Simvastatin and ML 141 inhibit endothelial host cell processes to limit the invasion of Streptococcus pyogenes

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dc.contributor.advisor McDowell, Susan A.
dc.contributor.author Caffo, Lindy Marie
dc.date.accessioned 2014-07-29T12:19:39Z
dc.date.available 2014-07-29T12:19:39Z
dc.date.issued 2014-07-19
dc.identifier.uri http://cardinalscholar.bsu.edu/handle/123456789/198452
dc.description en_US
dc.description.abstract Streptococcus pyogenes is a human pathogen that can manipulate host cell machinery in human umbilical vein endothelial cells (HUVEC), exploiting host cell endocytosis to become an intracellular pathogen. It is postulated that deep tissue infection is initiated by bacterial migration across the endothelial cell barrier. Deep tissue invasive S. pyogenes infection has been associated with persistent infections that potentially lead to sepsis and necrotizing fasciitis. Simvastatin, a common cholesterol-lowering drug, inhibits localization of Rho GTPase isoforms that regulate host cell endocytosis. We performed bioassays to examine how simvastatin may influence S. pyogenes invasion in HUVEC. Simvastatin treatment decreased S. pyogenes invasion 87±12%. Host cell actin stress fibers are typically disassembled in response to S. pyogenes infection; however, simvastatin treatment decreased actin stress fiber disassembly by 12% compared to control. Simvastatin decreased HUVEC binding to fibronectin by 47±1% compared to treatments lacking simvastatin treatment. S. pyogenes uses fibronectin for invasion of host cells. Because these cellular processes are regulated by CDC42, we addressed if specific inhibition of CDC42 would limit S. pyogenes invasion. CDC42 activation is inhibited with a newly-characterized target inhibitor, ML 141. Compared to control groups, ML 141 reduced S. pyogenes HUVEC invasion by 85±3% and host cell actin depolymerization by 9%. Overall, simvastatin and ML 141 treatments inhibit S. pyogenes invasion of HUVEC. Additional human pathogens, including Staphylococcus aureus and Neisseria gonorrhoeae, use the fibronectin-binding mechanism to invade host cells; our work may provide a future defense strategy against multiple invasive pathogens. en_US
dc.description.sponsorship Department of Biology
dc.subject.lcsh Statins (Cardiovascular agents) -- Physiological effect.
dc.subject.lcsh Sulfonamides -- Physiological effect.
dc.subject.lcsh Endothelial cells.
dc.subject.lcsh Guanosine triphosphatase.
dc.subject.lcsh Streptococcus pyogenes.
dc.title Simvastatin and ML 141 inhibit endothelial host cell processes to limit the invasion of Streptococcus pyogenes en_US
dc.title.alternative Simvastatin and 4-[3-(4-methoxyphenyl)-5-phenyl-3,4 dihydropyrazol-2-yl]benzenesulfonamide inhibit endothelial host cell processes to limit the invasion of Streptococcus pyogenes
dc.description.degree Thesis (M.S.) en_US
dc.identifier.cardcat-url http://liblink.bsu.edu/catkey/1771913


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  • Master's Theses [5318]
    Master's theses submitted to the Graduate School by Ball State University master's degree candidates in partial fulfillment of degree requirements.

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