Changing of the Guard: How the Lyme Disease Spirochete Subverts the Host Immune Response

Lyme disease, also known as Lyme borreliosis, is the most common tick-transmitted disease in the Northern Hemisphere. The disease is caused by the bacterial spirochete and other related species. One of the many fascinating features of this unique pathogen is an elaborate system for antigenic variation, whereby the sequence of the surface-bound lipoprotein VlsE is continually modified through segmental gene conversion events. This perpetual changing of the guard allows the pathogen to remain one step ahead of the acquired immune response, enabling persistent infection. Accordingly, the locus is the most evolutionarily diverse genetic element in Lyme disease-causing borreliae. Small stretches of information are transferred from a series of silent cassettes in the locus to generate an expressed mosaic gene version that contains genetic information from several different silent cassettes, resulting in ∼10 possible sequences. Yet, despite its extreme evolutionary flexibility, the locus has rigidly conserved structural features. These include a telomeric location of the gene, an inverse orientation of and the silent cassettes, the presence of nearly perfect inverted repeats of ∼100 bp near the 5' end of , and an exceedingly high concentration of G runs in and the silent cassettes. We discuss the possible roles of these evolutionarily conserved features, highlight recent findings from several studies that have used next-generation DNA sequencing to unravel the switching process, and review advances in the development of a mini- system for genetic manipulation of the locus.