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dc.contributor.advisorBeth McCormick
dc.contributor.authorZukauskas, Andrew
dc.date2022-08-11T08:08:46.000
dc.date.accessioned2022-08-23T16:08:03Z
dc.date.available2022-08-23T16:08:03Z
dc.date.issued2018-06-28
dc.date.submitted2018-08-06
dc.identifier.doi10.13028/n2ys-1960
dc.identifier.urihttp://hdl.handle.net/20.500.14038/32370
dc.description.abstractStreptococcus pneumoniae (S. pneumoniae) is a Gram-positive, encapsulated bacterium capable of causing significant morbidity and mortality throughout the world. A hallmark of S. pneumoniae infection is infiltration of neutrophils (PMNs) that assist in controlling the spread infection but may also contribute to pathology. Paradoxically, studies have shown that limiting PMN infiltration into the lumen of the lung during infection actually betters clinical outcome in experimental S. pneumoniae infection. The final step in PMN luminal trafficking is a Hepoxilin A3 (HXA3)-dependent migration across the pulmonary epithelium. HXA3 is a PMN chemoattractant that forms gradients along the polarized epithelial face, drawing PMNs from the basolateral to the apical surface during proinflammatory responses. HXA3 requires assistance of an integral- membrane protein transporter to escape the cell and form the gradient. The pulmonary HXA3 transporter is currently unidentified. In this work, we identify the pulmonary HXA3 transporter as the ATP-Binding Cassette Transporter (ABC transporter) Multi-drug Resistance Associated Protein 2 (ABCC2, MRP2). We demonstrate that MRP1 and MRP2 are divergent ABC- transporters that control transepithelial PMN migration through efflux of a distinct anti-inflammatory substance and the pro-inflammatory HXA3 in the context of Streptococcus pneumoniae infection. Enrichment of MRP2 on the plasma membrane requires detection of the bacterial virulence factors pneumolysin (PLY) and hydrogen peroxide. PLY and hydrogen peroxide not only coordinate MRP2 apical membrane enrichment but also influence HXA3-dependent PMN transepithelial migration. They influence migration through stimulation of epithelial intracellular calcium increases that are crucial for HXA3 production as well as MRP2 translocation to the plasma membrane. PLY and hydrogen peroxide are not sufficient in their signaling alone, however, and require at least one additional bacterial signal to induce HXA3/MRP2 proinflammatory activities.
dc.language.isoen_US
dc.rightsCopyright is held by the author, with all rights reserved.
dc.subjectStreptococcus pneumoniae
dc.subjectNeutrophil
dc.subjectPMN
dc.subjectMRP1
dc.subjectMRP2
dc.subjectPneumolysin
dc.subjecthydrogen peroxide
dc.subjectABC-Transporter
dc.subjectHepoxilin A3
dc.subjectHXA3
dc.subjectBacteriology
dc.subjectImmunology of Infectious Disease
dc.subjectPathogenic Microbiology
dc.titleThe Role of Eukaryotic ABC-Transporters in Eliciting Neutrophil infiltration during Streptococcus pneumoniae infection
dc.typeDoctoral Dissertation
dc.identifier.legacyfulltexthttps://escholarship.umassmed.edu/cgi/viewcontent.cgi?article=1988&context=gsbs_diss&unstamped=1
dc.identifier.legacycoverpagehttps://escholarship.umassmed.edu/gsbs_diss/982
dc.legacy.embargo2018-08-06T00:00:00-07:00
dc.identifier.contextkey12610790
refterms.dateFOA2022-08-27T04:57:43Z
html.description.abstract<p><em>Streptococcus pneumoniae</em> (<em>S. pneumoniae</em>) is a Gram-positive, encapsulated bacterium capable of causing significant morbidity and mortality throughout the world. A hallmark of <em>S. pneumoniae</em> infection is infiltration of neutrophils (PMNs) that assist in controlling the spread infection but may also contribute to pathology. Paradoxically, studies have shown that limiting PMN infiltration into the lumen of the lung during infection actually betters clinical outcome in experimental <em>S. pneumoniae</em> infection. The final step in PMN luminal trafficking is a Hepoxilin A3 (HXA<sub>3</sub>)-dependent migration across the pulmonary epithelium. HXA<sub>3</sub> is a PMN chemoattractant that forms gradients along the polarized epithelial face, drawing PMNs from the basolateral to the apical surface during proinflammatory responses. HXA<sub>3</sub> requires assistance of an integral- membrane protein transporter to escape the cell and form the gradient. The pulmonary HXA<sub>3</sub> transporter is currently unidentified.</p> <p>In this work, we identify the pulmonary HXA<sub>3</sub> transporter as the ATP-Binding Cassette Transporter (ABC transporter) Multi-drug Resistance Associated Protein 2 (ABCC2, MRP2). We demonstrate that MRP1 and MRP2 are divergent ABC- transporters that control transepithelial PMN migration through efflux of a distinct anti-inflammatory substance and the pro-inflammatory HXA<sub>3</sub> in the context of <em>Streptococcus pneumoniae</em> infection. Enrichment of MRP2 on the plasma membrane requires detection of the bacterial virulence factors pneumolysin (PLY) and hydrogen peroxide. PLY and hydrogen peroxide not only coordinate MRP2 apical membrane enrichment but also influence HXA<sub>3</sub>-dependent PMN transepithelial migration. They influence migration through stimulation of epithelial intracellular calcium increases that are crucial for HXA<sub>3</sub> production as well as MRP2 translocation to the plasma membrane. PLY and hydrogen peroxide are not sufficient in their signaling alone, however, and require at least one additional bacterial signal to induce HXA<sub>3</sub>/MRP2 proinflammatory activities.</p>
dc.identifier.submissionpathgsbs_diss/982
dc.contributor.departmentMicrobiology and Physiological Systems
dc.description.thesisprogramMolecular Genetics and Microbiology
dc.identifier.orcid0000-0002-3469-1415


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