Document Type

Dissertation

Date of Degree

Spring 2017

Access Restrictions

Access restricted until 07/13/2018

Degree Name

PhD (Doctor of Philosophy)

Degree In

Microbiology

First Advisor

Lee-Ann H. Allen

Abstract

Francisella tularensis is a Gram-negative, facultative intracellular bacterium and the etiologic agent of the zoonosis tularemia. Inhalation of as few as 10 organisms can cause a severe pneumonic disease with a mortality rate reported to be around 30-60% in untreated cases. Due to its highly infectious nature, high mortality rate, and ease of aerosolization, the Centers for Disease Control considers F. tularensis a Tier 1 select agent and potential bioweapon. This organism is capable of producing a severe infection as it gains entry into a number of different host cell types and modulates numerous key innate immune responses. It is noteworthy that neutrophils contribute to tissue destruction and disease severity, as exemplified by studies demonstrating that blocking neutrophil recruitment into infected tissues leads to reduced bacterial load and an overall increase in host survival. Therefore, we hypothesized that neutrophil function is dysregulated in the context of tularemia, a result of modification of neutrophil antimicrobial mechanisms by F. tularensis.

Previously, we demonstrated that F. tularensis prolongs human neutrophil lifespan by interfering with the intrinsic, extrinsic, and phagocytosis-induced apoptotic pathways. How this prolongation occurs is incompletely defined; however, our published data suggest secreted or extracellular factors function in this process. The major aims of the studies outline in this thesis were aimed at investigating the effectors produced by F. tularensis that function in the inhibition of human neutrophil apoptosis and the survival signaling within these immune cells that may lead to their prolonged lifespan. Moreover, we examined the related, less virulent strain, F. novicida, to determine the extent to which this organism shares the ability to modulate neutrophil apoptosis like F. tularensis.

Herein, we report that F. tularensis activates multiple survival signaling pathways in neutrophils. In addition, we provide insight into the properties of the extracellular, antiapoptotic factors produced by F. tularensis, and furthermore, describe the identification of Francisella-derived lipoproteins as functional antiapoptotic effectors acting specifically via TLR2/1. Lastly, we report the novel finding that F. novicida manipulates apoptosis and extends neutrophil lifespan by utilizing a similar, yet distinct mechanism as F. tularensis.

Pages

xvii, 169 pages

Bibliography

Includes bibliographical references (pages 145-169).

Comments

This thesis has been optimized for improved web viewing. If you require the original version, contact the University Archives at the University of Iowa: http://www.lib.uiowa.edu/sc/contact/

Copyright

Copyright © 2017 Lauren Cornick Kinkead

Available for download on Friday, July 13, 2018

Included in

Microbiology Commons

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