The Lyme disease spirochete, Borrelia burgdorferi, as a model vector-borne pathogen: insights on regulation of gene and protein expression

Abstract

The Lyme disease spirochete persists in nature through cycles between ticks and vertebrates. Although the spirochete interacts with numerous, distinct tissues and environmental conditions during its infectious cycle, Borrelia burgdorferi appears to possess a limited ability to sense its external environment. This apparent paradox is being resolved through detailed investigations of the molecular mechanisms through which B. burgdorferi controls production of virulence-associated factors such as the Erp outer surface proteins. The results have led to development of a model for how B. burgdorferi controls expression of its diverse proteins, wherein physiological and metabolic states that are unique to specific points in the infectious cycle trigger changes in gene and protein expression levels.

Figure 1.

The midgut of unfed ticks is nutrient poor, and B. burgdorferi does not replicate to any great extent. When the tick feeds on vertebrate blood, B. burgdorferi uses those nutrients to increase metabolism and rapidly replicate. When in an unfed tick midgut, B. burgdorferi produces low to no Erp or OspC proteins. As the tick feeds, bacterial levels of Erp and OspC surface proteins increase significantly. Several studied regulatory factors are also differentially expressed in unfed and feeding ticks: EbfC and RpoS (which are required for elevated production of Erps and OspC, respectively) increase during tick feeding, while BpuR and BpaB (which repress production of Erps) decrease during feeding.

Figure 2.

Schematic of interactions between known regulatory proteins and target DNAs and RNAs. Maximum expression of ospC requires RpoS, but it is not certain whether that sigma factor directs transcription of the ospC promoter or if it controls production of one or more trans-acting regulatory factor. Experimental data indicate that at least one other factor is involved with control of erp transcription (“Factor X”), by competing against the repressive effect of Gac. The illustrated structures of EbfC, BpuR, and Gac are adapted from their solved structures [,–67], while those of BpaB and DnaA were modeled with AlphaFold (https://alphafold.ebi.ac.uk). DNAs are illustrated as double helices, while mRNAs are illustrated as single helices. Transcriptional promoter −10 and −35 sites are indicated by black bars above the DNAs. Known protein-binding sites are indicated by colored boxes on the DNAs and RNAs.