Genomic analyses reveal putatively pathogenic genes and functional elements in borrelia burgdorferi, the lyme disease bacterium.

摘要

B. burgdorferi s.l. (B. burgdorferi sensu lato) represents a Gram-negative bacterial species complex that includes causative agents of Lyme disease. As an obligate parasite, B. burgdorferi`s persistence in nature depends on its innate ability to exist and survive in two distinct biological environments, the hard-bodied tick (vector) and small vertebrates (hosts), as it progresses through different stages of its enzootic cycle. To accomplish this feat, B. burgdorferi heavily depends on its ability to tightly regulate differentially expressed host- and vector-specific genes. However, very little is known about the genes and regulatory elements contributing to the pathogenicity of this increasingly prevalent pathogen. This is primarily due to the fact that B. burgdorferi is not a model organism and is difficult to culture and transform. Additionally, we were previously limited in our ability to do comparative genomic studies in this organism due to the unavailability of whole-genome sequences. The recent release of whole-genome sequences from 22 strains spanning 8 different genospecies of B. burgdorferi has since made it possible to conduct a comprehensive genome study in this organism. Here, we employ phylogenomics analyses (analysis of the genomes of a group of closely related species) on the core genome of B. burgdorferi in order to identify putative genes and functional elements that may contribute to the pathogenicity of this organism. We conducted three main analyses: i) test of positive natural selection within the coding regions of the core genome replicons, ii) test of evolutionary constraints within the non-coding regions of cp26 and lp54, and iii) structural and phylogenetic comparison of OspA and OspB (Outer Surface Protein A and B), two paralogous virulence-associated lipoproteins. Consequently, we identified three genes putatively involved in adaptive host immunity, fifteen genes putatively involved in adaptive divergence, two new genes putatively under direct transcription RpoS (an alternative regulatory subunit of RNA polymerase), a number of putative cis and trans-acting regulatory elements, and fourteen fixed differences between OspA and OspB concentrated in the region proximal to the C-terminus barrel domain and the N-terminus globular domain. These findings highlight a number of coding and non-coding sequences that may contribute to the virulence of Borrelia burgdorferi in humans. These findings provide a basis for future experimental studies towards the discovery of therapeutic, diagnostic, and preventive approaches to Lyme disease.