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* Department of Bacteriology and Immunology, Haartman Institute and Helsinki University Central Hospital, and
Peptide and Protein Laboratory, Haartman Institute, University of Helsinki, Helsinki, Finland; and
Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Like all invasive pathogens B. burgdorferi must have means to evade the complement system (4), an important component of both the innate and adaptive immune systems. Strikingly, Borrelia survives in its mammalian hosts despite vigorous Ab responses. Strains of B. burgdorferi belonging to either the B. burgdorferi sensu stricto or the B. afzelii genospecies are resistant to human serum, whereas strains of the B. garinii subtype are serum sensitive (5). The serum-resistant strains are able to promote factor I-mediated cleavage of the key complement component C3b by binding the regulators factor H and factor H-like protein 1 from serum onto the spirochetal surface (6). Among the pathogenic streptococci, binding of factor H to the bacteria has been shown to be mediated via the surface-expressed M proteins in Streptococcus pyogenes (7) and by the PspC family member Hic protein in type 3 pneumococci (8, 9). Recent studies suggest that B. burgdorferi could also use specific surface molecules to evade complement attack (6, 10).
The genome of Borrelia exhibits several interesting features. Compared with other pathogenic microorganisms, e.g., to pneumococcus with 2236 predicted coding regions (11), B. burgdorferi has only 851 genes encoded on its linear chromosome, while many other genes reside in numerous linear and circular extrachromosomal plasmid elements (12, 13, 14). The various plasmids appear to be essential for B. burgdorferi virulence expression and Lyme disease pathogenesis. Spontaneous plasmid loss during in vitro cultivation of B. burgdorferi can result in attenuated and/or avirulent isolates (15). The plasmids encode many proteins, which are differentially expressed by B. burgdorferi as it is transmitted between its arthropod vector and mammalian hosts. The differentially expressed proteins include several homologs of outer surface protein E (OspE),3 OspF, and Elp lipoprotein families (16, 17). As the functions of these plasmid-encoded, surface-expressed lipoproteins have been unknown, we studied whether they bind complement factor H and thus act as immune evasion molecules of B. burgdorferi. Binding of factor H would be critical for the survival of Borrelia spirochetes when they infect mammalian hosts and spread into their tissues. We show that factor H binds to a spectrum of the OspE family of proteins whose expression is induced as the spirochetes are transmitted from ticks to mammals.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Outer surface lipoproteins from B. burgdorferi sensu stricto 297 and B31 strains were expressed in Escherichia coli as GST or polyhistidine-tagged fusion proteins and purified. GST fusion constructs for OspE, p21, OspF, BbK2.10, BbK2.11, ElpA1, ElpA2, ElpB1, ElpB2, OspA, and OspC were generated and purified to homogeneity as previously described (16, 17, 18). The GST moiety was removed from all fusion proteins with thrombin before use in the binding assays. Polyhistidine-tagged ErpA, ErpP, ErpL, and ErpX proteins were generated by cloning PCR-amplified products representing the mature portion of each protein into the pBAD-TOPO vector (Invitrogen, Carlsbad, CA) using the respective primers: erpA, 5'-TGCAAAGCAATGGAGAGGTAAAGGTC; erpA, 3'-TTTTAAATTTCTTTTAAGCTCTTC; erpP, 5'-TGCAAAATTCATACTTCATATGATGAG; erpP, 3'-TTTTAAATTTTTTTTAAGCACTTCTAGTGG; erpL, 5'-TGCAAGAATTATGCAAGTGGTG; erpL, 3'-TTCTTTTTTATCTTCTTCTATTCCC; erpX, 5'-TGCAAGATTGATGCAACTGGTAAAGATGC; and erpX, 3'-CTGACTGTAACTGATGTATCCTTTAATTTC. All resulting constructs were sequenced to confirm that the inserted DNA was in-frame and that no errors were incorporated during PCR amplification. Fusion constructs were grown in tryptone-yeast broth supplemented with 100 µg ampicillin to an OD600 of 0.7 before arabinose was added to a final concentration of 0.2% to induce expression of the fusion proteins. Polyhistidine-tagged proteins were affinity-purified using nickel chromatography as instructed by the manufacturers (Amersham Pharmacia Biotech, Piscataway, NJ; and Invitrogen, Carlsbad, CA).
Surface plasmon resonance
Surface plasmon resonance binding experiments were conducted
using the Biacore 2000 biosensor instrument (Biacore, Uppsala, Sweden).
The proteins were amine-coupled to carbonyl groups of CM5 sensor chips
according to the manufacturer’s instructions. The buffer was chosen
according to the pI of the analyte: maleate and sodium acetate buffers
were used for proteins whose calculated pI values were over or below 6,
respectively. The coupling levels of proteins varied between 500-3000
resonance units. The binding of complement factor H (Calbiochem, San
Diego, CA; purity >95% by SDS-PAGE) to immobilized proteins was
assayed at 22 and 37°C or only at 25°C. Recombinant OspE, OspF, and
Elp family proteins (Fig. 1
a)
were coupled to a CM5 chip and the binding of fluid phase factor H was
analyzed. Factor H at different concentrations in 50 mM
veronal-buffered saline (VBS) was used as the ligand. The pH dependence
of binding was examined with a set of adjusted pH values and a series
of different factor H concentrations in 150 mM PBS. The binding
kinetics were fitted to the simultaneous
Ka/Kd
determination feature of the Biaevaluation 3.1 software package and a
natural logarithmic Langmuir binding (1:1) and mass transfer model. The
sequences of the proteins used in the Biacore assays and peptide
mapping were retrieved from the National Center for Biotechnology
Information sequence database and aligned using the ClustalX 1.8
software package (19)
(http://www-igmbc.u-strasbrg.fr/BioInfo/clustalx,
ftp://ftp-igmbc.u-strasbrg.fr). A phylogenetic analysis was
performed based on sequence comparisons of the proteins;
ClustalX was used to generate an N-J-tree (Fig. 4a), which
was plotted using the Phylip software package
(http://evolution.genetics.washington.edu/phylip.html).
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For immunofluorescence experiments with B. burgdorferi, midguts were dissected out of B. burgdorferi strain 297-infected ticks (nymphal stage) before feeding (n = 12) or after feeding to repletion (n = 10). Extracted midguts were diluted in 20 µl PBS (pH 7.4) before being disrupted by repeated pipetting. Ten microliters of each sample (midguts from unfed or fed ticks) were spotted onto fluoro slides (Erie Scientific, Portsmouth, NH), and indirect immunofluorescence assays were performed as described previously (17). For these experiments, rat polyclonal antiserum directed against OspA, OspC, OspE, ElpB1, or OspF was used as the primary Ab at 1/25 dilutions. Alexa 488-labeled goat anti-rat IgG (H and L chain specific) was diluted in PBS/0.2% BSA at 1/1000 and used as the secondary Abs. Slides were washed and fixed in acetone before fluorescent imaging was performed. For each protein analyzed, multiple fields were viewed before images of representative fields were captured using a Spot digital camera and associated software (Diagnostic Instruments, Sterling Heights, MI).
Peptide scanning
The amino acid sequences chosen for peptide scanning analysis from the National Center for Biotechnology Information protein sequence databank (http://www.ncbi.nlm.nih.gov) were OspE-N40 (AAA22959), OspE-297 (AAC34953), p21–297 (AAC34957), ErpA-B31-cp1 (AAF07400), ErpP-B31-cp9 (AAF07678), OspE-IP90 (AAC62927), and p21-DK1 (CAA69689). p21-DK1 is an OspF family member from B. afzelii DK1. The combined phylogenetic and peptide mapping data would support that the name of this protein be changed so as not to reflect an association with OspE orthologs. OspE-IP90 is a C-terminally truncated sequence from the B. garinii IP90 strain that does not bind factor H. All sequences were fragmented into 15-aa peptides with a 3-aa transition and a 12-aa overlap. The peptides were synthesized as spots onto polyethylene glycol-derivatized cellulose membranes (AIMS Scientific Products, Braunschweig, Germany; http://www.aims-scientific-products.de) using the peptide scanning instrument AutoSpot Robot ASP222 (Abimed Analysen-Technik, Langenfeld, Germany). Subsequently, a protein overlay assay with radiolabeled factor H (6, 20) was conducted. The membranes were washed and exposed on a phosphorimager plate. Amino acid sequences of the tested proteins were aligned using the Megalign and ClustalX programs.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) (18). Factor H bound to OspE-N40,
OspE-297, p21–297, ErpA-B31, and ErpP-B31, which all belong to the
same protein family (Figs. 2-4). The
binding interactions were dependent on pH and ionic strength,
indicating their ionic nature.
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, c and d). At
physiological ionic strength (150 mM VBS, pH 7.4, 22°C) the
Kd values for ErpA-B31 and ErpP-B31
were 102 and 129 nM, respectively (Fig. 3, c and d). At
37°C similar Kd values resulted in
higher on rates (
105
M-1s-1) and off rates
(10-2s-1) for both
ErpA and ErpP. The concentration of factor H in human serum is 3.3 µM
or higher. This suggests that in blood the OspE proteins on
Borrelia readily become saturated by factor H molecules. The
various OspE paralogs have 80% sequence homology with each other and
form a distinct protein family (Fig. 4).
While OspE-297 and p21–297 bound factor H optimally at acidic pH (not
shown) and ErpP-B31 bound at neutral pH, ErpA-B31 binding covered the
widest pH range (Fig. 3) that overlaps the stability range of factor H
at pH 5–9.
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other
than the OspE paralogs bound factor H (not shown). In addition, our
prior studies have excluded factor H binding to numerous other surface
molecules of B. burgdorferi, including OspA-297, OspC-Bbia,
OspD-N40, P35/Bbk32-Bbia, and DbpA-N40 proteins from the respective
B. burgdorferi sensu stricto strains (21).
Because the plasmid-encoded outer surface proteins of
Borrelia have been suggested to be differentially expressed
in the arthropod vectors and mammalian hosts, we next analyzed the
lipoprotein expression patterns in B. burgdorferi-infected
Ixodes scapularis ticks. We performed indirect
immunofluorescence analysis on spirochetes within tick midguts before
and after feeding to repletion. As shown in Fig. 5, no spirochetes were identified that
expressed OspE, OspF, and ElpB1 in the midguts of unfed ticks. However,
within fed ticks there was a pronounced induction of expression for
OspE, OspF, and ElpB1. As a control for these experiments, the
expression of OspA and OspC in unfed and fed tick midguts also was
analyzed. As expected, there was a marked reduction in OspA and a
concomitant increase in OspC expression during tick feeding
(22).
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a). Five candidate
regions (I–V) were detected. When highlighted in a sequence alignment
(Fig. 6b), it can be seen that the binding sites are almost
identical in the different OspE homologs but are absent from the OspF
and Elp family members. No homologous sequences were found in the OspA
and OspC proteins either. Sequence comparisons showed that the B.
burgdorferi sequences for p21, OspE, ErpA, and ErpP from the 297
and B31 strains were more closely related to each other than to the
B. garinii IP90 OspE.
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b) are that they contain and
are flanked by charged residues, especially lysines, and are predicted
to be exposed on the surface of the spirochete. The pI values of the
OspE paralogs vary noticeably among the family members and across
their sequences. In general, they have a zwitterionic charge
distribution with numerous positively and negatively charged amino acid
residues throughout their primary sequences. Variations in the regions
flanking the binding domains as well as charged residue substitutions
in the binding domains also seem to modulate the pH optimum of the
whole protein for factor H binding. In general, conservation of the
binding regions supports a critical role for the factor H-OspE
interactions. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) and upon transmission
to mammals by ticks (17) is also consistent with this
function during the infectious process. The physiological conditions in
tick-ingested blood are different from those in the mammalian host. As
the interaction between factor H and OspE proteins is preserved in
conditions of a wide pH range, it is likely that Borrelia
burgdorferi can protect itself from complement attack also in
ingested blood in the tick midgut, where the pH is 6.8
(27). The serum resistance of Borrelia strains is associated with the ability of bound factor H to promote C3b cleavage by factor I (6). Soluble OspE can compete with the binding of factor H to the surface of Borrelia, and when preincubated in serum, OspE can enhance the cytolytic activity of serum against B. burgdorferi (21). Collectively, our data indicate that the OspE family of factor H binding proteins is associated with virulence in the human host. The close homology of factor H molecules in different animals and the fact that Borrelia infects a wide variety of vertebrates suggest that OspE-related proteins are also associated with in virulence mammalian hosts other than man. Indeed, we (6) observed that B. burgdorferi and B. afzelii can bind rabbit factor H from growth medium, and recently Stevenson et al. (23) observed that factor H from a variety of animal species binds to B. burgdorferi OspE/F/Elp proteins (called Erps). Stevenson et al. (23) obtained results consistent with our data concerning the B31 strain. They further concluded and speculated that all the Erp proteins would bind factor H in different host environments and affect the host specificity of the pathogen. Based on the binding and sequence data available, our results suggest that at least in the case of human factor H, the binding is specific for the OspE-related proteins only. Of the other proteins using the sensitive Biacore assay, only the ErpX-B31 protein was found to weakly bind factor H at pH 5.5, but not under physiological conditions. No other OspF or Elp protein bound human factor H. Furthermore, the factor H binding C-termini of OspE family proteins have amino acid sequences that are absent from the other Erp (OspF and Elp) proteins.
Recent evidence (28) suggests that plasmids harboring the OspE paralogs in borrelial strains share homology with bacteriophages. The plasmids could thus mediate horizontal transfer of genetic information among Borreliae. If this mechanism were in current use for the transfer of genetic material in Lyme disease spirochetes, it could result in the transfer of complement resistance in the Borreliae, similar to the transfer of antibiotic resistance in pathogenic bacteria. Thus, OspE paralogs may represent mobile units with which complement resistance can be transmitted from one population or strain to another. Plasmids encoding the OspE/F/Elp orthologs are often lost from a B. burgdorferi strain upon several generations of in vitro culture, with a concomitant attenuation in virulence. This probably also explains the loss of serum resistance and reduced numbers of demonstrable factor H binding proteins in Borrelia strains cultured for prolonged periods in vitro (29).
A puzzling question is why B. garinii strains are sensitive to complement killing. The likely reasons are, first, that B. garinii carries low copy numbers of OspE genes and, second, that the OspE proteins in B. garinii differ from those in the other genospecies. Consistent with these conjectures, primers or probes based on known OspE sequences do not readily recognize DNA from B. garinii, and the only currently established B. garinii OspE sequence ends before the most C-terminal region, implicated here in factor H interactions (30). Unlike all other OspE-related proteins, the B. garinii OspE contains four repeats consisting of SLSDQG in its N-terminal part (30). A missing C terminus, critical amino acid differences, or a smaller number of OspE paralogs could explain the sensitivity of B. garinii to complement killing. More studies are needed to explain why the garinii strains are sensitive to complement attack. The complement sensitivity of B. garinii may explain its preference to cause infections in the CNS (31). B. garinii could survive within the CNS because the amount of cytotoxic complement is limited in this body compartment. How B. garinii can reach the CNS and which additional immune evasion strategies it uses remain to be investigated. Additional information about the pathogenesis of B. garinii infection, in particular, will be of help in the development of an efficient treatment against all three genospecies.
In conclusion, our study reveals that a distinct set of plasmid-encoded homologous proteins, the OspE protein family, is responsible for factor H binding-mediated complement resistance in Borrelia burgdorferi. Recombinatorial processes have led to a redundancy of OspE-like gene products whose expression becomes induced and which function under a variety of physiological conditions within the arthropod and mammalian hosts. Identification of the different virulence factors and the underlying mechanisms of immune evasion can provide new tools to prevent and treat borreliosis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Seppo Meri, Department of Bacteriology and Immunology, P.O. Box 21, University of Helsinki, Haartmaninkatu 3, FIN-00014 Helsinki, Finland. E-mail address: seppo.meri{at}helsinki.fi
3 Abbreviations used in this paper: OspE, outer surface protein E; VBS, veronal-buffered saline.
Received for publication May 28, 2002. Accepted for publication July 24, 2002.
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C. H. Eggers, M. J. Caimano, and J. D. Radolf Analysis of Promoter Elements Involved in the Transcriptional Initiation of RpoS-Dependent Borrelia burgdorferi Genes J. Bacteriol., November 1, 2004; 186(21): 7390 - 7402. [Abstract] [Full Text] [PDF]
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I. Leduc, P. Richards, C. Davis, B. Schilling, and C. Elkins A Novel Lectin, DltA, Is Required for Expression of a Full Serum Resistance Phenotype in Haemophilus ducreyi Infect. Immun., June 1, 2004; 72(6): 3418 - 3428. [Abstract] [Full Text] [PDF]
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A. Alitalo, T. Meri, T. Chen, H. Lankinen, Z.-Z. Cheng, T. S. Jokiranta, I. J. T. Seppala, P. Lahdenne, P. S. Hefty, D. R. Akins, et al. Lysine-Dependent Multipoint Binding of the Borrelia burgdorferi Virulence Factor Outer Surface Protein E to the C Terminus of Factor H J. Immunol., May 15, 2004; 172(10): 6195 - 6201. [Abstract] [Full Text] [PDF]
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K. Babb, J. D. McAlister, J. C. Miller, and B. Stevenson Molecular Characterization of Borrelia burgdorferi erp Promoter/Operator Elements J. Bacteriol., May 1, 2004; 186(9): 2745 - 2756. [Abstract] [Full Text] [PDF]
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P. Kraiczy, J. Hellwage, C. Skerka, H. Becker, M. Kirschfink, M. M. Simon, V. Brade, P. F. Zipfel, and R. Wallich Complement Resistance of Borrelia burgdorferi Correlates with the Expression of BbCRASP-1, a Novel Linear Plasmid-encoded Surface Protein That Interacts with Human Factor H and FHL-1 and Is Unrelated to Erp Proteins J. Biol. Chem., January 23, 2004; 279(4): 2421 - 2429. [Abstract] [Full Text] [PDF]
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J. C. Miller, K. von Lackum, K. Babb, J. D. McAlister, and B. Stevenson Temporal Analysis of Borrelia burgdorferi Erp Protein Expression throughout the Mammal-Tick Infectious Cycle Infect. Immun., December 1, 2003; 71(12): 6943 - 6952. [Abstract] [Full Text] [PDF]
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 J. V. McDowell, E. Tran, D. Hamilton, J. Wolfgang, K. Miller, and R. T. Marconi Analysis of the Ability of Spirochete Species Associated with Relapsing Fever, Avian Borreliosis, and Epizootic Bovine Abortion To Bind Factor H and Cleave C3b J. Clin. Microbiol., August 1, 2003; 41(8): 3905 - 3910. [Abstract] [Full Text] [PDF]
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R. Iyer, O. Kalu, J. Purser, S. Norris, B. Stevenson, and I. Schwartz Linear and Circular Plasmid Content in Borrelia burgdorferi Clinical Isolates Infect. Immun., July 1, 2003; 71(7): 3699 - 3706. [Abstract] [Full Text] [PDF]
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M. S. Metts, J. V. McDowell, M. Theisen, P. R. Hansen, and R. T. Marconi Analysis of the OspE Determinants Involved in Binding of Factor H and OspE-Targeting Antibodies Elicited during Borreliaburgdorferi Infection in Mice Infect. Immun., June 1, 2003; 71(6): 3587 - 3596. [Abstract] [Full Text] [PDF]
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J. V. McDowell, J. Wolfgang, E. Tran, M. S. Metts, D. Hamilton, and R. T. Marconi Comprehensive Analysis of the Factor H Binding Capabilities of Borrelia Species Associated with Lyme Disease: Delineation of Two Distinct Classes of Factor H Binding Proteins Infect. Immun., June 1, 2003; 71(6): 3597 - 3602. [Abstract] [Full Text] [PDF]
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J. C. Miller and B. Stevenson Immunological and genetic characterization of Borrelia burgdorferi BapA and EppA proteins Microbiology, May 1, 2003; 149(5): 1113 - 1125. [Abstract] [Full Text] [PDF]
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