Endotoxins (E) are a unique and abundant family of glycolipids located in the outer leaflet of the outer membrane of Gram-negative bacteria. Host immune responses to endotoxin depend on ordered endotoxin-host protein interactions, resulting in delivery of an endotoxin monomer to MD-2 which acts as a potent agonist of Toll-Like Receptor (TLR) 4. Activated TLR4 is unique among TLRs in its ability to mobilize two distinct intracellular signaling pathways: the MyD88- and TRIF-dependent pathways. The regulated action of both pathways is likely important for optimal host immune responses to Gram-negative bacterial infection, but how this is achieved is not well understood Recent studies have indicated an essential role for host CD14 in TRIF-dependent signaling by activated TLR4 but the extent to which these observations reflect a general role of CD14 in endotoxin-triggered TRIF signaling or one more narrowly restricted to the specific endotoxins and/or cell types used is uncertain. We have addressed this question by identifying a novel CD14-independent mechanism for efficient delivery of E monomer to MD-2 and TLR4 activation, that is mediated by endotoxin.albumin complexes. We have used these complexes to demonstrate CD14-independent activation of MD-2⋅TLR4 by a wider range of endotoxin species than previously thought possible and activation of both MyD88- and TRIF-dependent pathways. Taken together, the findings in this thesis indicate that the molecular structure and physical presentation of endotoxin as well as CD14-independent properties of the host cell help determine the extent to which CD14 is required for TRIF-dependent signaling by activated TLR4.
| Identifer | oai:union.ndltd.org:uiowa.edu/oai:ir.uiowa.edu:etd-3236 |
| Date | 01 May 2012 |
| Creators | Esparza, Greg Angel |
| Contributors | Weiss, Jerrold P. |
| Publisher | University of Iowa |
| Source Sets | University of Iowa |
| Language | English |
| Detected Language | English |
| Type | dissertation |
| Format | application/pdf |
| Source | Theses and Dissertations |
| Rights | Copyright © 2011 Greg A. Esparza |
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