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

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Authors
Caffo, Lindy Marie
Advisor
McDowell, Susan A.
Issue Date
2014-07-19
Keyword
Degree
Thesis (M.S.)
Department
Department of Biology
Other Identifiers
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.

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