Type
Text
Type
Dissertation
Advisor
Furie, Martha B, Krug, Laurie T | Benach, Jorge L | Kew, Richard R | Thanassi, David G | Sherry, Barbara
Date
2012-05-01
Keywords
endothelial cell, EPCR, Francisella, immune evasion, tularemia | Microbiology--Immunology
Department
Department of Molecular Genetics and Microbiology
Language
en_US
Source
This work is sponsored by the Stony Brook University Graduate School in compliance with the requirements for completion of degree.
Identifier
http://hdl.handle.net/11401/71165
Publisher
The Graduate School, Stony Brook University: Stony Brook, NY.
Format
application/pdf
Abstract
The endothelium can be activated by various bacterial pathogens to secrete proinflammatory cytokines and recruit circulating leukocytes. However, there is a distinct lack of activation of these cells by Francisella tularensis, the causative agent of tularemia. Given the importance of endothelial cells in facilitating innate immunity, we investigated the ability of the attenuated live vaccine strain (LVS) and virulent Schu S4 strain of F. tularensis to inhibit the proinflammatory response of human umbilical vein endothelial cells (HUVEC). Living F. tularensis LVS and Schu S4 did not stimulate secretion of the chemokine CCL2 by HUVEC, whereas material released from heat-killed bacteria did. Furthermore, the living bacteria suppressed secretion in response to heat-killed F. tularensis. This phenomenon was dose- and contact-dependent, and it occurred relatively rapidly upon infection. The living bacteria did not inhibit the activation of HUVEC by E. coli LPS, highlighting the relative specificity of this suppression. The endothelial protein C receptor (EPCR) confers anti-inflammatory properties when bound by activated protein C. When the EPCR was blocked, F. tularensis lost the ability to suppress activation of HUVEC. To our knowledge, this is the first report that a bacterial pathogen inhibits the host immune response via the EPCR. As the suppressive effect of F. tularensis on endothelial cells requires contact with the cell and a functional EPCR, we investigated the fate of the EPCR. When HUVEC were exposed to live bacteria, there was less EPCR expressed on the cell surface but also less EPCR released into the medium. Furthermore, the EPCR was internalized by endothelial cells shortly after contact with the bacteria. The bacterial gene acrA, a part of a multi-drug efflux pump, was implicated as necessary to block activation of endothelial cells. | 154 pages
Recommended Citation
Bublitz, DeAnna, "The Inhibitory Effect of Francisella tularensis on Endothelial Cells" (2012). Stony Brook Theses and Dissertations Collection, 2006-2020 (closed to submissions). 372.
https://commons.library.stonybrook.edu/stony-brook-theses-and-dissertations-collection/372