A Complex Interaction: Cooperation Between Multiple Macrophage Defense Pathways in Response to Francisella novicida Infection 公开
Jones, Crystal L. (2012)
Published
Abstract
A COMPLEX INTERACTION: COOPERATION BETWEEN MULTIPLE MACROPHAGE DEFENSE PATHWAYS IN RESPONSE TO FRANCISELLA NOVICIDA INFECTION
By Crystal L. Jones
Early detection of microorganisms by the innate immune system is provided by Toll-like receptors (TLRs), and activation of these receptors leads to the expression of proinflammatory cytokines. Some intracellular bacteria can subvert the TLR response by rapidly escaping the phagosome and replicating in the cytosol. However, these bacteria are recognized by the AIM2 inflammasome, a multi-protein complex comprised of the sensor protein AIM2, the scaffolding protein ASC and the cysteine protease caspase-1. Inflammasome activation leads to the release of proinflammatory cytokines IL-1β and IL-18 and death of the infected cell, an important host defense that eliminates the pathogen's replicative niche. While TLRs and inflammasomes are critical for controlling Francisella novicida infection, it was not known whether these host pathways cooperate to activate defenses against this intracellular pathogen. We showed that TLR2 contributes to rapid inflammasome activation since in its absencethere was a delay in cell death, caspase-1 activation and IL-18 release in macrophages and in vivo. These data show that the host coordinates signals between two spatially separated host defense pathways to more rapidly respond to bacterial infection. In spite of this, F. novicida evades TLR2 activation by repressing the expression of bacterial lipoproteins (BLPs) using the protein FTN_0757. A ΔFTN_0757 mutant of F. novicida induced robust TLR2-dependent cytokine production in macrophages, produced increased amounts of BLPs compared to wild-type bacteria, and was severely attenuated in vivo. One BLP, FTN_1103, was significantly upregulated in the ΔFTN_0757 mutant, and deletion of FTN_1103 led to a significant decrease in cytokine and BLP production and partially rescued the in vivo attenuation of the ΔFTN_0757 mutant. Taken together, these data reveal a novel mechanism of immune evasion that is likely used by other intracellular bacterial pathogens to escape host defenses.
Table of Contents
Table of Contents
Abstract...iv
Acknowledgements...vi
Table of Contents...viii
List of Tables and Figures...x
Chapter 1: Introduction...1
1. Francisella tularensis
1.1. History, Epidemiology and Taxonomy...2
1.2. Tularemia...4
1.3. F. tularensis as a Bioweapon...5
2. Innate Immune Response to Francisella Infection
2.1. Macrophages...7
2.2. Toll-like Receptors...9
2.3. Cytosolic Defenses...11
3. Adaptive Immune Response to Francisella
Infection...16
References...21
Table 1...35
Figures...36
Chapter 2: TLR2 Signaling Contributes to Rapid Inflammasome
Activation during
Francisella novicida Infection...39
Abstract...40
Introduction...41
Materials and Methods...45
Results...50
Discussion...59
References...64
Figures...73
Chapter 3: Repression of Bacterial Lipoprotein Production by
Francisella novicida
Facilitates Evasion of Innate Immune Recognition...87
Abstract...88
Introduction...89
Materials and Methods...92
Results...98
Discussion...106
References...109
Tables...116
Figures...117
Chapter 4: Discussion...128
Discussion...129
References...135
Figures...137
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