Staphylococcus aureus virulence factors dictate host signaling pathways and immune responses

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dc.contributor.authorOrtiz Marty, Rebecca Josefinaen
dc.contributor.committeechairMullarky, Isis K.en
dc.contributor.committeememberLi, Liwuen
dc.contributor.committeememberAkers, Robert Michaelen
dc.contributor.committeememberMeng, Xiang-Jinen
dc.contributor.departmentDairy Scienceen
dc.date.accessioned2017-04-06T15:44:38Zen
dc.date.adate2012-01-19en
dc.date.available2017-04-06T15:44:38Zen
dc.date.issued2011-12-07en
dc.date.rdate2016-10-07en
dc.date.sdate2011-12-21en
dc.description.abstractStaphylococcus aureus causes nosocomial- and community- acquired infections. This versatile pathogen expresses virulence factors (VF) that enhance establishment of infection and immune evasion. Our research focused on defining the roles of S. aureus VF on host immune responses during intracellular or extracellular infections. Accessory gene regulator (agr) controls VF expression and intracellular survival. Our goal was to determine mammary epithelial cells (MEC) responses to intracellular infection and subsequent polymorphonuclear leukocyte (PMN) responses. Intracellular S. aureus increased thrombomodulin expression by MEC and activated protein C (APC) production. APC inhibited PMN chemotaxis. Findings depicted an indirect role for VF on PMN responses, so next we determined signaling pathways and cytokine responses of PMN to S. aureus toxins. Live S. aureus infections increased activation of stress signaling pathways and highlighted a role for agr-regulated genes in MAPK p38 phosphorylation and α-hemolysin in ERK phosphorylation and IL-8 expression in PMN. Continuing our studies of VF, chemotaxis inhibitory protein of S. aureus (CHIPS) inhibits monocyte chemotaxis. We hypothesized that CHIPS inhibited C5a receptor (C5aR) signaling. Monocytes pretreated with CHIPS did not inhibit C5aR signaling. Nevertheless, signaling pathways can reduce PMN function in models such as glucocorticoid treatment. Immunosuppressive effects of glucocorticoids on PMN are restored with OmniGen-AF® supplementation. Glucocorticoid receptor and Toll-like receptor signaling potentially crosstalk to restore PMN function. OmniGen-AF® supplementation restored dexamethasone-induced immunosuppression in a MyD88-dependent manner. Overall, this research focused on characterizing immune responses to S. aureus infections and PMN signaling pathways and how it is key to understanding pathogenesis.en
dc.description.degreePh. D.en
dc.identifier.otheretd-12212011-215830en
dc.identifier.sourceurlhttp://scholar.lib.vt.edu/theses/available/etd-12212011-215830/en
dc.identifier.urihttp://hdl.handle.net/10919/77299en
dc.language.isoen_USen
dc.publisherVirginia Techen
dc.rightsIn Copyrighten
dc.rights.urihttp://rightsstatements.org/vocab/InC/1.0/en
dc.subjectStaphylococcus aureusen
dc.subjectpolymorphonuclear leukocytesen
dc.subjectsignaling pathwaysen
dc.subjecthemolysinsen
dc.titleStaphylococcus aureus virulence factors dictate host signaling pathways and immune responsesen
dc.typeDissertationen
dc.type.dcmitypeTexten
thesis.degree.disciplineDairy Scienceen
thesis.degree.grantorVirginia Polytechnic Institute and State Universityen
thesis.degree.leveldoctoralen
thesis.degree.namePh. D.en

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