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Principal Investigator: Jenna Susan Reed
Organization: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
Fiscal Year: 2024
Award: $39,995
Funding agency: National Heart Lung and Blood Institute
Abstract
Malaria afflicted 247 million people in 2021, of which over 600,000 died. In the most severe cases, patients can
develop organ-specific pathologies related to vascular leak, including cerebral malaria and malaria-associated
acute respiratory distress syndrome (MA-ARDS). The mechanisms of pulmonary vascular leak are poorly
understood, and the long-term goal of this work is to define the molecular mechanisms underlying pulmonary
vascular leak in malaria to develop rationale therapeutics to treat this condition. It has been previously shown
that CD8 T cells and platelets are activated by Plasmodium in humans and are required for vascular breakdown
in mouse models, but specific mechanisms underlying how these cells incur damage is still unclear. The central
hypothesis of this proposal is that platelets contribute both directly and indirectly to MA-ARDS by promoting
CD8 cytotoxicity leading to barrier dysfunction. The rationale of this work is that identifying how platelets
augment the pathogenicity of CD8 T cells will provide new avenues for chemotherapeutic targeting of MA-ARDS.
Published work from the Lamb lab and preliminary data shown here demonstrate that mice deficient in platelet
a-granules (Nbeal2-/-) survive Plasmodium berghei infection and fail to develop vascular leak in the lungs and
brain. In intestinal colitis models, published work by the Petrey lab has demonstrated that platelet granule-derived
hyaluronidase 2 (HYAL2) is responsible for driving degradation of hyaluronan (HA) in the endothelial glycocalyx
(eGC), which serves as a key modulator of barrier integrity. Our preliminary data show that HA fragments in the
plasma, an indicator of glycocalyx breakdown, are increased in infected wildtype mice but not in platelet a-
granule-deficient mice. The literature shows that HA fragments can promote cellular activation and proliferation,
and our preliminary data demonstrate that the Nbeal2-/-, which have low plasma HA, have low CD8 T cell
accumulation in the lung during Plasmodium infection. The published literature and our preliminary data have
led us to form the working hypothesis that platelet cleaves the endothelial glycocalyx, promoting CD8 T cell
activation and recruitment via circulating HA fragments and exposing endothelial cells to CD8 effector molecules,
resulting in barrier damage. We will test this hypothesis with the following specific aims:
Aim 1: Demonstrate that platelet a-granule HYAL2 is required for eGC breakdown in MA-ARDS.
Aim 2: Test the hypothesis that plasma HA promotes pathogenic CD8 trafficking via CD44 binding.
We expect that the work proposed in Aim 1 will determine the mechanism by which platelet hyaluronidase
causes pulmonary vascular leak during MA-ARDS, which has not previously been described in malaria, and
demonstrate how the resulting plasma HA modulates CD8 T cell activation and trafficking. We anticipate that the
findings from this work will provide a much-needed deeper understanding of the mechanisms of MA-ARDS,
inform on potential mechanisms underlying vascular leak in other disease models, and give insight into potential
pathways that could be targeted therapeutically to disrupt MA-ARDS in the clinic.
Terms: <ARDS><Acute Respiratory Distress><Acute Respiratory Distress Syndrome><Adult ARDS><Adult RDS><Adult Respiratory Distress Syndrome><After Care><After-Treatment><Aftercare><Alpha Granule><Automobile Driving><Binding><Blood Plasma><Blood Platelets><Blood Vessels><Brain><Brain Nervous System><CD44><CD44 Adhesion Receptor><CD44 Antigens><CD44 gene><CD44 molecule><CD8><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CD8B><CD8B1><CD8B1 gene><Cell Body><Cell Coat><Cell Function><Cell Physiology><Cell Process><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cerebral Malaria><Clinic><Colitis><Complication><Cytoplasmic Granules><Da Nang Lung><Data><Death Rate><Development><Down-Regulation><Duran-Reynals Permeability Factor><Dysfunction><Encephalon><Endothelial Cells><Endothelium><Enzyme Gene><Enzymes><Exhibits><Functional disorder><GL Enzyme><Glycocalyx><Glycosaminoglycans><Goals><HUTCH-1><Hermes Antigen><Human><Hyaglosidase><Hyaluronan><Hyaluronan Receptors><Hyaluronan-Binding Protein><Hyaluronate 4-glycanohydrolase><Hyaluronate Hydrolase><Hyaluronic Acid Binding Protein><Hyaluronidase><Hyaluronoglucosaminidase><Immunomodulation><In Vitro><Infection><Inflammation><Inflammatory><Intestinal><Intestines><Kinetics><Knowledge><LYT3><Literature><Lung><Lung Respiratory System><Lytic><Lytotoxicity><MDU3><Malaria><Marrow platelet><Mediating><Mice><Mice Mammals><Mission><Modeling><Modern Man><Molecular><Molecular Interaction><Mucopolysaccharides><Murine><Mus><NIH><National Institutes of Health><Organ><Paludism><Pathogenesis><Pathogenicity><Pathology><Pathway interactions><Patients><Persons><Pgp1><Physiopathology><Plasma><Plasma Serum><Plasmodium><Plasmodium Infections><Plasmodium berghei><Platelet Granule><Platelets><Proliferating><Proteins><Proteoglycan><Publishing><Reticuloendothelial System, Serum, Plasma><Role><Severity of illness><Shock Lung><Stiff lung><Study Subject><Subcellular Process><T cell response><T-Cell Activation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Testing><Therapeutic><Thrombocytes><Time><United States National Institutes of Health><Vascular Diseases><Vascular Disorder><Wild Type Mouse><Work><activate T cells><blood vessel disorder><bowel><burden of disease><burden of illness><cell type><cytotoxicity><developmental><disease burden><disease model><disease severity><disorder model><driving><gp85><granule><human disease><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><insight><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><molecular sieving><mortality rate><mortality ratio><mouse model><murine model><novel><pathophysiology><pathway><platelet function><post treatment><pulmonary><recruit><rodent plasmodia><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 coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><social role><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><thymus derived lymphocyte><trafficking><vascular><vascular dysfunction><vasculopathy><wet lung><wildtype mouse><α-Granule>