Research Article: Strain-Specific Variation of the Decorin-Binding Adhesin DbpA Influences the Tissue Tropism of the Lyme Disease Spirochete

Date Published: July 31, 2014

Publisher: Public Library of Science

Author(s): Yi-Pin Lin, Vivian Benoit, Xiuli Yang, Raúl Martínez-Herranz, Utpal Pal, John M. Leong, D. Scott Samuels.

http://doi.org/10.1371/journal.ppat.1004238

Abstract

Lyme disease spirochetes demonstrate strain- and species-specific differences in tissue tropism. For example, the three major Lyme disease spirochete species, Borrelia burgdorferi sensu stricto, B. garinii, and B. afzelii, are each most commonly associated with overlapping but distinct spectra of clinical manifestations. Borrelia burgdorferi sensu stricto, the most common Lyme spirochete in the U.S., is closely associated with arthritis. The attachment of microbial pathogens to cells or to the extracellular matrix of target tissues may promote colonization and disease, and the Lyme disease spirochete encodes several surface proteins, including the decorin- and dermatan sulfate-binding adhesin DbpA, which vary among strains and have been postulated to contribute to strain-specific differences in tissue tropism. DbpA variants differ in their ability to bind to its host ligands and to cultured mammalian cells. To directly test whether variation in dbpA influences tissue tropism, we analyzed murine infection by isogenic B. burgdorferi strains that encode different dbpA alleles. Compared to dbpA alleles of B. afzelii strain VS461 or B. burgdorferi strain N40-D10/E9, dbpA of B. garinii strain PBr conferred the greatest decorin- and dermatan sulfate-binding activity, promoted the greatest colonization at the inoculation site and heart, and caused the most severe carditis. The dbpA of strain N40-D10/E9 conferred the weakest decorin- and GAG-binding activity, but the most robust joint colonization and was the only dbpA allele capable of conferring significant joint disease. Thus, dbpA mediates colonization and disease by the Lyme disease spirochete in an allele-dependent manner and may contribute to the etiology of distinct clinical manifestations associated with different Lyme disease strains. This study provides important support for the long-postulated model that strain-specific variations of Borrelia surface proteins influence tissue tropism.

Partial Text

Lyme disease is distributed worldwide and is the most common arthropod-borne infectious disease in the United States [1]–[3]. The causative agent is the spirochete Borrelia burgdorferi sensu lato, which includes B. burgdorferi sensu stricto, B. garinii, and B. afzelii[4][5]. Following the bite of an infected Ixodes tick, the Lyme disease spirochete produces a local infection, resulting in the characteristic skin lesion erythema migrans. In the absence of antibiotic treatment, spirochetes may disseminate to multiple organs, including joints, the central nervous system, and the heart, resulting in diverse manifestations such as arthritis, neurological abnormalities, and carditis [2], [6]–[9].

Although it has long been known that different genospecies or strains of Borrelia burgdorferi sensu lato cause infections with different clinical manifestations in humans and distinct pathogenicity and/or tissues tropism in animal infection models, the reasons for these differences have remained obscure [9]–[12]. An attractive hypothesis put forth has been is that variation in spirochetal factors that control spread to or survival in different tissues contribute to the disparate behavior during mammalian infection [9], [12], [18], [21]. The ospC gene, which encodes a surface lipoprotein required for infection, is allelic variable, and a sampling of recombinant OspC variants from three invasive or noninvasive strains demonstrated a correlation between plasminogen binding and invasiveness in mice [18]. CRASP’s (complement regulator acquiring surface proteins) variants, which promote serum resistance, differ in their ability to bind to the complement regulatory proteins factor H and factor H like protein (FHL-1) [16], [17], [19]. Rigorous demonstration that allelic variation of genes encoding documented or putative virulence factors influences tissue tropism and/or disease manifestation requires experimental infection using isogenic strains, and has thus far been lacking. The dbpA gene, which encodes a Lyme disease spirochete adhesin required for full infectivity, is allelic variable, and DbpA variants differ in their ability to promote spirochetal attachment to decorin, dermatan sulfate, or mammalian cells [21], [39]. DbpAVS461ΔC11, a DbpA truncation that lacks 11 C-terminal amino acids was previously shown in semi-quantitative binding assays to be unable to bind dermatan sulfate or decorin [39]. We confirmed this finding by quantitative ELISA and SPR. The C-terminal 11 amino acids lacking in DbpAVS461ΔC11 are not generally well conserved among DbpA variants but do encompass the universally conserved residue K170, which has been shown to be required for decorin/dermatan sulfate-binding [30], [40], [45]. To test whether the adhesive activity of DbpA is specifically required for colonization, mice were infected with a B. burgdorferi dbpBA deletion mutant that ectopically produced wild type DbpAVS461 or DbpAVS461ΔC11. DbpAVS461ΔC11 was, in fact, also unable to facilitate colonization at the inoculation site, bladder, or ear, indicating that this binding activity of DbpA is likely required for tissue colonization.

 

Source:

http://doi.org/10.1371/journal.ppat.1004238

 

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