Document text
Principal Investigator: Matthew J. Flick
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2023
Award: $542,806
Funding agency: National Heart Lung and Blood Institute
SUMMARY
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2; CoV2) is the first highly pathogenic and
highly transmissible human coronavirus that is the causative agent for the worldwide COVID-19 pandemic. As
of November 2020, 50 million cases of CoV2 infection worldwide and 1.25 million deaths have been reported.
The U.S. accounts for the majority of cases, 9.7 million (20%) and deaths 235,000 (19%), and COVID-19 is
expected to add an $8 trillion burden to the U.S. health care system. A particularly challenging aspect of
clinical management is the variable patient response to CoV2 infection. Some infected individuals report few
symptoms whereas others display severe disease characterized by hypoxia, acute respiratory distress
syndrome, and multi-organ involvement that can lead to death. A pro-inflammatory ‘cytokine storm’ in COVID-
19 patients promotes derangements in vascular function and blood composition. Elevated fibrinogen and D-
dimer (the breakdown product of fibrin clots) track with significant elevations inflammatory markers (e.g., IL-6,
C-reactive protein), which significantly and positively correlate with poor patient outcomes. Autopsy studies of
COVID-19 patients have revealed intravascular and extravascular fibrin deposits in lung tissue and other organ
systems. A current critical knowledge gap is the molecular basis of how persistent fibrin deposits develop and
whether they are functionally linked to the pathophysiology of severe COVID-19 disease. Our central
hypothesis that an insufficiency in the plasminogen activation (PA) system is a trigger point for transition of
COVID-19 from mild to severe disease due accumulating, proinflammatory, and tissue-damaging fibrin
deposits within the lung and other organ systems. To test this hypothesis, our research team developed a
mouse-adapted CoV2 virus that replicates key immunological and hematological aspects of COVID-19 in
humans. This unique tool will be used in conjunction with mice carrying single or combined deficiencies or
functional mutations in fibrinogen or PA system components to define the natural course of hemostatic
changes following infection and elucidate functional contributions of coagulation and fibrinolytic factors to the
host response. Specifically, we will determine (i) the differences in local and systemic activity of host factors
that control fibrin(ogen) deposition, stabilization, and dissolution following mild vs. severe CoV2 infection; (ii)
how PA deficiency promotes severe disease following CoV2 infection characterized by exacerbation of local
and systemic inflammatory, organ damage, and host mortality; and (iii) the mechanisms linking fibrin(ogen) to
exacerbation of host inflammatory responses and induction of severe disease following CoV2 infection. The
proposed studies will provide novel insights into the contribution of the plasminogen/fibrinogen axis to the
CoV2 pathobiology, illuminate key mechanisms coupling deficiencies in PA system components to CoV2-
mediated thrombophilia, tissue damage, and loss of organ function, and provide essential proof-of-principle
data to facilitate translation of findings into new treatments for COVID-19.
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pandemic><COVID19 pathogenesis><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 related death><COVID19 related fatality><COVID19 related mortality><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><Capsid Proteins><Cell surface><Cessation of life><Clinical><Clinical Management><Clotting><CoV disease><CoV emergence><CoV-2><CoV2><Coagulation><Coagulation Disorder><Coagulation Factor I><Coagulation Factor One><Coagulation Factors><Coagulation Process><Coagulopathy><Coat Proteins><Coronaviridae><Coronaviridae Infections><Coronavirus><Coronavirus Infections><Coupling><Creativeness><D-dimer><D-dimer fibrin><D-dimer fragments><Da Nang Lung><Data><Death><Deposit><Deposition><Disease><Disorder><Disparities><Disparity><Dysfunction><EC 3.4.21.7><Engineering><Factor I><Factor One><Fibrin><Fibrin fragment D><Fibrinogen><Fibrosis><Fostering><Functional disorder><Genetic Alteration><Genetic Change><Genetic defect><Goals><HCoV><HPGF><Health Care Systems><Healthcare Systems><Hematology><Hemorrhage><Hemostatic Agents><Hemostatics><Hepatocyte-Stimulating Factor><Host Factor><Host Factor Protein><Human><Hybridoma Growth Factor><Hypercoagulability><Hypoxia><Hypoxic><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune response><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Individual><Infection><Inflammatory><Inflammatory Response><Integration Host Factors><Interleukin-6><Knowledge><Leukocytes><Leukocytes Reticuloendothelial System><Link><Lung><Lung Inflammation><Lung Parenchyma><Lung Respiratory System><Lung Tissue><MGI-2><Marrow leukocyte><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Murine><Mus><Mutation><Myeloid Differentiation-Inducing Protein><Organ><Organ System><Organ failure><Outcome><Oxygen Deficiency><Pathogenicity><Pathology><Patient outcome><Patient-Centered Outcomes><Patient-Focused 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epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><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 pandemic><Severe acute respiratory syndrome related corona virus 2><Shock Lung><Stiff lung><Structure of parenchyma of 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replication><virus multiplication><virus protein><wet lung><white blood cell><white blood corpuscle>