Lyme disease is an emerging tick-borne disease in the US, Europe, and Asia including China, and has become the most common vector-borne disease in both Europe and North America. Infection is caused by the spirochetal pathogen Borrelia burgdorferi sensu lato, transmitted via tick bites. The clinical manifestations of Lyme disease range from fever and skin lesions (erythema migrans) to multisystem disorders such as arthritis, carditis, and neuroborreliosis (Steere et al., 2004). Although treatable with antibiotics, the infection is underdiagnosed, and the late stages of Lyme disease are difficult to treat. No commercial vaccine is available. An alternative strategy is to block the transmission of B. burgdorferi. Understanding how B. burgdorferi is maintained in the enzootic cycle is the key for such strategy.

B. burgdorferi is maintained in an enzootic cycle containing two markedly different hosts, an arthropod vector and a mammalian host (Radolf et al., 2012; Samuels, 2011). B. burgdorferi must be able to adapt to both distinct host environments. On the other hand, as a non-free living pathogen, B. burgdorferi has a dramatically reduced genome. Remarkably, B. burgdorferi has evolved in utilizing its limited genomic capabilities to adapt to and survive in these two host environments. Therefore, B. burgdorferi provides a wonderful system to study mechanism of signal transduction and host adaptation. In this regard, bacterial twocomponent systems (TCSs) are the main signaling pathways that bacteria utilize to sense and respond to environmental conditions. A typical TCS consists of a histidine kinase as a sensor and a corresponding response regulator that mediates the cellular response (Stock et al., 2000). Most bacteria have many TCS systems. For example, Escherichia coli has over 30 TCSs. In contrast, the B. burgdorferi genome only has two TCSs,(in addition to the chemotactic CheA-CheY system), Hk1-Rrp1 and Hk2-Rrp2. Considering that B. burgdorferi encounters two hosts throughout its life cycle, could B. burgdorferi have evolved to employ these two TCSs to survive in each of the hosts?