Investigating Francisella intracellular survival mechanisms Public
Llewellyn, Anna Christine (2012)
Published
Abstract
Abstract
Investigating Francisella intracellular survival mechanisms
Anna C. Llewellyn
Despite being designated a Category A potential biothreat by the
Centers for Disease Control and Prevention, there is relatively
little known about the molecular genetics of Francisella
species pathogenesis. Recent in vivo genetic screens have
identified hundreds of Francisella genes predicted to be
involved in virulence, though in what way many of these genes may
contribute to disease is unknown. Therefore, I began my thesis work
with an intracellular replication screen to identify which
virulence factors are specifically required for intracellular
replication, an important component of Francisella
infection. From the results of this screen, two novel proteins were
chosen for further study: FTN_1133 and NaxD. Characterization of
FTN_1133 revealed the role of this novel Ohr-like organic
hydroperoxide resistance protein in withstanding reactive oxygen
species both in macrophages and in mice. This is the first report
of an Ohr-like protein involved in virulence. Next, NaxD, a member
of the previously functionally uncharacterized YdjC superfamily of
proteins, was shown to function as a deacetylase required for a
lipid A modification important for pathogenesis, intramacrophage
proliferation, and resistance to polymyxin B. Importantly, the role
of NaxD was conserved in the human pathogenic F. tularensis
as well as the mammalian pathogenic Bordetella
bronchiseptica. Further studies indicate that this lipid A
modification is required for resistance to specific intracellular
host CAMPs and evasion of innate immune recognition. Taken
together, the work presented in this dissertation elucidated the
role of Francisella proteins in intramacrophage
proliferation and resistance to host innate antimicrobial defenses.
These studies have contributed not only to the understanding of
Francisella's genetic requirements for intracellular
proliferation, but have revealed the role of Ohr-like proteins in
pathogenesis and elucidated the function and role in virulence of
members of the previously uncharacterized YdjC superfamily of
proteins. Given that both Ohr and YdjC proteins are encoded by many
virulent bacteria, this work has implications for our understanding
of the pathogenesis of both intracellular and extracellular
organisms and may represent attractive targets for drug and vaccine
development.
Table of Contents
Table of Contents
Chapter 1 Introduction...1
References...14
Chapter 2 Macrophage Replication Screen Identifies a Novel Francisella Hydroperoxide Resistance Protein Involved in Virulence...23
Abstract...24
Introduction...25
Results...28
Discussion...35
Materials & Methods...44
References...51
Supporting Information...80
Chapter 3 NaxD is a deacetylase required for lipid A modification and Francisella pathogenesis...111
Abstract...112
Introduction...112
Results...115
Discussion...124
Materials & Methods...127
References...137
Supporting Information...157
Chapter 4 Future Directions...167
References...170
Chapter 5 Discussion...175
References...179
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