Cyclic Di-GMP receptor PlzA controls virulence gene expression through RpoS in Borrelia burgdorferi

As an obligate pathogen, the Lyme disease spirochete Borrelia burgdorferi has a streamlined genome that encodes only two two-component 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.