vls Antigenic Variation Systems of Lyme Disease Borrelia: Eluding Host Immunity through both Random, Segmental Gene Conversion and Framework Heterogeneity.

Spirochetes that cause Lyme borreliosis (also called Lyme disease) possess the vls locus, encoding an elaborate antigenic variation system. This locus contains the expression site vlsE as well as a contiguous array of vls silent cassettes, which contain variations of the central cassette region of vlsE. The locus is present on one of the many linear plasmids in the organism, e.g. plasmid lp28-1 in the strain Borrelia burgdorferi B31. Changes in the sequence of vlsE occur continuously during mammalian infection and consist of random, segmental, unidirectional recombination events between the silent cassettes and the cassette region of vlsE. These gene conversion events do not occur during in vitro culture or the tick portion of the infection cycle of B. burgdorferi or the other related Borrelia species that cause Lyme disease. The mechanism of recombination is largely unknown, but requires the RuvAB Holliday junction branch migrase. Other features of the vls locus also appear to be required, including cis locations of vlsE and the silent cassettes and high G+C content and GC skew. The vls system is required for long-term survival of Lyme Borrelia in infected mammals and represents an important mechanism of immune evasion. In addition to sequence variation, immune selection also results in significant heterogeneity in the sequence of the surface lipoprotein VlsE. Despite antigenic variation, VlsE generates a robust antibody response, and both full-length VlsE and the C6 peptide (corresponding to invariant region 6) are widely used in immunodiagnostic tests for Lyme disease.