Title page for ETD etd-06262008-092657


Type of Document Dissertation
Author Fischer, Jeffrey Lynn
URN etd-06262008-092657
Title Chemotactic and Inflammatory Responses to and Recognition of Encephalitozoon spp. of Microsporidia
Degree Doctor of Philosophy (Ph.D.)
Department Biological Sciences
Advisory Committee
Advisor Name Title
Hollie Hale-Donze Committee Chair
Huangen Ding Committee Member
John Battista Committee Member
Karin Peterson Committee Member
Dennis Ring Dean's Representative
Keywords
  • chemokines
  • pattern recognition receptor
Date of Defense 2008-05-01
Availability unrestricted
Abstract
Microsporidiosis is an emerging disease among immunocompromised individuals who often present with chronic diarrhea. The intracellular, eukaryotic parasites responsible for this pathology can often disseminate, causing multiorgan infections. Dissemination of these pathogens is believed to occur through vehicular spread by macrophages. The macrophage response to microsporidia is poorly understood. The information, described herein, is focused on defining the host-pathogen interaction and subsequent inflammatory response in human monocyte-derived-macrophages (MDM) against Encephalitozoon spp. of microsporidia. Initial studies were designed to better define the infection kinetics in MDM using various microscopic analysis and novel staining approaches. Spore adherence and uptake occurs within the first 6 hr and parsitophorous vacuole formation within 24 hr after infection. Replication was shown to peak at 72 hr as measured by bromodeoxyuridine incorporation and spore formation by 120 hr. Treating the MDM with interferon gamma and bacterial lipopolysaccharide reduced parasitic burden. The role of MDM in initiating monocyte recruitment after infection was evaluated using co-culture chemotaxis assays, limited gene and protein arrays, ELISA, and neutralizing antibody assays. These studies identified three major monocyte chemoattractants, CCL2, CCL3, and CCL4 that were upregulated, produced, and secreted in response to Encephalitozoon infections. Furthermore, these were necessary for monocytic infiltration. Finally, investigations into the receptors involved in initiating host recognition and regulating chemokine production were examined. Toll-like receptor (TLR) 2 was shown to be activated by Encephalitozoon spores. Using siRNA gene knock-downs in MDM, TLR2 was revealed to activate NF-B within 1 hr after parasite exposure resulting in the production of not only CCL3 and CCL4 but also two pro-inflammatory cytokines, TNF- and IL-8. These results indicate that microsporidia are recognized by TLR2 and induce the production of chemotactic and inflammatory mediators needed for the recruitment of monocytes/macrophages, which allow for parasitic proliferation.
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