Title page for ETD etd-10262010-115113


Type of Document Dissertation
Author Bharathan, Mini
Author's Email Address mini@vt.edu
URN etd-10262010-115113
Title Monocyte Derived Dendritic Cells: Sentinels and Translators of Immune Response to Staphylococcus aureus
Degree PhD
Department Dairy Science
Advisory Committee
Advisor Name Title
Mullarky, Isis K. Committee Chair
Akers, Robert Michael Committee Member
Dalloul, Rami A. Committee Member
Sriranganathan, Nammalwar Committee Member
Keywords
  • T cells
  • Staphylococcus aureus
  • monocytes
  • dendritic cells
Date of Defense 2010-10-05
Availability unrestricted
Abstract
Staphylococcus aureus is a versatile opportunistic pathogen causing a wide spectrum of diseases in both humans and animals. My research focused on characterization of the immune responses of monocyte derived dendritic cells (DC) to S. aureus. We initially evaluated the potential of circulating monocytes to serve as precursors for DC during S. aureus infection. The CD14+ monocytes, when stimulated with irradiated (ISA) or live S. aureus (LSA), differentiated into CD11chigh CD11bhigh DC (MonoDC) in an autocrine fashion. This was associated with the up- regulation of granulocyte-macrophage colony stimulating factor (GMCSF) and tumor necrosis factor-α (TNF-α) gene transcription. We continued our studies to identify the role of TNF-α in the LSA induced differentiation of monocyte to MonoDC. Blocking TNF-α reduced the expression of CD11c and increased the expression of CD14 on LSA stimulated monocyte derived MonoDC. Stimulated monocytes were able to secrete monocyte chemotactic protein-1 (MCP-1), a chemokine that recruits monocytes to the site of infection/injury and induces the expression of β2 integrins on DC. Characterization of the response of DC derived from monocytes using GMCSF and IL-4 revealed that, intact S. aureus rather than its purified structural components were efficient in DC activation. In response to ISA or LSA stimulation, DC induced proliferation of T cells collected from the peripheral circulation of cows with a history of S. aureus mastitis. Subsequent characterization of the proliferating T cells identified the presence of memory T cells. Finally, we identified a unique population of DEC205+CD8α+

in monocyte derived DC. We further elucidated the role of DC DEC205, a C-type lectin, in S. aureus uptake. Blocking of receptor mediated endocytosis resulted in reduced uptake of S. aureus by DC. Confocal microscopy confirmed a role for DEC205 in S. aureus internalization and delivery to endosomes. DEC205 DC upon stimulation with S. aureus displayed enhanced maturation and antigen presentation. In conclusion, monocyte derived DC can uptake S. aureus and elicit cell mediated immune responses.

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