Coxiella burnetii is an obligate intracellular bacteria and the etiologic agent of Q fever. Although discovered over six decades ago, our understanding of the molecular mechanisms involved in disease development remains elementary. Few host cell processes actively modulated by C. burnetii have been identified. This study analyses host-cell pathways and processes that are specifically affected by C. burnetii proteins. It also defines C. burnetii induced temporal modulation of NF-kB activation throughout the infectious cycle. Additionally, it determines C. burnetii's growth cycle in an established tick cell line. First, the global expression of host cell mRNA was characterized following infection with C. burnetii Nine Mile Phase II and transient inhibition of bacterial protein synthesis with chloramphenicol. Using comparative microarray analysis, 36 host cell genes were identified to be distinctively modulated by C. burnetii proteins. Subsequent gene ontology analysis revealed expression changes in host cell functions such as innate immune response, cell death and proliferation, vesicle trafficking and development, lipid homeostasis, and cytoskeletal organization. A subset of pro-inflammatory cytokine genes was also identified whose expression is classically mediated through the NF-kB signaling pathway. This led to the demonstration that C. burnetii infection temporally modulates the activation of the NF-kB signaling pathway. Additionally, I have shown that C. burnetii readily infects Ixodes scapularis-derived cultured IDE8 cells, followed by a prolonged lag phase, then a doubling time similar to that in eukaryotic cells. Together these studies show that C. burnetii replicates and produces infectious progeny in arthropod cells, and temporally modulates mammalian host cell NF-kB signaling pathway as well as host cell gene expression in a bacterial protein synthesis specific manner.Department of Biochemistry and Molecular Biolog
