Virulence regulation by BadR in the Lyme disease spirochete

ABSTRACT Borrelia burgdorferi (Bb), the etiological agent of Lyme disease, maintains itself in nature via a complex life cycle involving an arthropod (tick) vector and small mammals. During its cycle between ticks and mammals, Bb undergoes dramatic adaptive changes in order to interact with and adapt to these two disparate niches. Previously, we found that BadR, a homologue of ROK repressors, binds to the rpoS promoter region and represses the expression of rpoS. Moreover, our preliminary findings have suggested that BadR has much broader biological relevance to the life cycle of Bb other than repressing rpoS expression. First, BadR is required for Bb's optimal growth. Second, BadR plays a vital role in the establishment of mammalian infection. Contrary to the wild-type strain, a badR deletion mutant is incapable of infecting mice, suggesting that BadR governs expression of key effector proteins associated with Bb's survival in the host. Phenotypic defects of the badR mutant in mice infection are NOT related to the well documented RpoN-RpoS regulatory pathway, because all of BosR, Rrp2, RpoN, and RpoS are still produced in the badR mutant. In fact, our preliminary global transcriptomic analyses using RNA-seq have identified numerous BosR/RpoS-independent genes regulated by BadR. In addition, we found that badR is expressed throughout Bb's tick-mammal infectious cycle. These combined data give rise to our hypothesis that BadR is a master regulator governing Bb's host adaption and virulence expression. This hypothesis will be addressed in two Specific Aims. In Aim 1 of this proposal, we will employ global transcriptome/proteome profiling to define the entire BadR regulon under various in vitro and in vivo conditions. In Aim 2, we will select BadR-regulated genes based on our global transcriptome/proteome analyses and characterize their contributions to Bb's infectious cycle. These combined studies will (i) refine our knowledge on BadR-mediated gene regulation; (ii) provide a transformative understanding of the in vivo importance of the regulon; and (iii) identify novel virulence determinants. Resultant findings could lead to the development of new strategies to prevent and/or treat Lyme disease.