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Strain-specific variation of the decorin-binding adhesin DbpA influences the tissue tropism of the lyme disease spirochete.

Lin YP, Benoit V, Yang X, Martínez-Herranz R, Pal U, Leong JM - PLoS Pathog. (2014)

Bottom Line: Borrelia burgdorferi sensu stricto, the most common Lyme spirochete in the U.S., is closely associated with arthritis.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.This study provides important support for the long-postulated model that strain-specific variations of Borrelia surface proteins influence tissue tropism.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.

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.

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DbpA variants promote distinct B. burgdorferi inoculation site colonization during early infection.C3H/HeN mice infected with 104B. burgdorferi strain ML23/pBBE22 (“ML23/Vector”), dbpBA deletion strain ML23ΔdbpBA/pBBE22(“Vector”), or the deletion strain bearing a plasmid encoding the indicated variants were sacrificed at 3 days post-infection. Bacterial loads at the inoculation site were determined by qPCR. Data shown are the mean bacterial loads ± SEM of 10 mice per group. Statistical significance was determined using a one-way ANOVA test. Significant (P<0.05) differences in spirochete number relative to the dbpBA deletion strain (“*”), between two strains relative to each other (“#”), or relative to the dbpAVS461ΔC11-complemented strain (“†”) are indicated. (n.d.): not determined.
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ppat-1004238-g002: DbpA variants promote distinct B. burgdorferi inoculation site colonization during early infection.C3H/HeN mice infected with 104B. burgdorferi strain ML23/pBBE22 (“ML23/Vector”), dbpBA deletion strain ML23ΔdbpBA/pBBE22(“Vector”), or the deletion strain bearing a plasmid encoding the indicated variants were sacrificed at 3 days post-infection. Bacterial loads at the inoculation site were determined by qPCR. Data shown are the mean bacterial loads ± SEM of 10 mice per group. Statistical significance was determined using a one-way ANOVA test. Significant (P<0.05) differences in spirochete number relative to the dbpBA deletion strain (“*”), between two strains relative to each other (“#”), or relative to the dbpAVS461ΔC11-complemented strain (“†”) are indicated. (n.d.): not determined.

Mentions: The defect in decorin- and/or dermatan sulfate-binding by DbpAVS461ΔC11 provided an opportunity to determine if these activities of DbpA are essential to promote B. burgdorferi colonization. C3H/HeN mice were infected with ML23ΔdbpBA producing DbpAVS461 or DbpAVS461ΔC11 and the bacterial load at the inoculation site was assessed at 3 days post-infection. Strains ML23 and ML23ΔdbpBA/pDbpBA were included as positive controls and colonized the site efficiently (∼300 bacteria per 100 ng of DNA), 60-fold higher than that of ML23ΔdbpBA harboring vector alone (Fig. 2). ML23ΔdbpBA producing DbpAVS461 promoted significant colonization (∼30 bacteria per 100 ng DNA, or ∼six-fold more than ML23ΔdbpBA) at the inoculation site. This finding indicated that production of DbpA alone could partially complement the defect of a B. burgdorferi ΔdbpBA mutant, consistent with previous studies [32], [33]. In contrast, ML23ΔdbpBA producing DbpAVS461ΔC11 did not mediate colonization at a level any greater than ML23ΔdbpBA carrying the empty vector.


Strain-specific variation of the decorin-binding adhesin DbpA influences the tissue tropism of the lyme disease spirochete.

Lin YP, Benoit V, Yang X, Martínez-Herranz R, Pal U, Leong JM - PLoS Pathog. (2014)

DbpA variants promote distinct B. burgdorferi inoculation site colonization during early infection.C3H/HeN mice infected with 104B. burgdorferi strain ML23/pBBE22 (“ML23/Vector”), dbpBA deletion strain ML23ΔdbpBA/pBBE22(“Vector”), or the deletion strain bearing a plasmid encoding the indicated variants were sacrificed at 3 days post-infection. Bacterial loads at the inoculation site were determined by qPCR. Data shown are the mean bacterial loads ± SEM of 10 mice per group. Statistical significance was determined using a one-way ANOVA test. Significant (P<0.05) differences in spirochete number relative to the dbpBA deletion strain (“*”), between two strains relative to each other (“#”), or relative to the dbpAVS461ΔC11-complemented strain (“†”) are indicated. (n.d.): not determined.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4117581&req=5

ppat-1004238-g002: DbpA variants promote distinct B. burgdorferi inoculation site colonization during early infection.C3H/HeN mice infected with 104B. burgdorferi strain ML23/pBBE22 (“ML23/Vector”), dbpBA deletion strain ML23ΔdbpBA/pBBE22(“Vector”), or the deletion strain bearing a plasmid encoding the indicated variants were sacrificed at 3 days post-infection. Bacterial loads at the inoculation site were determined by qPCR. Data shown are the mean bacterial loads ± SEM of 10 mice per group. Statistical significance was determined using a one-way ANOVA test. Significant (P<0.05) differences in spirochete number relative to the dbpBA deletion strain (“*”), between two strains relative to each other (“#”), or relative to the dbpAVS461ΔC11-complemented strain (“†”) are indicated. (n.d.): not determined.
Mentions: The defect in decorin- and/or dermatan sulfate-binding by DbpAVS461ΔC11 provided an opportunity to determine if these activities of DbpA are essential to promote B. burgdorferi colonization. C3H/HeN mice were infected with ML23ΔdbpBA producing DbpAVS461 or DbpAVS461ΔC11 and the bacterial load at the inoculation site was assessed at 3 days post-infection. Strains ML23 and ML23ΔdbpBA/pDbpBA were included as positive controls and colonized the site efficiently (∼300 bacteria per 100 ng of DNA), 60-fold higher than that of ML23ΔdbpBA harboring vector alone (Fig. 2). ML23ΔdbpBA producing DbpAVS461 promoted significant colonization (∼30 bacteria per 100 ng DNA, or ∼six-fold more than ML23ΔdbpBA) at the inoculation site. This finding indicated that production of DbpA alone could partially complement the defect of a B. burgdorferi ΔdbpBA mutant, consistent with previous studies [32], [33]. In contrast, ML23ΔdbpBA producing DbpAVS461ΔC11 did not mediate colonization at a level any greater than ML23ΔdbpBA carrying the empty vector.

Bottom Line: Borrelia burgdorferi sensu stricto, the most common Lyme spirochete in the U.S., is closely associated with arthritis.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.This study provides important support for the long-postulated model that strain-specific variations of Borrelia surface proteins influence tissue tropism.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts, United States of America.

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.

Show MeSH
Related in: MedlinePlus