A Battle to the (Cell) Death: Coxiella burnetii Thwarts Immunogenic Caspase-8-Dependent TNF-Alpha Production and Cell Death during Infection

Chelsea A. Osbron

doi:10.7273/000006891

Coxiella burnetii is a Gram-negative, obligate intracellular bacterial pathogen responsible for the global zoonosis Q fever. Typically found in ruminants, but also able to infect diverse species of ticks, birds, and other animals, C. burnetii can cause acute and chronic disease and holds considerable bioterrorism potential due to its environmental stability and ability to be aerosolized. No widely-available vaccine for C. burnetii exists, though not for lack of effort, and resistant strains have been found for doxycycline, the most recommended antibiotic for treatment. A greater understanding of C. burnetii pathogenesis is necessary to develop novel therapeutic options and vaccines. During infection, C. burnetii must combat and evade host immune signaling to survive; however, due to its intracellular nature, C. burnetii also relies specifically upon the host cell environment to establish and maintain its replicative niche. This places host programmed cell death responses, such as apoptosis, necroptosis, pyroptosis, and autophagy-mediated cell death, as top-priority pathways for C. burnetii. Indeed, bacterial manipulation of cell death signaling is an on-going area of research to which this dissertation contributes. Specifically, we investigate the relationships that exist between C. burnetii and the cell death protease caspase-8 during infection. Caspase-8 sits at the nexus of multiple programmed cell death pathways, namely apoptosis, necroptosis, and pyroptosis. Some of these pathways, like apoptosis, are known to be significant to C. burnetii infection; however, the importance of others, like necroptosis, are completely unknown, as is the role of caspase-8 itself. In Chapter 1, a general introduction to the research topic is given. In Chapter 2, the known interactions between C. burnetii and programmed cell death pathways are reviewed and evaluated. In Chapter 3, we first dissect the specific bacterial manipulation of caspase-8-mediated apoptosis and necroptosis by treating infected mammalian cells with TNFα to induce cell death and measuring activation of key signaling molecules such as cleavage of caspases-3, -8, and -9 and phosphorylation of RIPK1, RIPK3, and MLKL. Then, we probe the role of caspase-8 during early and late stages of C. burnetii infection of primary murine macrophages by measuring bacterial replication, host cell death, and TNFα production in cells lacking RIPK1, RIPK3, or caspase-8 functionality. Finally, in Chapter 4, prospects of C. burnetii research relating to cell death and beyond are discussed. In the research presented in this dissertation, we found that, not only is caspase-8 inhibited by C. burnetii to prevent host cell apoptosis during early infection, but infected cells are also sensitized to necroptosis. Moreover, we found that caspase-8 is vital for the control of C. burnetii replication in primary macrophages through regulation of TNFα production. The research presented in this dissertation describes novel host-pathogen interactions and points to caspase-8 as a key component of the innate immune response to C. burnetii infection.

A Battle to the (Cell) Death: Coxiella burnetii Thwarts Immunogenic Caspase-8-Dependent TNF-Alpha Production and Cell Death during Infection

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