OspC Is Potent Plasminogen Receptor on Surface of Borrelia burgdorferi

Önder, Özlem; Humphrey, Parris T.; McOmber, Brian; Korobova, Farida; Francella, Nicholas; Greenbaum, Doron C.; Brisson, Dustin

doi:10.1074/jbc.m111.290775

Cited by 100 publications

(95 citation statements)

References 66 publications

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“…In addition, recombinant DbpA proteins containing mutations in K82, K163, or K170 demonstrated a complete loss of decorin and dermatan sulfate binding during in vitro binding experiments (52), and this binding defect correlated with significant attenuation observed in B. burgdorferi strains expressing dbpA K82A , dbpA K163A , and dbpA K170A during murine infection. Considering that a number of B. burgdorferi surface proteins have been shown to interact with multiple host ligands (e.g., DbpA [35,40,76], OspC [77,78], Bgp [18], and CRASP-1 [23,79]), it remains possible that K82, K163, or K170 mediates interaction of DbpA with additional unidentified host ligands. However, these data support early studies showing the importance of decorin binding during mammalian infection (80).…”

Section: Resultsmentioning

confidence: 99%

Identification of Lysine Residues in the Borrelia burgdorferi DbpA Adhesin Required for Murine Infection

et al. 2014

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dDecorin-binding protein A (DbpA) of Borrelia burgdorferi mediates bacterial adhesion to heparin and dermatan sulfate associated with decorin. Lysines K82, K163, and K170 of DbpA are known to be important for in vitro interaction with decorin, and the DbpA structure, initially solved by nuclear magnetic resonance (NMR) spectroscopy, suggests these lysine residues colocalize in a pocket near the C terminus of the protein. In the current study, we solved the structure of DbpA from B. burgdorferi strain 297 using X-ray crystallography and confirmed the existing NMR structural data. In vitro binding experiments confirmed that recombinant DbpA proteins with mutations in K82, K163, or K170 did not bind decorin, which was due to an inability to interact with dermatan sulfate. Most importantly, we determined that the in vitro binding defect observed upon mutation of K82, K163, or K170 in DbpA also led to a defect during infection. The infectivity of B. burgdorferi expressing individual dbpA lysine point mutants was assessed in mice challenged via needle inoculation. Murine infection studies showed that strains expressing dbpA with mutations in K82, K163, and K170 were significantly attenuated and could not be cultured from any tissue. Proper expression and cellular localization of the mutated DbpA proteins were examined, and NMR spectroscopy determined that the mutant DbpA proteins were structurally similar to wild-type DbpA. Taken together, these data showed that lysines K82, K163, and K170 potentiate the binding of DbpA to dermatan sulfate and that an interaction(s) mediated by these lysines is essential for B. burgdorferi murine infection.

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Section: Resultsmentioning

confidence: 99%

Identification of Lysine Residues in the Borrelia burgdorferi DbpA Adhesin Required for Murine Infection

et al. 2014

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“…Several pathogenic bacteria that cause invasive infections (Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae, and Borrelia burgdorferi) can capture host plasminogen (PLG) and allow it to become activated to form the potent serine protease plasmin (13)(14)(15)(16)(17)(18)(19). Surface-bound plasmin enables bacteria to remove opsonins IgG and C3b, to degrade fibrin clots, and to promote bacterial spreading by cleaving tissue components (20 -22).…”

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confidence: 99%

Molecular Interactions of Human Plasminogen with Fibronectin-binding Protein B (FnBPB), a Fibrinogen/Fibronectin-binding Protein from Staphylococcus aureus

Pietrocola

Nobile

Gianotti

et al. 2016

Journal of Biological Chemistry

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Staphylococcus aureus is a commensal bacterium that has the ability to cause superficial and deep-seated infections. Like several other invasive pathogens, S. aureus can capture plasminogen from the human host where it can be converted to plasmin by host plasminogen activators or by endogenously expressed staphylokinase. This study demonstrates that sortase-anchored cell wall-associated proteins are responsible for capturing the bulk of bound plasminogen. Two cell wall-associated proteins, the fibrinogen-and fibronectin-binding proteins A and B, were found to bind plasminogen, and one of them, FnBPB, was studied in detail. Plasminogen captured on the surface of S. aureusor Lactococcus lactis-expressing FnBPB could be activated to the potent serine protease plasmin by staphylokinase and tissue plasminogen activator. Plasminogen bound to recombinant FnBPB with a K D of 0.532 M as determined by surface plasmon resonance. Plasminogen binding did not to occur by the same mechanism through which FnBPB binds to fibrinogen. Indeed, FnBPB could bind both ligands simultaneously indicating that their binding sites do not overlap. The N3 subdomain of FnBPB contains the full plasminogen-binding site, and this includes, at least in part, two conserved patches of surface-located lysine residues that were recognized by kringle 4 of the host protein.

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“…Recent work on the decorin and GAG binding adhesins, decorin binding proteins A and B (Dbp), has revealed a role for these proteins in tissue-specific colonization of the host after subcutaneous inoculation with B. burgdorferi (14,17). B. burgdorferi outer surface proteins also have been identified that bind to other host ligands, including P66 and BBB07, which bind to integrins (18,19), and OspC, which was recently found to bind plasminogen (20) in vitro.…”

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A Short-Term Borrelia burgdorferi Infection Model Identifies Tissue Tropisms and Bloodstream Survival Conferred by Adhesion Proteins

Caine

Coburn

2015

Infect Immun

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Borrelia burgdorferi, the causative agent of Lyme disease in the United States, is able to persist in the joint, heart, skin, and central nervous system for the lifetime of its mammalian host. Borrelia species achieve dissemination to distal sites in part by entry into and travel within the bloodstream. Much work has been performed in vitro describing the roles of many B. burgdorferi outer surface proteins in adhesion to host cell surface proteins and extracellular matrix components, although the biological relevance of these interactions is only beginning to be explored in vivo. A need exists in the field for an in vivo model to define the biological roles of B. burgdorferi adhesins in tissue-specific vascular interactions. We have developed an in vivo model of vascular interaction of B. burgdorferi in which the bacteria are injected intravenously and allowed to circulate for 1 h. This model has shown that the fibronectin binding protein BB0347 has a tropism for joint tissue. We also have shown an importance of the integrin binding protein, P66, in binding to vasculature of the ear and heart. This model also revealed unexpected roles for Borrelia adhesins BBK32 and OspC in bacterial burdens in the bloodstream. The intravenous inoculation model of short-term infection provides new insights into critical B. burgdorferi interactions with the host required for initial survival and tissue colonization. Borrelia burgdorferi, the causative agent of Lyme disease in the United States, is a vector-borne disease transmitted via the bite of an Ixodes scapularis tick (1, 2). Human infection with this bacterium often results in debilitating chronic arthritis, carditis, and/or neurologic symptoms if left untreated (3, 4). Upon entry into the host, Lyme disease Borrelia spirochetes are able to disseminate into the tissues and persist in the joints, heart, skin, and central nervous system (1). It is likely that Borrelia spp. are able to achieve rapid dissemination within the host by entry into and travel within the bloodstream. Colonization of specific host tissues is thought to occur through interactions of the bacteria with host cells of the microvasculature. A large variety of vascular beds are available in the host, determined by the size and type of vessel, as well as the organ with which they are associated (5, 6). One possible mechanism of B. burgdorferi attachment to various vascular beds and bacterial extravasation at particular tissue sites is through preferential interactions of various adhesive outer surface proteins on the bacterial surface with different types of endothelial cell surface proteins, carbohydrates, and/or extracellular matrix components. It has been shown that adhesion of B. burgdorferi to the vasculature occurs in a series of interactions (7). We hypothesize that the action of vascular binding and tissue colonization is not a random event but rather is determined by adhesion of B. burgdorferi surface proteins to tissue bed-specific endothelial cell (EC) surface receptors, such as VCAM1 on liver ECs,...

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OspC Is Potent Plasminogen Receptor on Surface of Borrelia burgdorferi

Cited by 100 publications

References 66 publications

Identification of Lysine Residues in the Borrelia burgdorferi DbpA Adhesin Required for Murine Infection

Identification of Lysine Residues in the Borrelia burgdorferi DbpA Adhesin Required for Murine Infection

Molecular Interactions of Human Plasminogen with Fibronectin-binding Protein B (FnBPB), a Fibrinogen/Fibronectin-binding Protein from Staphylococcus aureus

A Short-Term Borrelia burgdorferi Infection Model Identifies Tissue Tropisms and Bloodstream Survival Conferred by Adhesion Proteins

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