Keynote Presentation: c-di-GMP Signaling in Borrelia Burgdorferi: A Guiding Compass for Navigating the Enzootic Cycle with Live Q&A

Borrelia burgdorferi, the causative agent of Lyme disease, cycles between an Ixodes spp. vector and a vertebrate reservoir host, typically small rodents. Humans become infected when they intrude upon this enzootic cycle, providing a blood meal for an infected tick. To sustain its dual-host lifestyle, B. burgdorferi employs elegant regulatory mechanisms to remodel its transcriptome in response to tick- and mammalian host-derived signals, a process collectively referred to as ‘host-adaptation’. The majority of differentially-expressed genes involved host-adaptation by Lyme disease spirochetes are controlled by two regulatory pathways. The first centers on the Hk1/Rrp1 two component system, which acts through c-di-GMP and is required for spirochete survival during the tick feeding. The second pathway, BosR/Rrp2/RpoN/RpoS, where RpoS is the effector sigma factor, is activated in ticks and upregulates genes required for tick transmission and mammalian infection. Notably, RpoS also functions, either directly or indirectly, to repress the expression of tick-phase borrelial genes following transmission, leading to its designation as the ‘gatekeeper’. Using a novel RNAseq enrichment technique, we compared the transcriptomes of wild-type and rpoS mutant strains in ticks and mammals. These analyses established that the contours of differentially expressed genes differ dramatically during the tick and mammalian host phases of the enzootic cycle and that RpoS-dependent gene regulation is modulated by the presence/absence of c-di-GMP. Unexpectedly, we also found that BosR, a FUR family regulator, and the c-di-GMP effector PlzA reciprocally regulate RpoS’s gatekeeper function in mammals and ticks, respectively.

Learning Objectives:

1. Demonstrate an understanding of the enzootic cycle that maintains Borrelia burgdorferi, the causative agent of Lyme disease, in nature.

2. Demonstrate a basic understanding of how Borrelia burgdorferi senses and responds to environmental signals encountered in ticks and mammals.

3. Summarize how the two major transcriptional regulatory pathways encoded by Borrelia burgdorferi coordinate the expression of genes required for tick-to-mammal transmission and persistence in mammals, including humans.