Regulatory Network of the Lyme Disease Pathogen

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ABSTRACT Lyme disease is an emerging tick-borne disease and an important public health problem in the United States. The causative agent, Borrelia burgdorferi (Bb), must dramatically alter its gene expression as it traverses its enzootic cycle between the arthropod vector (Ixodes ticks) and rodent mammalian hosts. In the past several years, the PI’s previous work discovered a central regulatory pathway, the RpoS pathway, in B. burgdorferi. The RpoS pathway is a gatekeeper for B. burgdorferi to exit from ticks and infect mammals. RpoS control many antigens and virulence factors for mammalian infection. The PI’s previous work, along with others, demonstrated that transcriptional activation of rpoS is under the control of the sigma factor 54 (σ54) and a bacterial enhancer-binding protein (EBP), Rrp2. It is well established in other bacteria that EBP is essential and sufficient to activate a σ54-type promoter both in vivo and in vitro. Surprisingly, another regulator, BosR, was discovered independently by two groups a decade ago and showed that BosR directly regulates rpoS transcription from its σ54-type promoter. How BosR fits into this pathway is a significant gap in our understanding of the RpoS pathway. Based on our Preliminary Studies, we propose a provocative hypothesis: BosR is not a transcriptional activator; instead, BosR is a novel RNA binding protein that binds to rpoS mRNA and stabilizes its turnover. We will test this hypothesis in Aim 1. Given that few factors have been identified for regulating the RpoS pathway, we have successfully developed a genetic screen for identifying genes that influence the regulation of RpoS. Such screen allows us to identify genome-wide novel factors that modulate the RpoS pathway, uncover a comprehensive picture of how the RpoS pathway is regulated and how multi-signals influence the pathway in the enzootic cycle of Bb between the tick vector and the mammalian host, which is proposed in Aim 2.