Borrelia recurrentis Employs a Novel Multifunctional Surface Protein with Anti-Complement, Anti-Opsonic and Invasive Potential to Escape Innate Immunity

Grosskinsky, Sonja; Schott, Melanie; Brenner, Christiane; Cutler, Sally J.; Kraiczy, Peter; Zipfel, Peter F.; Simon, Markus M.; Wallich, Reinhard

doi:10.1371/journal.pone.0004858

Cited by 63 publications

(79 citation statements)

References 50 publications

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“…Complement acts as an important part of the host innate immunity, which is essential for recognition and elimination of microbes. In fact, B. hermsii, the louse-borne relapsing fever spirochete Borrelia recurrentis, and many Lyme disease organisms of the B. burgdorferi sensu lato complex can evade human complement attack by acquiring host regulators at their surface (13,19,20,26,36,43). Here we have identified and characterized the surface protein BpcA of B. parkeri, which binds to the human complement regulators CFH and CFHR-1, composed of five SCR domains.…”

Section: Discussionmentioning

confidence: 99%

Molecular Characterization of the Interaction ofBorrelia parkeriandBorrelia turicataewith Human Complement Regulators

et al. 2010

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In North America, tick-borne relapsing fever is caused by the species Borrelia hermsii, B. parkeri, and B. turicatae, which are transmitted to humans through the bite of the respective infected tick vectors. Here we describe the identification and functional characterization of a surface lipoprotein of B. parkeri, designated BpcA, that binds the human complement regulators factor H and factor H-related protein 1 and, simultaneously, the host protease plasminogen. In contrast, the homologous B. turicatae protein failed to bind human factor H and factor H-related protein 1 but retained its plasminogen binding capacity. Factor H bound to BpcA maintains its regulatory capacity to control C3b deposition and C3 convertase activity. Ectopic expression of BpcA in a serum-sensitive B. burgdorferi strain protects transformed cells from complement-mediated killing. Furthermore, bound plasminogen/plasmin endows B. parkeri and B. turicatae with the potential to degrade extracellular matrix components. These findings expand our understanding of the putative recent evolutionary separation of Borrelia parkeri and Borrelia turicatae, provide evidence that B. parkeri differs from B. turicatae in its ability to resist complement attack, and may help in understanding the pathological processes underlying tick-borne relapsing fever.

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Section: Discussionmentioning

confidence: 99%

Molecular Characterization of the Interaction ofBorrelia parkeriandBorrelia turicataewith Human Complement Regulators

et al. 2010

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“…Several microbial Factor H-binding proteins also bind plasminogen (34)(35)(36)(37). We therefore asked whether P. aeruginosa Lpd also binds plasminogen.…”

Section: Lpd Binds Human Plasminogenmentioning

confidence: 99%

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

Hallström

Mörgelin

Barthel

et al. 2012

The Journal of Immunology

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The opportunistic human pathogen Pseudomonas aeruginosa causes a wide range of diseases. To cross host innate immune barriers, P. aeruginosa has developed efficient strategies to escape host complement attack. In this study, we identify the 57-kDa dihydrolipoamide dehydrogenase (Lpd) as a surface-exposed protein of P. aeruginosa that binds the four human plasma proteins, Factor H, Factor H-like protein-1 (FHL-1), complement Factor H-related protein 1 (CFHR1), and plasminogen. Factor H contacts Lpd via short consensus repeats 7 and 18–20. Factor H, FHL-1, and plasminogen when bound to Lpd were functionally active. Factor H and FHL-1 displayed complement-regulatory activity, and bound plasminogen, when converted to the active protease plasmin, cleaved the chromogenic substrate S-2251 and the natural substrate fibrinogen. The lpd of P. aeruginosa is a rather conserved gene; a total of 22 synonymous and 3 nonsynonymous mutations was identified in the lpd gene of the 5 laboratory strains and 13 clinical isolates. Lpd is surface exposed and contributes to survival of P. aeruginosa in human serum. Bacterial survival was reduced when Lpd was blocked on the surface prior to challenge with human serum. Similarly, bacterial survival was reduced up to 84% when the bacteria was challenged with complement active serum depleted of Factor H, FHL-1, and CFHR1, demonstrating a protective role of the attached human regulators from complement attack. In summary, Lpd is a novel surface-exposed virulence factor of P. aeruginosa that binds Factor H, FHL-1, CFHR1, and plasminogen, and the Lpd-attached regulators are relevant for innate immune escape and most likely contribute to tissue invasion.

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“…Some factor H-binding proteins of other pathogens also interact with plasminogen (8,19,24,34,37,39). LenA, a leptospiral outer membrane protein known to bind factor H, was therefore tested for its ability to bind plasminogen.…”

Section: Leptospira Interrogans Binds Human Plasminogenmentioning

confidence: 99%

“…The ability of intact leptospires to bind plasminogen decreased significantly in the presence of a lysine analog, indicating a role for lysines in plasminogen binding (47). Several plasminogen binding bacterial proteins interact through their lysine residues (8,19,49). LenA has several lysine residues, mostly spread on its amino-terminal two-thirds (42).…”

Section: Leptospira Interrogans Binds Human Plasminogenmentioning

confidence: 99%

“…Several pathogens of medical importance, including Streptococcus pyogenes (5,9,32,37), Staphylococcus aureus (25,26), Yersinia pestis (28), Neisseria meningitidis, Neisseria gonorrhoeae (44), Pseudomonas aeruginosa (24), Candida albicans (34), Borrelia burgdorferi (8,11,12,21,23), Borrelia hermsii (39), and Borrelia recurrentis (19), acquire plasminogen on their surfaces and utilize the proteolytic activity of plasmin to disseminate to various host tissues/organs. Some pathogens have an endogenous mechanism for activating surface-bound plasminogen, while others utilize host-derived plasminogen activators (5,9,32,37).…”

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Leptospiral Endostatin-Like Protein A Is a Bacterial Cell Surface Receptor for Human Plasminogen

et al. 2010

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The spirochete Leptospira interrogans is a highly invasive pathogen of worldwide public health importance. Studies from our laboratories and another have demonstrated that L. interrogans can acquire host plasminogen on its surface. Exogenous plasminogen activators can then convert bound plasminogen into the functionally active protease plasmin. In this study, we extend upon those observations and report that leptospiral endostatin-like protein A (LenA) binds human plasminogen in a dose-dependent manner. LenA-plasminogen interactions were significantly inhibited by the lysine analog -aminocaproic acid, suggesting that the lysine-binding sites on the amino-terminal kringle portion of the plasminogen molecule play a role in the binding. Previous studies have shown that LenA also binds complement regulator factor H and the extracellular matrix component laminin. Plasminogen competed with both factor H and laminin for binding to LenA, which suggests overlapping ligand-binding sites on the bacterial receptor. Finally, LenA-bound plasminogen could be converted to plasmin, which in turn degraded fibrinogen, suggesting that acquisition of host-derived plasmin by LenA may aid bacterial dissemination throughout host tissues.

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Borrelia recurrentis Employs a Novel Multifunctional Surface Protein with Anti-Complement, Anti-Opsonic and Invasive Potential to Escape Innate Immunity

Cited by 63 publications

References 50 publications

Molecular Characterization of the Interaction ofBorrelia parkeriandBorrelia turicataewith Human Complement Regulators

Molecular Characterization of the Interaction ofBorrelia parkeriandBorrelia turicataewith Human Complement Regulators

Dihydrolipoamide Dehydrogenase of Pseudomonas aeruginosa Is a Surface-Exposed Immune Evasion Protein That Binds Three Members of the Factor H Family and Plasminogen

Leptospiral Endostatin-Like Protein A Is a Bacterial Cell Surface Receptor for Human Plasminogen

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