Borrelia burgdorferi, the etiological agent of Lyme disease, is the most prevalent vector-borne disease in the United States. The spirochetal population is naturally maintained by consistently cycling between Ixodid ticks and small vertebrates. To survive within these diverse niches, B. burgdorferi has evolved a unique physiology and regulatory network to sense and respond to environmental fluxes. Replication is a hallmark of the Lyme spirochete’s enzootic life cycle, specifically at the nymphal tick-to-vertebrate interface. The mechanisms and regulatory schema for the basic cellular processes in B. burgdorferi, or indeed any member of the phylum spirochaetota, are largely unknown. The central hypothesis of this dissertation is that DnaA coordinates the physiology and gene expression of B. burgdorferi during the period of rapid replication, as experienced during tick feeding. This body describes the first insights into how the master initiator protein DnaA functions and is regulated in B. burgdorferi. This includes the impact of DnaA on replication, division, elongation, gene expression, and protease-dependent degradation of DnaA
