Staphylococcus aureus surface protein SdrE binds the complement regulator factor H to evade the immune response

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.

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Identification and Functional Characterization of Complement Regulator-Acquiring Surface Protein 1 of the Lyme Disease Spirochetes Borrelia afzelii and Borrelia garinii

Infection and Immunity ◽

10.1128/iai.73.4.2351-2359.2005 ◽

2005 ◽

Vol 73 (4) ◽

pp. 2351-2359 ◽

Cited By ~ 75

Author(s):

Reinhard Wallich ◽

Joseph Pattathu ◽

Veronique Kitiratschky ◽

Christiane Brenner ◽

Peter F. Zipfel ◽

...

Keyword(s):

Lyme Disease ◽

Binding Site ◽

Binding Protein ◽

Functional Characterization ◽

Surface Protein ◽

Factor H ◽

Borrelia Garinii ◽

Borrelia Afzelii ◽

Complement Regulator

ABSTRACT Complement regulator-acquiring surface protein 1 (CRASP-1) is the dominant factor-H-like protein 1 (FHL-1)- and factor-H-binding protein of Borrelia burgdorferi and is suggested to contribute to persistence of the pathogen. The prototype CRASP-1 of B. burgdorferi sensu stricto (CRASP-1Bb) has been formerly characterized. As shown recently, serum-resistant Borrelia afzelii strains express a unique FHL-1 and factor H-binding protein, designated CRASP-1Ba. Here, we describe for the first time the isolation and functional characterization of the gene encoding the full-length CRASP-1Ba of 28 kDa, which, upon processing, is predicted to be 26.4 kDa. CPASP-1Ba of B. afzelii spirochetes is associated with a genetic locus encoding the orthologous gbb54 gene family that maps to the linear plasmid of approximately 54 kb. Ligand affinity blotting techniques demonstrate that both native and recombinant CRASP-1Ba molecules strongly bind to FHL-1 and much more weakly to factor H. The FHL-1 and factor-H-binding site in CRASP-1Ba is shown to be localized to a 12-amino-acid residue domain at the C terminus of the protein. For comparison, the corresponding cspA-like gene(s) of a serum-sensitive Borrelia garinii strain has also been cloned and characterized. Most notably, two CRASP-1-related B. garinii proteins were identified; however, both molecules bind only weakly to FHL-1 and not at all to factor H. The present identification of the binding site of CRASP-1Ba represents an important step forward in our understanding of the pathogenesis of Lyme disease and may be helpful to design therapeutic regimens to interfere with complement evasion strategies of human pathogenic Borrelia strains.

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The Human Complement Regulator Factor H Binds Pneumococcal Surface Protein PspC via Short Consensus Repeats 13 to 15

Infection and Immunity ◽

10.1128/iai.70.10.5604-5611.2002 ◽

2002 ◽

Vol 70 (10) ◽

pp. 5604-5611 ◽

Cited By ~ 64

Author(s):

Thomas G. Duthy ◽

Rebecca J. Ormsby ◽

Eleni Giannakis ◽

A. David Ogunniyi ◽

Uwe H. Stroeher ◽

...

Keyword(s):

Alternative Pathway ◽

Regulatory System ◽

Surface Protein ◽

Fluid Phase ◽

Direct Consequence ◽

Factor H ◽

Negative Regulator ◽

Short Consensus Repeats ◽

High Concentrations ◽

Complement Regulator

ABSTRACT The innate ability of Streptococcus pneumoniae to resist complement activation and complement-mediated phagocytosis may be a direct consequence of the ability of the bacteria to bind components of the complement regulatory system. One such component, factor H (fH), is a crucial fluid-phase negative regulator of the alternative pathway of complement and is utilized by a number of pathogenic organisms to resist complement attack. The pneumococcal surface protein C (PspC [also known as CbpA] and SpsA) has been shown to bind fH, although the exact binding site within one or more of the 20 short consensus repeats (SCRs) of the molecule is not known. The purpose of the current study was to map specific SCRs on fH responsible for this binding. Initial experiments utilizing type 2 pneumococcal strain D39 and its isogenic PspC-negative derivative (D39/pspC mutant) showed that fH binding was PspC dependent. A purified recombinant protein derivative of PspC that lacked the proline-rich region (PspCΔPro) had a reduced binding efficiency for fH, thereby directly showing the importance of this region for the fH interaction. We have specifically shown by inhibition experiments that SCRs responsible for heparin and C3b binding of fH are not involved in binding PspC and the interaction between fH and PspC is largely hydrophobic, since no inhibition was observed in the presence of high concentrations of NaCl. Construction of SCR proteins encompassing the whole fH molecule showed that SCRs 8 to 15 (SCR 8-15) mediated binding to PspC. Further localization experiments revealed that SCR 13 and SCR 15 were required for full binding, although partial binding was retained when either SCR was removed.

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Identification and characterization of a new cell surface protein possessing factor H-binding activity in the swine pathogen and zoonotic agent Streptococcus suis

Journal of Medical Microbiology ◽

10.1099/jmm.0.057877-0 ◽

2013 ◽

Vol 62 (7) ◽

pp. 1073-1080 ◽

Cited By ~ 13

Author(s):

Katy Vaillancourt ◽

Laetitia Bonifait ◽

Louis Grignon ◽

Michel Frenette ◽

Marcelo Gottschalk ◽

...

Keyword(s):

Cell Surface ◽

Surface Protein ◽

Streptococcus Suis ◽

Binding Activity ◽

Factor H ◽

Complement Factor ◽

Cell Surface Protein ◽

Amino Terminal ◽

Swine Pathogen ◽

Complement Regulator

Streptococcus suis is a major swine pathogen and an emerging zoonotic agent. The ability of pathogenic bacteria to bind the complement regulator factor H on their cell surface may allow them to avoid complement attack and phagocytosis. The aim of this study was to characterize a new cell surface protein possessing factor H-binding activity in S. suis serotype 2. The capacity of S. suis to bind the complement regulator factor H on its surface was demonstrated by ELISA. Using a factor I–cofactor assay, it was found that the functional activity of factor H bound to S. suis was kept. Since the product of gene SSU0186 in S. suis P1/7 shared similarity with a Streptococcus pneumoniae protein (named PspC) possessing factor H-binding activity, it was proposed as a putative factor H receptor in S. suis. SSU0186 has a 1686 bp open reading frame encoding a 561 amino acid protein containing the Gram-positive cell wall anchoring motif (LPXTG) at the carboxy-terminal, an amino-terminal signal sequence, an α-helix domain, a proline-rich region and a G5 domain. The SSU0186 gene was cloned in Escherichia coli and the purified recombinant factor H-binding protein showed a molecular mass of 95 kDa, as determined by SDS-PAGE. The protein possessed the functional property of binding factor H. Sera from S. suis-infected pigs reacted with the recombinant factor H receptor, suggesting that it is produced during the course of infections. In conclusion, we identified a novel S. suis cell surface protein that binds the complement factor H. This cell surface protein may help S. suis to resist complement attack and phagocytosis and contribute to pathogenesis.

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Further structural insights into the binding of complement factor H by complement regulator-acquiring surface protein 1 (CspA) ofBorrelia burgdorferi

Acta Crystallographica Section F Structural Biology and Crystallization Communications ◽

10.1107/s1744309113012748 ◽

2013 ◽

Vol 69 (6) ◽

pp. 629-633 ◽

Cited By ~ 9

Author(s):

Joseph J. E. Caesar ◽

Reinhard Wallich ◽

Peter Kraiczy ◽

Peter F. Zipfel ◽

Susan M. Lea

Keyword(s):

Surface Protein ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Complement Regulator ◽

Structural Insights

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Clumping Factor A Interaction with Complement Factor I Increases C3b Cleavage on the Bacterial Surface of Staphylococcus aureus and Decreases Complement-Mediated Phagocytosis

Infection and Immunity ◽

10.1128/iai.01065-09 ◽

2010 ◽

Vol 78 (4) ◽

pp. 1717-1727 ◽

Cited By ~ 65

Author(s):

Pamela S. Hair ◽

Charlene G. Echague ◽

Amber M. Sholl ◽

Justin A. Watkins ◽

Joan A. Geoghegan ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Surface Protein ◽

Factor H ◽

Complement Factor ◽

Wild Type ◽

Bacterial Surface ◽

Complement Control Protein ◽

Factor I ◽

Protein Factor ◽

Fibrinogen Binding

ABSTRACT The human complement system is important in the immunological control of Staphylococcus aureus infection. We showed previously that S. aureus surface protein clumping factor A (ClfA), when expressed in recombinant form, bound complement control protein factor I and increased factor I cleavage of C3b to iC3b. In the present study, we show that, compared to the results for the wild type, when isogenic ClfA-deficient S. aureus mutants were incubated in serum, they bound less factor I, generated less iC3b on the bacterial surface, and bound fewer C3 fragments. It has been shown previously that two amino acids in ClfA (P336 and Y338) are essential for fibrinogen binding. However, S. aureus expressing ClfA(P336A Y338S) was less virulent than ClfA-deficient strains in animal models. This suggested that ClfA contributed to S. aureus virulence by a mechanism different than fibrinogen binding. In the present study, we showed that S. aureus expressing ClfA(P336A Y338S) was more susceptible to complement-mediated phagocytosis than a ClfA-null mutant or the wild type. Unlike ClfA, ClfA(P336A Y338S) did not enhance factor I cleavage of C3b to iC3b and inhibited the cofactor function of factor H. Fibrinogen enhanced factor I binding to ClfA and the S. aureus surface. Twenty clinical S. aureus strains all expressed ClfA and bound factor I. High levels of factor I binding by clinical strains correlated with poor phagocytosis. In summary, our results suggest that the interaction of ClfA with factor I contributes to S. aureus virulence by a complement-mediated mechanism.

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PspK of Streptococcus pneumoniae Increases Adherence to Epithelial Cells and Enhances Nasopharyngeal Colonization

Infection and Immunity ◽

10.1128/iai.00755-12 ◽

2012 ◽

Vol 81 (1) ◽

pp. 173-181 ◽

Cited By ~ 50

Author(s):

L. E. Keller ◽

C. V. Jones ◽

J. A. Thornton ◽

M. E. Sanders ◽

E. Swiatlo ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Epithelial Cells ◽

Immunoglobulin A ◽

Surface Protein ◽

Invasive Disease ◽

Factor H ◽

Host Cells ◽

Content Type ◽

Capsule Locus ◽

Complement Regulator

Streptococcus pneumoniae(the pneumococcus) colonizes the human nasopharynx and can cause invasive disease aided by the pneumococcal capsule. Group II nontypeableS. pneumoniae(NTSp) lacks a polysaccharide capsule, and a subgroup of NTSp carriage isolates has been found to have a novel gene, pneumococcal surface protein K (pspK), which replaces the capsule locus. A recent rise in the number of NTSp isolates colonizing the human nasopharynx has been observed, but the colonization factors of NTSp have not been well studied. PspK has been shown to play a role in mouse colonization. We therefore examined PspK-mediated immune evasion along with adherence to host cells and colonization. PspK bound human secretory immunoglobulin A (sIgA) but not the complement regulator factor H and did not decrease C3b deposition on the pneumococcal surface. PspK increased binding of pneumococci to epithelial cells and enhanced pneumococcal colonization independently of the genetic background. Understanding how NTSp colonizes and survives within the nasopharynx is important due to the increase in NTSp carriage. Our data suggest that PspK may aid in the persistence of NTSp within the nasopharynx but is not involved in invasion.

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The complement regulator-acquiring surface protein 3 of the Lyme disease spirochete Borrelia spielmanii interacts with distinct members of the factor H protein family

Molecular Immunology ◽

10.1016/j.molimm.2009.05.230 ◽

2009 ◽

Vol 46 (14) ◽

pp. 2834

Author(s):

Peter Kraiczy ◽

Annekatrin Seling ◽

Volker Fingerle ◽

Christine Skerka ◽

Reinhard Wallich ◽

...

Keyword(s):

Lyme Disease ◽

Surface Protein ◽

Protein Family ◽

Factor H ◽

Complement Regulator ◽

H Protein

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

Clinical and Developmental Immunology ◽

10.1155/2012/349657 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 29

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.

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