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 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.

scholarly journals Borrelia burgdorferi Binding of Host Complement Regulator Factor H Is Not Required for Efficient Mammalian Infection

2007 ◽  
Vol 75 (6) ◽  
pp. 3131-3139 ◽  
Author(s):  
Michael E. Woodman ◽  
Anne E. Cooley ◽  
Jennifer C. Miller ◽  
John J. Lazarus ◽  
Kathryn Tucker ◽  
...  
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Alternative Pathway ◽  
Host Factor ◽  
Factor H ◽  
Surface Proteins ◽  
Wild Type ◽  
Factor B ◽  
Mammalian Infection ◽  
Deficient Mice

ABSTRACT The causative agent of Lyme disease, Borrelia burgdorferi, is naturally resistant to its host's alternative pathway of complement-mediated killing. Several different borrelial outer surface proteins have been identified as being able to bind host factor H, a regulator of the alternative pathway, leading to a hypothesis that such binding is important for borrelial resistance to complement. To test this hypothesis, the development of B. burgdorferi infection was compared between factor H-deficient and wild-type mice. Factor B- and C3-deficient mice were also studied to determine the relative roles of the alternative and classical/lectin pathways in B. burgdorferi survival during mammalian infection. While it was predicted that B. burgdorferi should be impaired in its ability to infect factor H-deficient animals, quantitative analyses of bacterial loads indicated that those mice were infected at levels similar to those of wild-type and factor B- and C3-deficient mice. Ticks fed on infected factor H-deficient or wild-type mice all acquired similar numbers of bacteria. Indirect immunofluorescence analysis of B. burgdorferi acquired by feeding ticks from the blood of infected mice indicated that none of the bacteria had detectable levels of factor H on their outer surfaces, even though such bacteria express high levels of surface proteins capable of binding factor H. These findings demonstrate that the acquisition of host factor H is not essential for mammalian infection by B. burgdorferi and indicate that additional mechanisms are employed by the Lyme disease spirochete to evade complement-mediated killing.

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.

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 Differential Binding of Host Complement Inhibitor Factor H by Borrelia burgdorferi Erp Surface Proteins: a Possible Mechanism Underlying the Expansive Host Range of Lyme Disease Spirochetes

2002 ◽  
Vol 70 (2) ◽  
pp. 491-497 ◽  
Author(s):  
Brian Stevenson ◽  
Nazira El-Hage ◽  
Melissa A. Hines ◽  
Jennifer C. Miller ◽  
Kelly Babb
Keyword(s):  
Lyme Disease ◽  
Borrelia Burgdorferi ◽  
Host Range ◽  
General Characteristic ◽  
Factor H ◽  
Surface Proteins ◽  
Broad Host Range ◽  
Complement Inhibitor ◽  
Wide Range ◽  
Mammalian Infection

ABSTRACT The Lyme disease spirochete, Borrelia burgdorferi, is capable of infecting a wide variety of vertebrates. This broad host range implies that B. burgdorferi possesses the ability to contravene the immune defenses of many potential hosts. B. burgdorferi produces multiple different Erp proteins on its outer membrane during mammalian infection. It was reported previously that one Erp protein can bind human factor H (J. Hellwage, T. Meri, T. Heikkilä, A. Alitalo, J. Panelius, P. Lahdenne, I. J. T. Seppälä, and S. Meri, J. Biol. Chem. 276:8427–8435, 2001). In this paper we report that the ability to bind the complement inhibitor factor H is a general characteristic of Erp proteins. Furthermore, each Erp protein exhibits different relative affinities for the complement inhibitors of various potential animal hosts. The data suggest that the presence of multiple Erp proteins on the surface can allow a single B. burgdorferi bacterium to resist complement-mediated killing in any of the wide range of potential hosts that it might infect. Thus, Erp proteins likely contribute to the persistence of B. burgdorferi in nature and to the ability of this bacterium to cause Lyme disease in humans and other animals.

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 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 Cyclic AMP-dependent Protein Lysine Acylation in Mycobacteria Regulates Fatty Acid and Propionate Metabolism

2013 ◽  
Vol 288 (20) ◽  
pp. 14114-14124 ◽  
Author(s):  
Subhalaxmi Nambi ◽  
Kallol Gupta ◽  
Moitrayee Bhattacharyya ◽  
Parvathy Ramakrishnan ◽  
Vaishnavi Ravikumar ◽  
...  
Keyword(s):  
Critical Role ◽  
Fatty Acyl ◽  
Intracellular Camp ◽  
Dependent Manner ◽  
Multiple Substrates ◽  
Propionate Metabolism ◽  
Lysine Residues ◽  
Dependent Protein ◽  
First Time ◽  
Camp Levels

Acetylation of lysine residues is a posttranslational modification that is used by both eukaryotes and prokaryotes to regulate a variety of biological processes. Here we identify multiple substrates for the cAMP-dependent protein lysine acetyltransferase from Mycobacterium tuberculosis (KATmt). We demonstrate that a catalytically important lysine residue in a number of FadD (fatty acyl CoA synthetase) enzymes is acetylated by KATmt in a cAMP-dependent manner and that acetylation inhibits the activity of FadD enzymes. A sirtuin-like enzyme can deacetylate multiple FadDs, thus completing the regulatory cycle. Using a strain deleted for the KATmt ortholog in Mycobacterium bovis Bacillus Calmette-Guérin (BCG), we show for the first time that acetylation is dependent on intracellular cAMP levels. KATmt can utilize propionyl CoA as a substrate and, therefore, plays a critical role in alleviating propionyl CoA toxicity in mycobacteria by inactivating acyl CoA synthetase (ACS). The precision by which mycobacteria can regulate the metabolism of fatty acids in a cAMP-dependent manner appears to be unparalleled in other biological organisms and is ideally suited to adapt to the complex environment that pathogenic mycobacteria experience in the host.

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