Borrelia burgdorferi basic membrane proteins A and B participate in the genesis of Lyme arthritis

Abstract

Lyme arthritis results from colonization of joints by Borrelia burgdorferi and the ensuing host response. Using gene array–based differential analysis of B. burgdorferi gene expression and quantitative reverse trancription-polymerase chain reaction, we identified two paralogous spirochete genes, bmpA and bmpB, that are preferentially up-regulated in mouse joints compared with other organs. Transfer of affinity-purified antibodies against either BmpA or BmpB into B. burgdorferi–infected mice selectively reduced spirochete numbers and inflammation in the joints. B. burgdorferi lacking bmpA/B were therefore generated to further explore the role of these proteins in the pathogenesis of Lyme disease. B. burgdorferi lacking bmpA/B were infectious in mice, but unable to persist in the joints, and they failed to induce severe arthritis. Complementation of the mutant spirochetes with a wild-type copy of the bmpA and bmpB genes partially restored the original phenotype. These data delineate a role for differentially produced B. burgdorferi antigens in spirochete colonization of mouse joints, and suggest new strategies for the treatment of Lyme arthritis.

Borrelia burgdorferi BmpA Is a Laminin-Binding Protein

“…The relative importance of BmpC and BmpD has yet to be evaluated. Since those mutant bacteria retained their other bmp paralogs plus the gene for the other infection-associated laminin-binding protein, ErpX (13,49,52), those results raise the possibility that borrelial laminin-binding proteins are produced at different levels in different tissues and/or that colonization of some host tissues requires synergy between adhesins. Transcription of the bmp locus involves multiple promoters and terminators (28,55,56), suggestive of complex, potentially independent expression patterns for each gene.…”

“…This characterization may explain the results from a previous study, which found that a recombinant bacteriophage expressing a fragment of BmpD on its capsid tended to adhere to mouse tissues (2). BmpA and BmpB both play important roles during mammalian infection, as evidenced by the fact that mutants defective in either gene are unable to persistently infect mouse joints (49). The relative importance of BmpC and BmpD has yet to be evaluated.…”

Characterization of Unique Regions ofBorrelia burgdorferiSurface-Located Membrane Protein 1

“…Antiserum binding to unfixed or fixed B. burgdorferi spirochetes was examined by immunofluorescence assay as described previously (36). Silylated glass slides (PGC Scientific, Frederick, MD) were spotted with 1 ϫ 10 7 spirochetes: one group remained without fixation, while another group was fixed with methanol for 10 min at room temperature.…”

“…Silylated glass slides (PGC Scientific, Frederick, MD) were spotted with 1 ϫ 10 7 spirochetes: one group remained without fixation, while another group was fixed with methanol for 10 min at room temperature. For immunofluorescence labeling, the spirochetes were blocked with PBS-T and incubated with specific antiserum directed against the three Lmp1 regions (1:500 dilution in PBS-T), Lp6.6 (38), or OspA (35) followed by secondary antibodies and processed for microscopic examination as described previously (36).…”

“…Microbial antigens that are produced in a time-or tissue-specific manner might assist B. burgdorferi to overcome host defenses and to persist in local environments. Differentially expressed gene products, particularly surface antigens, could directly participate in host-pathogen interaction or host immune evasion, contributing to microbial survival and organ-specific pathogenesis (36,51). In recent years, a few spirochete gene products have been identified that are either indispensable or contribute significantly to host or vector infectivity and transmission through the tickmouse infection cycle (9,23,25,26,28,37,39,40,45,47,52,53).…”