The role of VlsE antigenic variation in the Lyme disease spirochete: persistence through a mechanism that differs from other pathogens

Abstract

SummaryThe linear plasmid, lp28-1, is required for persistent infection by the Lyme disease spirochete, Borrelia burgdorferi. This plasmid contains the vls antigenic variation locus, which has long been thought to be important for immune evasion. However, the role of the vls locus as a virulence factor during mammalian infection has not been clearly defined. We report the successful removal of the vls locus through telomere resolvase-mediated targeted deletion, and demonstrate the absolute requirement of this lp28-1 component for persistence in the mouse host. Moreover, successful infection of C3H/HeN mice with an lp28-1 plasmid in which the left portion was deleted excludes participation of other lp28-1 non-vls genes in spirochete virulence, persistence and the process of recombinational switching at vlsE. Data are also presented that cast doubt on an immune evasion mechanism whereby VlsE directly masks other surface antigens similar to what has been observed for several other pathogens that undergo recombinational antigenic variation.

Biology of Infection with Borrelia burgdorferi

“…Some are involved in early infection, such as OspC [112][113][114][115][116], which are presumably required for host colonization or resistance to innate immunity. Others are involved in resistance to acquired immunity, such as VlsE [13,109,117,118].…”

“…VlsE is a B. burgdorferi protein that is required for persistent mammalian infection [13,109,117,118] and whose synthesis begins around the time that OspC production ceases (Fig. 1) [103].…”

“…Although its function is unknown, this lipoprotein has an elaborate system for variation [22]. Variation at the VlsE locus appears to be required for persistence [118,142], probably because its (unknown) essential function requires its presence on the bacterial surface, where it will be targeted by the adaptive immune response of the mammalian host.…”

Telomere as an Important Player in Regulation of Microbial Pathogen Virulence

“…Bacteria lost the lp28-1 exhibit an intermediate infectivity phenotype where it is hard to establish a persistent infection in the mouse model (Bankhead & Chaconas 2007). Deletion of vlsE and silent vls cassettes also led to reduced persistent infection, indicating that antigenic variation through vls switching is an important virulence mechanism in B. burgdorferi (Bankhead & Chaconas 2007;Labandeira-Rey & Skare 2001;Purser & Norris 2000;Zhang et al 1997). The vlsE and the silent vls genes are highly homologous at the sequence level, and most of the sequence differences within the cassette regions are concentrated in six variable regions, VR1-VR6 (Zhang & Norris 1998b).…”

Functional Equivalence of OspA and OspB, but Not OspC, in Tick Colonization by Borrelia burgdorferi

“…The VlsE protein is antigenically variable, with new coding sequences generated by gene conversion of vlsE, using adjacent silent cassette sequences located on the lp28-1 plasmid (10,14,15). Antigenic variation of the VlsE protein is required for persistent infection of immunocompetent hosts by B. burgdorferi (16,17).…”