Phagocytosis and signaling in the innate immune system

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dc.contributor.advisorWu, Louisa Pen_US
dc.contributor.authorGonzalez, Elizabeth Anne Catesen_US
dc.contributor.departmentCell Biology & Molecular Geneticsen_US
dc.contributor.publisherDigital Repository at the University of Marylanden_US
dc.contributor.publisherUniversity of Maryland (College Park, Md.)en_US
dc.date.accessioned2012-10-11T05:59:40Z
dc.date.available2012-10-11T05:59:40Z
dc.date.issued2012en_US
dc.description.abstractThe innate immune response provides broad spectrum defense through germline encoded components. Many aspects of innate immunity, such as the activation of NF&#954;B transcription factors and phagocytosis, are highly conserved within the animal kingdom. The innate immune response of the cow, in particular, is important due to the cow's agricultural value. A major proportion of acute disease in domestic cattle is caused by Gram-negative bacteria, which produce the outer membrane component lipopolysaccharide (LPS). LPS binds to Toll-like receptor (TLR) 4 and activates multiple signaling pathways, which have been well-studied in humans, but not in ruminants. Human myeloid differentiation-factor 88 (MyD88) and TIR-domain containing adaptor protein (TIRAP) are critical proteins in the LPS-induced NF&#954;B and apoptotic signaling pathways in humans. We demonstrated through the expression of dominant negative constructs in bovine endothelial cells that both MyD88 and TIRAP activate NF&#954;B in the cow. Additionally, bovine TIRAP was also shown to transduce LPS&ndash;induced apoptosis, indicating that multiple aspects of the TLR4&ndash;dependent signaling pathways are conserved between cows and humans. The model organism <italic>Drosophila melanogaster</italic>, was subsequently utilized to investigate the role of another branch of the innate immune response: phagocytosis. The extracellular fluid surrounding phagocytic cells in <italic>Drosophila</italic> has a high concentration of the amino acid glutamate. While glutamate has been well-characterized as a neurotransmitter, its effect, if any, on immune cells is largely unknown. We identified that a putative glutamate transporter in <italic>D. melanogaster</italic>, <italic>polyphemus (polyph)</italic>, is critical to the fly's immune response. Flies with a disrupted <italic>polyph</italic> gene exhibit decreased phagocytosis of microbial-derived bioparticles but not of latex beads. Additionally, <italic>polyph<italic> flies show increased susceptibility to <italic>S.aureus</italic> infection, decreased induction of the antimicrobial peptide (AMP) Cecropin, increased melanization response, and increased ROS production. Glutamate transport has previously been shown to regulate the synthesis of the antioxidant glutathione. We demonstrate that a polyph&ndash;dependent redox system is necessary to maintain the immune cells' function against an infection. By utilizing two species, the cow and the fly, to study the innate immune system, we have gained unique and novel insights into NF&#954;B activation and phagocytosis.en_US
dc.identifier.urihttp://hdl.handle.net/1903/13200
dc.subject.pqcontrolledCellular biologyen_US
dc.subject.pqcontrolledGeneticsen_US
dc.subject.pquncontrolledcowen_US
dc.subject.pquncontrolledDrosophilaen_US
dc.subject.pquncontrolledInnate immunityen_US
dc.subject.pquncontrolledphagocytosisen_US
dc.subject.pquncontrolledTLRen_US
dc.titlePhagocytosis and signaling in the innate immune systemen_US
dc.typeDissertationen_US

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