Borrelia burgdorferi Protein BBK32 Binds to Soluble Fibronectin via the N-terminal 70-kDa Region, Causing Fibronectin to Undergo Conformational Extension

Harris, Gemma; Ma, Wenjiang; Maurer, Lisa M.; Potts, Jennifer R.; Mosher, Deane F.

doi:10.1074/jbc.m114.578419

Cited by 22 publications

(43 citation statements)

References 44 publications

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“…It is possible that pFn polymerization exposed cryptic sites in pFn facilitating binding to endothelial surface receptors, and/or directly strengthened and stabilized adhesion complexes after bond formation. Additionally, BBK32-Fn binding not only induces conformational elongation and polymerization of pFn but also structurally stabilizes a large intrinsically disordered region of BBK32 by a high-affinity tandem β-zipper mechanism (25)(26)(27). Thus, by stabilizing BBK32 conformation, pFn may improve this adhesin's ability to withstand force.…”

Section: Discussionmentioning

confidence: 99%

“…Preservation of the inert, nonadhesive properties of this molecule is important in blood, where constitutive exposure of pFn ligand-binding sites would affect blood flow, thrombosis, and movement and adhesion of circulating cells (11,21). However, upon activation or force-induced stretching or conformational change induced by certain FnBPs, pFn undergoes a conformational change that exposes ligand-binding sites (11,12,26,27,35).…”

Section: B Burgdorferi-endothelial Interactions Under Vascular Shearmentioning

confidence: 99%

“…BBK32, which binds to Fn by a mechanism similar to the binding mechanisms of S. aureus FnBPA and streptococcal FnBPs (21,25), causes conformational changes in pFn that induce formation of an extended structure (26) and formation of superfibronectin, a highly cross-linked, exceptionally sticky, polymerized form of Fn (27,28). Several other pathogens and FnBPs adhere to Fn under force conditions similar to the force conditions found in the vasculature, suggesting that the use of Fn for vascular adhesion may be widespread among microbes (29)(30)(31)(32).…”

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confidence: 99%

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Plasma fibronectin stabilizes Borrelia burgdorferi –endothelial interactions under vascular shear stress by a catch-bond mechanism

Niddam

Ebady

Bansal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Bacterial dissemination via the cardiovascular system is the most common cause of infection mortality. A key step in dissemination is bacterial interaction with endothelia lining blood vessels, which is physically challenging because of the shear stress generated by blood flow. Association of host cells such as leukocytes and platelets with endothelia under vascular shear stress requires mechanically specialized interaction mechanisms, including force-strengthened catch bonds. However, the biomechanical mechanisms supporting vascular interactions of most bacterial pathogens are undefined. Fibronectin (Fn), a ubiquitous host molecule targeted by many pathogens, promotes vascular interactions of the Lyme disease spirochete Borrelia burgdorferi. Here, we investigated how B. burgdorferi exploits Fn to interact with endothelia under physiological shear stress, using recently developed live cell imaging and particle-tracking methods for studying bacterial-endothelial interaction biomechanics. We found that B. burgdorferi does not primarily target insoluble matrix Fn deposited on endothelial surfaces but, instead, recruits and induces polymerization of soluble plasma Fn (pFn), an abundant protein in blood plasma that is normally soluble and nonadhesive. Under physiological shear stress, caps of polymerized pFn at bacterial poles formed part of mechanically loaded adhesion complexes, and pFn strengthened and stabilized interactions by a catch-bond mechanism. These results show that B. burgdorferi can transform a ubiquitous but normally nonadhesive blood constituent to increase the efficiency, strength, and stability of bacterial interactions with vascular surfaces. Similar mechanisms may promote dissemination of other Fn-binding pathogens.catch bond | fibronectin | force | vascular | bacteria

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Section: Discussionmentioning

confidence: 99%

Section: B Burgdorferi-endothelial Interactions Under Vascular Shearmentioning

confidence: 99%

mentioning

confidence: 99%

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Plasma fibronectin stabilizes Borrelia burgdorferi –endothelial interactions under vascular shear stress by a catch-bond mechanism

Niddam

Ebady

Bansal

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Tissues contain diversity within their ECM, with various subunits and ratios of collagens, fibronectin, integrins, fibrinogen, and laminin (65). ECM-binding adhesins have been characterized in many pathogens, and some have been discovered in B. burgdorferi, including DbpA, BBK32, P66, Bgp, BBB07, and BBA33 (21)(22)(23)(24)(25)(26)(27)54). B. burgdorferi has an outer surface rich in lipoproteins, many of which are hypothesized to interact with host structures and provide for optimal adhesion and/or immune evasion.…”

Section: Discussionmentioning

confidence: 99%

“…The ability of B. burgdorferi to evade the immune response and colonize tissues lies within the numerous lipoproteins that adorn its outer surface (20). Many of these lipoproteins have been characterized as ECM (extracellular matrix) adhesins, including those that bind to decorin (DbpA), fibronectin (BBK32), glycosaminoglycans (Bgp; BBK32; DbpA), and integrins (BBB07, P66), as well as many others with unknown host ligands (21)(22)(23)(24)(25)(26)(27). B. burgdorferi also expresses on its surface a variable surface antigen, VlsE, and five different factor H binding proteins designated complement regulator-acquiring surface proteins, which are involved in the evasion of complement-dependent killing (28,29).…”

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confidence: 99%

BB0744 Affects Tissue Tropism and Spatial Distribution of Borrelia burgdorferi

et al. 2015

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bBorrelia burgdorferi, the etiologic agent of Lyme disease, produces a variety of proteins that promote survival and colonization in both the Ixodes species vector and various mammalian hosts. We initially identified BB0744 (also known as p83/100) by screening for B. burgdorferi strain B31 proteins that bind to ␣ 1 ␤ 1 integrin and hypothesized that, given the presence of a signal peptide, BB0744 may be a surface-exposed protein. In contrast to this expectation, localization studies suggested that BB0744 resides in the periplasm. Despite its subsurface location, we were interested in testing whether BB0744 is required for borrelial pathogenesis. To this end, a bb0744 deletion was isolated in a B. burgdorferi strain B31 infectious background, complemented, and queried for the role of BB0744 following experimental infection. A combination of bioluminescent imaging, cultivation of infected tissues, and quantitative PCR (qPCR) demonstrated that ⌬bb0744 mutant B. burgdorferi bacteria were attenuated in the ability to colonize heart tissue, as well as skin locations distal to the site of infection. Furthermore, qPCR indicated a significantly reduced spirochetal load in distal skin and joint tissue infected with ⌬bb0744 mutant B. burgdorferi. Complementation with bb0744 restored infectivity, indicating that the defect seen in ⌬bb0744 mutant B. burgdorferi was due to the loss of BB0744. Taken together, these results suggest that BB0744 is necessary for tissue tropism, particularly in heart tissue, alters the ability of B. burgdorferi to disseminate efficiently, or both. Additional studies are warranted to address the mechanism employed by BB0744 that alters the pathogenic potential of B. burgdorferi.

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Interaction with the host: the role of fibronectin and extracellular matrix proteins in the adhesion of Gram-negative bacteria

Vaca

Thibau

Schütz

et al. 2019

Med Microbiol Immunol

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The capacity of pathogenic microorganisms to adhere to host cells and avoid clearance by the host immune system is the initial and most decisive step leading to infections. Bacteria have developed different strategies to attach to diverse host surface structures. One important strategy is the adhesion to extracellular matrix (ECM) proteins (e.g., collagen, fibronectin, laminin) that are highly abundant in connective tissue and basement membranes. Gram-negative bacteria express variable outer membrane proteins (adhesins) to attach to the host and to initiate the process of infection. Understanding the underlying molecular mechanisms of bacterial adhesion is a prerequisite for targeting this interaction by "anti-ligands" to prevent colonization or infection of the host. Future development of such "anti-ligands" (specifically interfering with bacteria-host matrix interactions) might result in the development of a new class of anti-infective drugs for the therapy of infections caused by multidrug-resistant Gram-negative bacteria. This review summarizes our current knowledge about the manifold interactions of adhesins expressed by Gram-negative bacteria with ECM proteins and the use of this information for the generation of novel therapeutic antivirulence strategies.

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Borrelia burgdorferi Protein BBK32 Binds to Soluble Fibronectin via the N-terminal 70-kDa Region, Causing Fibronectin to Undergo Conformational Extension

Cited by 22 publications

References 44 publications

Plasma fibronectin stabilizes Borrelia burgdorferi –endothelial interactions under vascular shear stress by a catch-bond mechanism

Plasma fibronectin stabilizes Borrelia burgdorferi –endothelial interactions under vascular shear stress by a catch-bond mechanism

BB0744 Affects Tissue Tropism and Spatial Distribution of Borrelia burgdorferi

Interaction with the host: the role of fibronectin and extracellular matrix proteins in the adhesion of Gram-negative bacteria

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