burden in COVID-19.
Terms: <(TNF)-α><2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><Acute><B-Cell Differentiation Factor Gene><B-Cell Stimulatory Factor 2 Gene><BSF-2 Gene><BSF2 Gene><Beta Proprotein Interleukin 1><Beta-2 Gene Interferon><Biological Markers><Blood><Blood Clotting><Blood Coagulation Disorders><Blood Neutrophil><Blood Plasma><Blood Platelets><Blood Polymorphonuclear Neutrophil><Blood Reticuloendothelial System><Blood Vessels><Blood coagulation><CBP-30><CBP-35><CBP35><COVID complications><COVID infected patient><COVID patient><COVID positive patient><COVID related complications><COVID-19><COVID-19 affected><COVID-19 complications><COVID-19 consequence><COVID-19 effect><COVID-19 impact><COVID-19 impacted><COVID-19 infected patient><COVID-19 infection><COVID-19 patient><COVID-19 positive patient><COVID-19 related complications><COVID-19 virus><COVID-19 virus infection><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 virus><CV-19><Cachectin><Carbohydrate-Binding Protein 35><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Clinical><Clotting><CoV emergence><CoV-2><CoV2><Coagulation><Coagulation Disorder><Coagulation Process><Coagulopathy><Coronavirus Infectious Disease 2019><D-Galactose><D-Galactoside-Binding Lectin><D-dimer><D-dimer fibrin><D-dimer fragments><Data><Deterioration><Development><Dose><Endothelial Cells><Enoxaparin><Epsilon-Binding Protein><Experimental Models><Fibrin fragment D><Future><Galactopyranose><Galactopyranoside><Galactose><Galactose Binding Lectin><Galaptins><Galectin 3><Galectins><Generations><HL-29><HSF Gene><Health><Hematopoietic><Hepatocyte Stimulatory Factor Gene><Histone H3><Histones><Hospital Admission><Hospitalization><Human><Hybridoma Growth Factor Gene><IFNB2 Gene><IL-1 beta><IL-1 β><IL-1-b><IL-1β><IL-6 Gene><IL1-Beta><IL1-β><IL1B Protein><IL1F2><IL1β><IL6><IL6 gene><IgE Binding Protein><IgEBP><Immunoglobulin Enhancer-Binding Protein><Infection><Inflammation><Inflammatory><Infusion><Infusion procedures><Interleukin 1beta><Interleukin 6 (Interferon, Beta 2) Gene><Interleukin-1 beta><Interleukin-1β><Interleukin-6 Gene><Intracellular Communication and Signaling><Iowa><K-18><K-18 conjugate><K18><K18 combination><L-29 Lectin><L-31><L-34><L30 Lectin><LGALS3><Lectin><Link><Literature><Lovenox><MOF syndrome><Mac-2 Antigen><Macrophage-2 Antigen><Macrophage-Derived TNF><Marrow Neutrophil><Marrow platelet><Measures><Mediating><Mediator><Mice><Mice Mammals><Modern Man><Monocyte-Derived TNF><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><NF-kB><NF-kappa B><NF-kappaB><NFKB><Neutrophil Activation><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nuclear Factor kappa B><Nuclear Transcription Factor NF-kB><Outcome><Pathway interactions><Patients><Phase><Phlebothrombosis><Plasma><Plasma Serum><Platelet Activation><Platelets><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Pre-Clinical Model><Preclinical Models><Predisposition><Preinterleukin 1 Beta><Preventive><Proteins><Randomized, Controlled Trials><Receptor Protein><Recovery><Reporting><Research><Research Design><Research Resources><Resources><Reticuloendothelial System, Serum, Plasma><Role><S-Type Lectins><SARS><SARS corona virus 2><SARS coronavirus disease><SARS-CO-V2><SARS-COVID-2><SARS-CoV disease><SARS-CoV-2><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV2><SARS-CoV2 infection><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><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><Severe Acute Respiratory Syndrome CoV 2><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 coronavirus 2><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome related corona virus 2><Signal Transduction><Signal Transduction Systems><Signaling><Study Type><Susceptibility><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><Thrombase><Thrombin><Thrombocytes><Thrombosis><Transcription Factor NF-kB><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Universities><Venous Thrombosis><Viral Diseases><Virus Diseases><Wuhan coronavirus><angiotensin converting enzyme 2><angiotensin converting enzyme II><beta-D-Galactosyl-Specific Lectin><beta-Galactoside Binding Lectin><bio-markers><biologic marker><biological signal transduction><biomarker><bleeding disorder><clotting disorder><cohort><complications due to COVID-19><corona virus emergence><coronavirus disease 2019><coronavirus disease 2019 consequence><coronavirus disease 2019 effect><coronavirus disease 2019 impact><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 impact><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus emergence><coronavirus infectious disease-19><coronavirus patient><cytokine><cytokine release syndrome><cytokine storm><developmental><druggable target><emergent CoV><emergent corona virus><emergent coronavirus><emerging CoV><emerging corona virus><emerging coronavirus><extracellular><fibrin fragment D-dimer><fibrin fragment D1 dimer><fibrin fragment DD><fibrinogenase><hCoV19><hemopoietic><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><infusions><kappa B Enhancer Binding Protein><microvesicles><mouse model><multiorgan failure><multiple organ system failure><murine model><nCoV><nCoV2><neutrophil><new CoV><new corona virus><new coronavirus><novel><novel CoV><novel corona virus><novel coronavirus><nuclear factor kappa beta><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><poor health outcome><pre-clinical><preclinical><prevent><preventing><prophylactic><randomized control trial><randomized, clinical trials><receptor><recruit><reduced health outcome><response><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><social role><study design><therapeutic target><thromboembolic complications><thrombogenesis><thrombogenicity><thrombosis complications><thrombotic><thrombotic complications><thrombotic disease><thrombotic disorder><translation strategy><translational approach><translational strategy><trial comparing><vascular><viral infection><virus infection><virus-induced disease><worse health outcome>