Dissertation/Thesis Abstract

A matter of life or death: Modulation of neutrophil apoptosis and complement activation by Francisella tularensis
by Schwartz, Justin Todd, Ph.D., The University of Iowa, 2013, 229; 3566705
Abstract (Summary)

Francisella tularensis is a facultative intracellular bacterium and the causative agent of tularemia, a severe and potentially fatal disease in humans. This pathogen is extremely infectious by the aerosol route and inhalation of as few as 10 organisms can cause severe pneumonic disease. Consequently, F. tularensis was developed as a bioweapon by several nations and is considered a category A select agent by the Centers for Disease Control and Prevention. The ability of F. tularensis to cause overwhelming infections at low infectious doses suggests this organism has adapted efficient mechanisms to evade containment by the host innate immune system. The goal of this thesis was to better understand the mechanisms by which Francisella modulates innate host defenses, with particular focus on interactions between this pathogen and two important effectors of innate immunity: neutrophils and the complement system. We demonstrate that F. tularensis profoundly modulates neutrophil lifespan during infection, delaying spontaneous apoptosis by inhibiting both the intrinsic and extrinsic apoptotic pathways to maintain an intracellular niche for persistence and proliferation. Furthermore, we show that F. tularensis can override activation of the apoptotic program induced by extracellular apoptotic signals that may drive neutrophil apoptosis at the site of infection. Initial characterization of the molecular mechanisms behind apoptosis inhibition by this pathogen suggests that F. tularensis employs multiple, redundant mechanisms to promote global anti-apoptosis in the cell. Transcriptome analyses of infected PMNs using oligonucleotide microarrays show that 365 unique apoptosis and cell survival genes are differentially regulated between 3-24 hr, several of which directly modulate intrinsic and extrinsic pathway signaling. Moreover, we demonstrate that levels of the potent caspase inhibitor, X-linked inhibitor of apoptosis protein (XIAP), are maintained over the course of infection, which may represent an important mechanism of caspase inhibition by this pathogen. We also confirm reports that F. tularensis can activate complement during incubation in nonimmune serum, and demonstrate for the first time that natural IgM antibodies bind to the bacterial surface and mediate complement opsonization to promote phagocytosis by both human neutrophils and macrophages. Finally, we identify the first neutrophil receptors, CR1 and CR3, involved in the uptake of complement-opsonized F. tularensis . In sum, our data presented here significantly advance our understanding of the host-pathogen relationship between F. tularensis and components of innate immunity, and suggest that this pathogen modulates both neutrophil and complement function to evade innate immune defenses and cause disease.

Indexing (document details)
Advisor: Allen, Lee-Ann H.
Commitee: Apicella, Michael A., Jones, Bradley D., Moreland, Jessica G., Weiss, Jerrold P.
School: The University of Iowa
Department: Microbiology
School Location: United States -- Iowa
Source: DAI-B 74/10(E), Dissertation Abstracts International
Subjects: Microbiology
Keywords: Apoptosis, Complement activation, Francisella tularensis, Neutrophils
Publication Number: 3566705
ISBN: 978-1-303-18105-4
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