Date of Award
Doctor of Philosophy (PhD)
Cell & Molecular Biology
Host immune cells use multiple strategies to detect and protect against microbial infections. In turn, pathogens have evolved ways to evade these strategies to remain undetected. The elegant interplay between these host-pathogen interactions is displayed by studies on the innate immune system, which is on a constant evolutionary arms race with invading microbes. In this dissertation, we explore the innate immune response to the bacterial pathogen Coxiella burnetii. This intracellular pathogen has an intimate association with host cells and evades multiple host defense pathways, making it a unique model system in which to study pathogen countermeasures. C. burnetii infects alveolar macrophages and causes the emerging disease Q fever. It uses a type IV secretion system (T4SS) to inject over 100 bacterial effector proteins into the host cytoplasm, which modulate many host cellular processes to form a replicative niche for the bacteria inside the cell. We describe here the discovery of a bacterial effector that inhibits host signaling pathways and modulates the immune response. This effector interacts with the PAF1 Complex (PAF1C), a host factor that is highly involved in transcriptional processes and is a target of viral pathogens to counteract the antiviral response. We demonstrate that PAF1C promotes gene expression downstream of various innate immune receptors and describe for the first time a role for PAF1C in restricting a bacterial pathogen. Future studies will investigate whether the C. burnetii effector suppresses PAF1C function to inhibit the host immune response. Lastly, we investigate the interactions between C. burnetii and the inflammasome pathway. This host defense mechanism leads to the secretion of IL-1 cytokines and an inflammatory form of cell death, to simultaneously alert the body to the infection and eliminate the pathogen’s replicative niche. Our preliminary data show that C. burnetii suppresses various inflammasome responses and does not induce cell death in human macrophages. Collectively, our findings provide insight into how C. burnetii interacts with and evades the innate immune response, and further elucidate the host factors that contribute to defense against bacterial pathogens.
Lopes Fischer, Natasha, "Evasion Of Innate Immunity By The Pathogen Coxiella Burnetii" (2022). Publicly Accessible Penn Dissertations. 5479.