Borrelia host adaptation Regulator (BadR) regulates rpoS to modulate host adaptation and virulence factors in Borrelia burgdorferi

Abstract

SummaryThe RpoS transcription factor of Borrelia burgdorferi is a 'gatekeeper' because it activates genes required for spirochaetes to transition from tick to vertebrate hosts. However, it remains unknown how RpoS becomes repressed to allow the spirochaetes to transition back from the vertebrate host to the tick vector. Here we show that a putative carbohydrate-responsive regulatory protein, designated BadR (Borrelia host adaptation Regulator), is a transcriptional repressor of rpoS. BadR levels are elevated in B. burgdorferi cultures grown under in vitro conditions mimicking unfed-ticks and badR-deficient strains are defective for growth under these same conditions. Microarray and immunoblot analyses of badR-deficient strains showed upregulation of rpoS and other factors important for virulence in vertebrate hosts, as well as downregulation of putative tick-specific determinants (e.g. linear plasmid 28-4 genes). DNA-binding assays revealed BadR binds to upstream regions of rpoS. Site-directed mutations in BadR and the presence of phosphorylated sugars affected BadR's binding to the rpoS promoters. badR-deficient B. burgdorferi were unable to colonize mice. Several putative tick-specific targets have been identified. Our study identified a novel regulator, BadR, and provides a link between nutritional environmental cues utilized by spirochaetes to adaptation to disparate conditions found in the tick and vertebrate hosts.

Contributions of Environmental Signals and Conserved Residues to the Functions of Carbon Storage Regulator A of Borrelia burgdorferi

“…Expression of several key lipoproteins of B. burgdorferi such as outer surface protein C (OspC) and decorin binding proteins A and B (DbpA/B) that contribute to vertebrate host infection were shown to be dependent on the Rrp2-RpoN-RpoS pathway (20)(21)(22)(23). Additional factors that contribute to rpoS-dependent expression of vertebrate host-specific determinants were identified, expanding the significance of this linear pathway in the pathophysiology of B. burgdorferi (4,15,16,24,25). Studies on activation of the Rrp2-RpoN-RpoS pathway focused on the role of a cognate histidine kinase (hk2) and a metabolite, acetyl phosphate, derived from phosphorylation of acetate by the enzyme acetate kinase (AckA; BB0622) (23).…”

“…B. burgdorferi undergoes rapid adaptation to vastly different environmental conditions present in the tick vector or the susceptible vertebrate hosts (1). A number of studies have elucidated not only the effects of one or more hostspecific signals but also the contributions of relatively few regulators in modulating gene expression in B. burgdorferi (2)(3)(4).…”

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

“…Although how BosR fits into Rrp2-and RpoN-dependent activation of rpoS remains unclear, in vitro data showed that BosR can directly bind to the promoter region of rpoS (13,17). In addition, a small RNA-binding protein (DsrA), a ROC-type repressor (BadR), and a plasmid-coded protein (BBI16) have all been shown to be involved in regulation of RpoS level in B. burgdorferi (18,19).…”

Apparent Role for Borrelia burgdorferi LuxS during Mammalian Infection

“…Along that line, B. burgdorferi cannot use ribose as a carbon source, yet the spirochete encodes a putative ABC transport system that resembles known ribose transporters (10,37). B. burgdorferi also encodes two proteins that resemble pentose-sensing DNA-binding proteins, one of which has been named BadR and demonstrated to be a transcriptional regulator (10,38). Alternatively, noting that two proteobacteria use radically different methods to respond to AI-2, it is possible that a distantly related spirochete may have evolved yet another mechanism.…”