The cyclic-di-GMP signaling pathway in the Lyme disease spirochete, Borrelia burgdorferi

Abstract

In nature, the Lyme disease spirochete Borrelia burgdorferi cycles between the unrelated environments of the Ixodes tick vector and mammalian host. In order to survive transmission between hosts, B. burgdorferi must be able to not only detect changes in its environment, but also rapidly and appropriately respond to these changes. One manner in which this obligate parasite regulates and adapts to its changing environment is through cyclic-di-GMP (c-di-GMP) signaling. c-di-GMP has been shown to be instrumental in orchestrating the adaptation of B. burgdorferi to the tick environment. B. burgdorferi possesses only one set of c-di-GMP-metabolizing genes (one diguanylate cyclase and two distinct phosphodiesterases) and one c-di-GMP-binding PilZ-domain protein designated as PlzA. While studies in the realm of c-di-GMP signaling in B. burgdorferi have exploded in the last few years, there are still many more questions than answers. Elucidation of the importance of c-di-GMP signaling to B. burgdorferi may lead to the identification of mechanisms that are critical for the survival of B. burgdorferi in the tick phase of the enzootic cycle as well as potentially delineate a role (if any) c-di-GMP may play in the transmission and virulence of B. burgdorferi during the enzootic cycle, thereby enabling the development of effective drugs for the prevention and/or treatment of Lyme disease.

Keywords: Borrelia burgdorferi; Lyme disease; c-di-GMP; chemotaxis; motility; virulence.

Figure 1

A simplified working model of the c-di-GMP signaling pathway in B. burgdorferi. Hk1 and Rrp1 are present in the same operon and are thought to comprise a TCS. The diguanylate cyclase activity of Rrp1 is dependent upon its phosphorylation state, which presumably occurs in the cell by its cognate sensor kinase, Hk1. PlzA, a c-di-GMP-binding protein, is hypothesized to affect multiple virulence characteristics in B. burgdorferi. PlzA has been shown to positively regulate BosR protein levels, which regulates rpoS expression. RpoS, in turn, induces expression of genes, such as ospC, which are known to be important for mammalian infection as well as for genes involved in chitobiose utilization, which was shown to be important for colonization in the tick. rpoS expression is also governed by the Hk2-Rrp2 TCS; thus, PlzA serves as the connector between both TCS in B. burgdorferi. There is also a possibility that the PlzA-c-di-GMP complex interacts with another target(s), mediating glycerol utilization, colony morphology, and chemotaxis. The levels of c-di-GMP are controlled by the opposing activities of Rrp1 and PdeA and PdeB, the phosphodiesterases in B. burgdorferi. PdeA is an EAL-domain PDE, which hydrolyzes c-di-GMP to pGpG as its major product, which is then subsequently hydrolyzed to GMP by nonspecific PDEs. PdeB contains a HD-GYP domain, which hydrolyzes c-di-GMP into pGpG transiently en route to 2 GMPs as the predominant end product. It is unknown if pGpG plays a role in regulating motility or any cellular function in B. burgdorferi. Abbreviations: AcP, acetyl phosphate. Thicker arrow next to PdeA indicates pGpG is the major hydrolysis product; thicker arrow next to PdeB indicates the major product of PdeB hydrolysis is 2 GMPs.