New Zealand White Rabbits Effectively Clear Borrelia burgdorferi B31 despite the Bacterium's Functional vlsE Antigenic Variation System

Borrelia burgdorferi is a tick-borne bacterium responsible for approximately 300,000 annual cases of Lyme disease (LD) in the United States, with increasing incidences in other parts of the world. The debilitating nature of LD is mainly attributed to the ability of B. burgdorferi to persist in patients for many years despite strong anti-Borrelia antibody responses. Antimicrobial treatment of persistent infection is challenging. Similar to infection of humans, B. burgdorferi establishes long-term infection in various experimental animal models except for New Zealand White (NZW) rabbits, which clear the spirochete within 4 to 12 weeks. LD spirochetes have a highly evolved antigenic variation vls system, on the lp28-1 plasmid, where gene conversion results in surface expression of the antigenically variable VlsE protein. VlsE is required for B. burgdorferi to establish persistent infection by continually evading otherwise potent antibodies. Since the clearance of B. burgdorferi is mediated by humoral immunity in NZW rabbits, the previously reported results that LD spirochetes lose lp28-1 during rabbit infection could potentially explain the failure of B. burgdorferi to persist. However, the present study unequivocally disproves that previous finding by demonstrating that LD spirochetes retain the vls system. However, despite the vls system being fully functional, the spirochete fails to evade anti-Borrelia antibodies of NZW rabbits. In addition to being protective against homologous and heterologous challenges, the rabbit antibodies significantly ameliorate LD-induced arthritis in persistently infected mice. Overall, the current data indicate that NZW rabbits develop a protective antibody repertoire, whose specificities, once defined, will identify potential candidates for a much-anticipated LD vaccine.