IV002 A molecular mechanism of complement resistance of Borrelia burgdorferi: Binding of immune regulators factor H and FHL-1 to complement regulator-acquiring surface proteins

2003 ◽  
Vol 293 ◽  
pp. 130
Keyword(s):  
Borrelia Burgdorferi ◽  
Molecular Mechanism ◽  
Factor H ◽  
Surface Proteins ◽  
Complement Resistance ◽  
Complement Regulator

scholarly journals Borrelia burgdorferi Infection-Associated Surface Proteins ErpP, ErpA, and ErpC Bind Human Plasminogen

2008 ◽  
Vol 77 (1) ◽  
pp. 300-306 ◽  
Author(s):  
Catherine A. Brissette ◽  
Katrin Haupt ◽  
Diana Barthel ◽  
Anne E. Cooley ◽  
Amy Bowman ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Critical Role ◽  
Aminocaproic Acid ◽  
Factor H ◽  
Surface Proteins ◽  
Primary Role ◽  
Dependent Manner ◽  
Lysine Residues ◽  
Complement Regulator ◽  
Mammalian Infection

ABSTRACT Host-derived plasmin plays a critical role in mammalian infection by Borrelia burgdorferi. The Lyme disease spirochete expresses several plasminogen-binding proteins. Bound plasminogen is converted to the serine protease plasmin and thereby may facilitate the bacterium's dissemination throughout the host by degrading extracellular matrix. In this work, we demonstrate plasminogen binding by three highly similar borrelial outer surface proteins, ErpP, ErpA, and ErpC, all of which are expressed during mammalian infection. Extensive characterization of ErpP demonstrated that this protein bound in a dose-dependent manner to lysine binding site I of plasminogen. Removal of three lysine residues from the carboxy terminus of ErpP significantly reduced binding of plasminogen, and the presence of a lysine analog, ε-aminocaproic acid, inhibited the ErpP-plasminogen interaction, thus strongly pointing to a primary role for lysine residues in plasminogen binding. Ionic interactions are not required in ErpP binding of plasminogen, as addition of excess NaCl or the polyanion heparin did not have any significant effect on binding. Plasminogen bound to ErpP could be converted to the active enzyme, plasmin. The three plasminogen-binding Erp proteins can also bind the host complement regulator factor H. Plasminogen and factor H bound simultaneously and did not compete for binding to ErpP, indicating separate binding sites for both host ligands and the ability of the borrelial surface proteins to bind both host proteins.

scholarly journals Molecular Characterization of Borrelia burgdorferi erp Promoter/Operator Elements

2004 ◽  
Vol 186 (9) ◽  
pp. 2745-2756 ◽  
Author(s):  
Kelly Babb ◽  
Jason D. McAlister ◽  
Jennifer C. Miller ◽  
Brian Stevenson
Keyword(s):  
Borrelia Burgdorferi ◽  
Dna Sequences ◽  
Fluorescent Protein ◽  
Factor H ◽  
Surface Proteins ◽  
Virulence Determinants ◽  
Transcriptional Initiation ◽  
Bacterial Proteins ◽  
Complement Regulator ◽  
Green Fluorescent

ABSTRACT Many Borrelia burgdorferi Erp outer surface proteins have been demonstrated to bind the host complement regulator factor H, which likely contributes to the ability of these organisms to evade the host innate immune system. B. burgdorferi controls Erp protein synthesis throughout the bacterial infectious cycle, producing the proteins during mammalian infections but repressing their synthesis during tick infections. Defining the mechanism by which B. burgdorferi regulates the expression of these virulence determinants will provide important insight into the biological and pathogenic properties of the Lyme disease spirochete. The present study demonstrates that two highly conserved DNA sequences located 5′ of erp operons specifically bind bacterial proteins. Analyses with B. burgdorferi of transcriptional fusions between erp promoter/operator DNAs and the gene for green fluorescent protein indicated that the expression of these operons is regulated at the level of transcriptional initiation. These analyses also indicated significant differences in the promoter strengths of various erp operons, which likely accounts for reported variations in expression levels of different Erp proteins. Mutagenesis of promoter-gfp fusions demonstrated that at least one of the proteins which bind erp operator DNA functions as a repressor of transcription.

scholarly journals Contribution of the Infection-Associated Complement Regulator-Acquiring Surface Protein 4 (ErpC) to Complement Resistance ofBorrelia burgdorferi

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Claudia Hammerschmidt ◽  
Teresia Hallström ◽  
Christine Skerka ◽  
Reinhard Wallich ◽  
Brian Stevenson ◽  
...  
Keyword(s):  
Human Serum ◽  
Magnetic Beads ◽  
Surface Protein ◽  
Factor H ◽  
Surface Proteins ◽  
Complement Components ◽  
Complement Resistance ◽  
Complement Regulators ◽  
Complement Regulator ◽  
The Impact

Borrelia burgdorferievades complement-mediated killing by interacting with complement regulators through distinct complement regulator-acquiring surface proteins (CRASPs). Here, we extend our analyses to the contribution of CRASP-4 in mediating complement resistance ofB. burgdorferiand its interaction with human complement regulators. CRASP-4 (also known as ErpC) was immobilized onto magnetic beads and used to capture proteins from human serum. Following Western blotting, factor H (CFH), CFH-related protein 1 (CFHR1), CFHR2, and CFHR5 were identified as ligands of CRASP-4. To analyze the impact of native CRASP-4 on mediating survival of serum-sensitive cells in human serum, aB. gariniistrain was generated that ectopically expresses CRASP-4. CRASP-4-producing bacteria bound CFHR1, CFHR2, and CFHR5 but not CFH. In addition, transformed spirochetes deposited significant amounts of lethal complement components on their surface and were susceptible to human serum, thus indicating that CRASP-4 plays a subordinate role in complement resistance ofB. burgdorferi.

scholarly journals Coordinated Expression of Borrelia burgdorferi Complement Regulator-Acquiring Surface Proteins during the Lyme Disease Spirochete's Mammal-Tick Infection Cycle

2007 ◽  
Vol 75 (9) ◽  
pp. 4227-4236 ◽  
Author(s):  
Tomasz Bykowski ◽  
Michael E. Woodman ◽  
Anne E. Cooley ◽  
Catherine A. Brissette ◽  
Volker Brade ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Expression Patterns ◽  
Resistance Mechanism ◽  
Factor H ◽  
Surface Proteins ◽  
Mrna Levels ◽  
Tick Infection ◽  
Complement Regulator ◽  
Mammalian Infection

ABSTRACT The Lyme disease spirochete, Borrelia burgdorferi, is largely resistant to being killed by its hosts’ alternative complement activation pathway. One possible resistance mechanism of these bacteria is to coat their surfaces with host complement regulators, such as factor H. Five different B. burgdorferi outer surface proteins having affinities for factor H have been identified: complement regulator-acquiring surface protein 1 (BbCRASP-1), encoded by cspA; BbCRASP-2, encoded by cspZ; and three closely related proteins, BbCRASP-3, -4, and -5, encoded by erpP, erpC, and erpA, respectively. We now present analyses of the recently identified BbCRASP-2 and cspZ expression patterns throughout the B. burgdorferi infectious cycle, plus novel analyses of BbCRASP-1 and erp-encoded BbCRASPs. Our results, combined with data from earlier studies, indicate that BbCRASP-2 is produced primarily during established mammalian infection, while BbCRASP-1 is produced during tick-to-mammal and mammal-to-tick transmission stages but not during established mammalian infection, and Erp-BbCRASPs are produced from the time of transmission from infected ticks into mammals until they are later acquired by other feeding ticks. Transcription of cspZ and synthesis of BbCRASP-2 were severely repressed during cultivation in laboratory medium relative to mRNA levels observed during mammalian infection, and cspZ expression was influenced by culture temperature and pH, observations which will assist identification of the mechanisms employed by B. burgdorferi to control expression of this borrelial infection-associated protein.

Binding of the human Factor H-related protein (FHR-1) to Borrelia burgdorferi is mediated by complement regulator-acquiring surface proteins

2007 ◽  
Vol 44 (1-3) ◽  
pp. 182
Author(s):  
Katrin Haupt ◽  
Reinhard Wallich ◽  
Peter Kraiczy ◽  
Volker Brade ◽  
Christine Skerka ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Human Factor ◽  
Factor H ◽  
Surface Proteins ◽  
Related Protein ◽  
Complement Regulator

scholarly journals Further Characterization of Complement Regulator-Acquiring Surface Proteins of Borrelia burgdorferi

2001 ◽  
Vol 69 (12) ◽  
pp. 7800-7809 ◽  
Author(s):  
Peter Kraiczy ◽  
Christine Skerka ◽  
Volker Brade ◽  
Peter F. Zipfel
Keyword(s):  
Borrelia Burgdorferi ◽  
Detailed Comparison ◽  
Factor H ◽  
Surface Proteins ◽  
Human Complement ◽  
Causative Agents ◽  
Complement Regulator ◽  
Low Passage ◽  
The Individual

ABSTRACT The three genospecies Borrelia burgdorferi,Borrelia garinii, and Borrelia afzelii, all causative agents of Lyme disease, differ in their susceptibilities to human complement-mediated lysis. We recently reported that serum resistance of borrelias correlates largely with their ability to bind the human complement regulators FHL-1/reconectin and factor H. To date, two complement regulator-acquiring-proteins (CRASP-1 and CRASP-2) have been identified in serum-resistant B.afzelii isolates (P. Kraiczy, C. Skerka, M. Kirschfink, V. Brade, and P. F. Zipfel, Eur. J. Immunol. 31:1674–1684, 2001). Here, we present a comprehensive study of the CRASPs detectable in both serum-resistant and intermediate serum-sensitive B. afzelii and B. burgdorferi isolates. These CRASPs were designated according to the genospecies either as BaCRASPs, when derived fromB. afzelii, or as BbCRASPs, for proteins identified in B. burgdorferi isolates. Each borrelial isolate expresses distinct CRASPs that can be differentiated by their mobility and binding phenotypes. A detailed comparison reveals overlapping and even identical binding profiles for BaCRASP-1 (27.5 kDa), BbCRASP-1 (25.9 kDa), and BbCRASP-2 (23.2 kDa), which bind FHL-1/reconectin strongly and interact weakly with factor H. In contrast, two B. afzelii proteins (BaCRASP-4 [19.2 kDa] and BaCRASP-5 [22.5 kDa]) and three B. burgdorferi proteins (BbCRASP-3 [19.8 kDa], BbCRASP-4 [18.5 kDa], and BbCRASP-5 [17.7 kDa]) bind factor H but not FHL-1/reconectin. Most CRASPs bind both human immune regulators at their C-terminal ends. Temperature-dependent up-regulation of CRASPs (BaCRASP-1, BaCRASP-2, and BaCRASP-5) is detected in low-passage borrelias cultured at 33 or 37°C compared with those cultured at 20°C. The characterization of the individual CRASPs on the molecular level is expected to identify new virulence factors and potential vaccine candidates.

scholarly journals Borrelia burgdorferi Complement Regulator-Acquiring Surface Protein 2 Does Not Contribute to Complement Resistance or Host Infectivity

PLoS ONE ◽  
2008 ◽  
Vol 3 (8) ◽  
pp. 3010e ◽  
Author(s):  
Adam S. Coleman ◽  
Xiuli Yang ◽  
Manish Kumar ◽  
Xinyue Zhang ◽  
Kamoltip Promnares ◽  
...  
Keyword(s):  
Borrelia Burgdorferi ◽  
Surface Protein ◽  
Complement Resistance ◽  
Complement Regulator

scholarly journals Borrelia burgdorferi Complement Regulator-Acquiring Surface Protein 1 of the Lyme Disease Spirochetes Is Expressed in Humans and Induces Antibody Responses Restricted to Nondenatured Structural Determinants

2006 ◽  
Vol 74 (12) ◽  
pp. 7024-7028 ◽  
Author(s):  
Evelyn Rossmann ◽  
Veronique Kitiratschky ◽  
Heidelore Hofmann ◽  
Peter Kraiczy ◽  
Markus M. Simon ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Surface Protein ◽  
Factor H ◽  
Antibody Responses ◽  
Dominant Factor ◽  
Serum Samples ◽  
Structural Determinants ◽  
Pathogen Persistence ◽  
Complement Regulator

ABSTRACT Borrelia burgdorferi complement regulator-acquiring surface protein 1 (CRASP-1), the dominant factor H and FHL-1-binding protein of the Lyme disease spirochete B. burgdorferi, is implicated in pathogen persistence and was recently reported to be nonimmunogenic in humans. Here we show that serum samples from Lyme disease patients contain antibodies with exclusive specificity for nondenatured structural determinants of CRASP-1.

scholarly journals Borrelia burgdorferi EbfC, a Novel, Chromosomally Encoded Protein, Binds Specific DNA Sequences Adjacent to erp Loci on the Spirochete's Resident cp32 Prophages

2006 ◽  
Vol 188 (12) ◽  
pp. 4331-4339 ◽  
Author(s):  
Kelly Babb ◽  
Tomasz Bykowski ◽  
Sean P. Riley ◽  
M. Clarke Miller ◽  
Edward DeMoll ◽  
...  
Keyword(s):  
Dna Binding ◽  
Borrelia Burgdorferi ◽  
Dna Sequences ◽  
Membrane Surface ◽  
Factor H ◽  
Host Protein ◽  
Site Specific ◽  
Isolation And Characterization ◽  
Wide Range ◽  
Complement Regulator

ABSTRACT All examined isolates of the Lyme disease spirochete, Borrelia burgdorferi, naturally maintain numerous variants of a prophage family as circular cp32 episomes. Each cp32 carries a locus encoding one or two different Erp outer membrane, surface-exposed lipoproteins. Many of the Erp proteins bind a host complement regulator, factor H, which is hypothesized to protect the spirochete from complement-mediated killing. We now describe the isolation and characterization of a novel, chromosomally encoded protein, EbfC, that binds specific DNA sequences located immediately 5′ of all erp loci. This is one of the first site-specific DNA-binding proteins to be identified in any spirochete. The location of the ebfC gene on the B. burgdorferi chromosome suggests that the cp32 prophages have evolved to use this bacterial host protein for their own benefit and that EbfC probably plays additional roles in the bacterium. A wide range of other bacteria encode homologs of EbfC, none of which have been well characterized, so demonstration that B. burgdorferi EbfC is a site-specific DNA-binding protein has broad implications across the eubacterial kingdom.

scholarly journals LuxS-Mediated Quorum Sensing in Borrelia burgdorferi, the Lyme Disease Spirochete

2002 ◽  
Vol 70 (8) ◽  
pp. 4099-4105 ◽  
Author(s):  
Brian Stevenson ◽  
Kelly Babb
Keyword(s):  
Lyme Disease ◽  
Quorum Sensing ◽  
Borrelia Burgdorferi ◽  
Cell Communication ◽  
Factor H ◽  
Autoinducer 2 ◽  
Specific Proteins ◽  
Complement Regulator ◽  
Regulate Protein ◽  
Infection Processes

ABSTRACT The establishment of Borrelia burgdorferi infection involves numerous interactions between the bacteria and a variety of vertebrate host and arthropod vector tissues. This complex process requires regulated synthesis of many bacterial proteins. We now demonstrate that these spirochetes utilize a LuxS/autoinducer-2 (AI-2)-based quorum-sensing mechanism to regulate protein expression, the first system of cell-cell communication to be described in a spirochete. The luxS gene of B. burgdorferi was identified and demonstrated to encode a functional enzyme by complementation of an Escherichia coli luxS mutant. Cultured B. burgdorferi responded to AI-2 by altering the expression levels of a large number of proteins, including the complement regulator factor H-binding Erp proteins. Through this mechanism, a population of Lyme disease spirochetes may synchronize production of specific proteins needed for infection processes.

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