Abstract of, “Regulation of Human Neutrophil Functions by the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd, Ph.D., Brown University, May 2014

Byrd, Angel Shree'

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Year:: 2014
Contributor:: Byrd, Angel Shree' (creator); Reichner, Jonathan (Director); Gruppuso, Philip (Reader); Sanders, Jennifer (Reader); Frackelton, A. Raymond (Reader); Salomon, Arthur (Reader); Brown University. BIOMED: Pathobiology (sponsor)
Genre:: theses
Subject:: NEONATES; CGD; MYELOPOEISIS; ECM; and NETS; Newborn infants; Phagocytes; Granulocytes; Colegio de México
Extent:: xlix, 237 p.
DOI: https://doi.org/10.7301/Z0VQ312H

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Abstract:: Neutrophil-mediated host defense against pathogens includes the extrusion of a lattice of DNA and microbicidal enzymes known as Neutrophil Extracellular Traps (NETs). The receptor:ligand interactions and intracellular signaling mechanisms responsible for elaborating NETs were determined for the response to Candida albicans. Since the host response of extravasated neutrophils to mycotic infections within tissues necessitates contact with ECM, this study also identified a novel and significant regulatory role for the ubiquitous matrix component fibronectin (Fn) in NET release. We report that recognition of purified fungal pathogen-associated molecular pattern β-glucan by human neutrophils causes rapid (≤ 30 mins) homotypic aggregation and NET release by a mechanism that requires Fn. Alone, immobilized β-glucan induces reactive oxygen species (ROS) production but not NET release, whereas in the context of Fn, ROS production is suppressed and NETs are extruded. NET release to Fn + β-glucan is robust, accounting for 17.2 ± 3.4% of total DNA in the cell population. Release is dependent on β-glucan recognition by CR3 (CD11b/CD18), but not Dectin-1, or ROS. The process of NET release included filling of intracellular vesicles with nuclear material that was eventually extruded. We identify a role for ERK in homotypic aggregation and NET release. NET formation to C. albicans hyphae was also found to depend on β-glucan recognition by CR3, require Fn and ERK but not ROS, and results in hyphal destruction. We report a new regulatory mechanism of NETosis in which the extracellular matrix is a key component of the rapid anti-fungal response. We also report that neonatal neutrophils formed aggregates and released NETs rapidly and independent of ROS production. Providing additional evidence of the ROS independent mechanism of aggregation and NET release, neutrophils from Chronic Granulomatous Disease (CGD) patients formed large homotypic aggregates and released NETs to β-glucan and Fn. Therefore, the susceptibility of these immunocompromised populations to fungal infections may not be due to an inherent inability of neutrophils to aggregate and produce NETs in response to the fungal PAMP β-glucan. Ultimately, we hope innovative therapeutic approaches can mediate a regulatory balance in immunocompromised patients to improve health outcomes.
Notes:: Thesis (Ph.D. -- Brown University (2014)

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Byrd, Angel Shree', "Abstract of, “Regulation of Human Neutrophil Functions by the Integrin, CR3 – An Extracellular Matrix-Based Mechanism of Rapid Neutrophil Extracellular Trap Formation” by Angel S. Byrd, Ph.D., Brown University, May 2014" (2014). Pathobiology Theses and Dissertations. Brown Digital Repository. Brown University Library. https://doi.org/10.7301/Z0VQ312H

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Pathobiology Theses and Dissertations

Theses and Dissertations for the Pathobiology department.
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