scholarly journals Effects of Expression of Streptococcus pneumoniae PspC on the Ability of Streptococcus mitis to Evade Complement-Mediated Immunity

2021 ◽  
Vol 12 ◽  
Author(s):  
Helina Marshall ◽  
Ricardo J. José ◽  
Mogens Kilian ◽  
Fernanda C. Petersen ◽  
Jeremy S. Brown
Keyword(s):  
Streptococcus Pneumoniae ◽  
Surface Protein ◽  
Factor H ◽  
Streptococcus Mitis ◽  
Poor Growth ◽  
Virulence Phenotype ◽  
Highly Sensitive ◽  
Invasive Infections ◽  
Physiological Fluid ◽  
Complement Regulator

Streptococcus pneumoniae and Streptococcus mitis are genetically closely related and both frequently colonise the naso-oropharynx, yet S. pneumoniae is a common cause of invasive infections whereas S. mitis is only weakly pathogenic. We hypothesise that sensitivity to innate immunity may underlie these differences in virulence phenotype. We compared the sensitivity of S. pneumoniae and S. mitis strains to complement-mediated immunity, demonstrating S. mitis strains were susceptible to complement-mediated opsonophagocytosis. S. pneumoniae resistance to complement is partially dependent on binding of the complement regulator Factor H by the surface protein PspC. However, S. mitis was unable to bind factor H. The S. pneumoniae TIGR4 strain pspC was expressed in the S. mitis SK142 strain to create a S. mitis pspC+ strain. Immunoblots demonstrated the S. mitis pspC+ strain expressed PspC, and flow cytometry confirmed this resulted in Factor H binding to S. mitis, reduced susceptibility to complement and improved survival in whole human blood compared to the wild-type S. mitis strain. However, in mouse models the S. mitis pspC+ strain remained unable to establish persistent infection. Unlike S. pneumoniae strains, culture in serum or blood did not support increased CFU of the S. mitis strains. These results suggest S. mitis is highly sensitive to opsonisation with complement partially due to an inability to bind Factor H, but even when complement sensitivity was reduced by expression of pspC, poor growth in physiological fluid limited the virulence of S. mitis in mice.

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

2012 ◽  
Vol 81 (1) ◽  
pp. 173-181 ◽  
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.

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

2005 ◽  
Vol 73 (4) ◽  
pp. 2351-2359 ◽  
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.

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

2002 ◽  
Vol 70 (10) ◽  
pp. 5604-5611 ◽  
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.

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

2013 ◽  
Vol 62 (7) ◽  
pp. 1073-1080 ◽  
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.

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

Immunobiology ◽  
2012 ◽  
Vol 217 (11) ◽  
pp. 1204
Author(s):  
Julia A. Sharp ◽  
Charlene G. Echague ◽  
Pamela S. Hair ◽  
Michael D. Ward ◽  
Julius O. Nyalwidhe ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Response ◽  
Surface Protein ◽  
Factor H ◽  
Complement Regulator

scholarly journals Antigenic Variation inStreptococcus pneumoniaePspC Promotes Immune Escape in the Presence of Variant-Specific Immunity

mBio ◽  
2018 ◽  
Vol 9 (2) ◽  
Author(s):  
M. Georgieva ◽  
L. Kagedan ◽  
Ying-Jie Lu ◽  
C. M. Thompson ◽  
M. Lipsitch
Keyword(s):  
Streptococcus Pneumoniae ◽  
Sequence Variation ◽  
Antigenic Variation ◽  
Biological Function ◽  
Immune Escape ◽  
Surface Protein ◽  
Factor H ◽  
Sequence Diversity ◽  
Protein Antigens ◽  
Specific Immunity

ABSTRACTGenomic analysis reveals extensive sequence variation and hot spots of recombination in surface proteins ofStreptococcus pneumoniae. While this phenomenon is commonly attributed to diversifying selection by host immune responses, there is little mechanistic evidence for the hypothesis that diversification of surface protein antigens produces an immune escape benefit during infection withS. pneumoniae. Here, we investigate the biological significance of sequence variation within theS. pneumoniaecell wall-associated pneumococcal surface protein C (PspC) protein antigen. UsingpspCallelic diversity observed in a large pneumococcal collection, we produced variant-specific protein constructs that span the sequence variability within thepspClocus. We show that antibodies raised against these PspC constructs are variant specific and prevent association between PspC and the complement pathway mediator, human factor H. We found that PspC variants differ in their capacity to bind factor H, suggesting that sequence variation withinpspCreflects differences in biological function. Finally, in an antibody-dependent opsonophagocytic assay,S. pneumoniaeexpressing a PspC variant matching the antibody specificity was killed efficiently. In contrast, killing efficacy was not evident againstS. pneumoniaeexpressing mismatched PspC variants. Our data suggest that antigenic variation within the PspC antigen promotes immune evasion and could confer a fitness benefit during infection.IMPORTANCELoci encoding surface protein antigens inStreptococcus pneumoniaeare highly polymorphic. It has become a truism that these polymorphisms are the outcome of selective pressure onS. pneumoniaeto escape host immunity. However, there is little mechanistic evidence to support the hypothesis that diversifying protein antigens produces a benefit for the bacteria. Using the highly diversepspClocus, we have now characterized the functional and immune implications of sequence diversity within the PspC protein. We have characterized the spectrum of biological function among diverse PspC variants and show thatpspCsequence diversity reflects functional differences. Further, we show that sequence variation in PspC confers an immune escape benefit in the presence of anti-PspC variant-specific immunity. Overall, the results of our studies provide insights into the functional implications of protein sequence diversity and the role of variant-specific immunity in its maintenance.

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

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

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.

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