Cyclic Di-GMP Receptor PlzA Controls Virulence Gene Expression through RpoS in Borrelia burgdorferi

Abstract

bAs an obligate pathogen, the Lyme disease spirochete Borrelia burgdorferi has a streamlined genome that encodes only two twocomponent signal transduction systems, Hk1-Rrp1 and Hk2-Rrp2 (in addition to CheA-CheY systems). The output of Hk1-Rrp1 is the production of the second messenger cyclic di-GMP (c-di-GMP), which is indispensable for B. burgdorferi to survive in the tick vector. The output of Hk2-Rrp2 is the transcriptional activation of the global regulator RpoS, which is essential for the pathogen to accomplish its tick-mouse transmission and to establish mammalian infection. Although evidence indicates that these two systems communicate with each other, how they are connected is not fully understood. In this study, we showed that the c-di-GMP-binding protein PlzA, a downstream effector of Rrp1, positively modulates the production of RpoS, a global regulator and downstream target of Rrp2. Thus, PlzA functions as a connector that links Hk1-Rrp1 with Hk2-Rrp2. We further showed that PlzA regulates rpoS expression through modulation of another regulator, BosR, at both the transcriptional and the posttranscriptional levels. In addition, PlzA was also capable of regulating rpoS expression independently of Rrp1, suggesting that besides being a c-di-GMP-binding protein, PlzA has other functions. Along with the previous finding of PlzA controlling motility, these studies demonstrate that PlzA is a multifunctional protein. These findings further reinforce the notion that B. burgdorferi utilizes its limited signaling systems and regulators to govern multiple cellular processes during its complex enzootic cycle between ticks and mammals.

DhhP, a Cyclic di-AMP Phosphodiesterase of Borrelia burgdorferi, Is Essential for Cell Growth and Virulence

“…However, the bosR mRNA level was only moderately reduced, with no statistical significance, in the dhhP mutant (Fig. 8D), suggesting that deletion of dhhP affects BosR mainly at the posttranscriptional level, a phenomenon that has been observed under several other conditions (39,57,66). Thus, DhhP appears to be required for BosR accumulation, which in turn controls production of RpoS and RpoS-dependent virulence factors, including OspC.…”

“…Amazingly, B. burgdorferi accomplishes these dramatic processes with its streamlined genome and limited regulatory repertoire (32). For example, in contrast to many bacteria that have numerous c-di-GMP signaling systems (33)(34)(35)(36), B. burgdorferi has only one c-di-GMP synthase (BB0419, diguanylate cyclase), and it plays an essential role in spirochetal survival in ticks as well as modulating B. burgdorferi motility and mammalian infection (37)(38)(39)(40)(41)(42)(43).…”

BosR Is A Novel Fur Family Member Responsive to Copper and Regulating Copper Homeostasis in Borrelia burgdorferi

“…One possibility is that Cu(II) binding of BosR results in conformational changes that render the protein more susceptible to turnover or degradation in vivo. Several studies have indicated that BosR expression is regulated at both transcriptional and posttranscriptional levels (46)(47)(48)(49).…”

Phosphoenolpyruvate Phosphotransferase System Components Modulate Gene Transcription and Virulence of Borrelia burgdorferi

“…Conversely, Hk2-Rrp2 activates the RpoNRpoS pathway, which is essential for this pathogen to successfully accomplish tick-mouse transmission and establish mammalian infection (11)(12)(13). Recent studies demonstrated that a c-di-GMPbinding protein, PlzA, connects these two signal transduction pathways (14). Environmental stimuli such as temperature, pH, oxygen, carbon dioxide, and undefined mammalian host cell signals have been shown to modulate gene expression in Borrelia (15)(16)(17)(18)(19).…”