scholarly journals Demonstration of Factor H-Like Protein 1 Binding to Treponema denticola, a Pathogen Associated with Periodontal Disease in Humans

2005 ◽  
Vol 73 (11) ◽  
pp. 7126-7132 ◽  
Author(s):  
John V. McDowell ◽  
Justin Lankford ◽  
Lola Stamm ◽  
Tania Sadlon ◽  
David L. Gordon ◽  
...  
Keyword(s):  
Periodontal Disease ◽  
Factor H ◽  
Treponema Denticola ◽  
Binding Ability ◽  
Independent Manner ◽  
Complement Regulatory Proteins ◽  
Factor I ◽  
Short Consensus Repeats ◽  
Alternative Complement ◽  
Recombinant Fragments

ABSTRACT Treponema denticola is an important contributor to periodontal disease. In this study we investigated the ability of T. denticola to bind the complement regulatory proteins factor H and factor H-like protein 1 (FHL-1). The binding of these proteins has been demonstrated to facilitate evasion of the alternative complement cascade and/or to play a role in adherence and invasion. Here we demonstrate that T. denticola specifically binds FHL-1 via a 14-kDa, surface-exposed protein that we designated FhbB. Consistent with its FHL-1 binding specificity, FhbB binds only to factor H recombinant fragments spanning short consensus repeats (SCRs) 1 to 7 (H7 construct) and not to SCR constructs spanning SCRs 8 to 15 and 16 to 20. Binding of H7 to FhbB was inhibited by heparin. The specific involvement of SCR 7 in the interaction was demonstrated using an H7 mutant (H7AB) in which specific charged residues in SCR 7 were replaced by alanine. This construct lost FhbB binding ability. Analyses of the ability of FHL-1 bound to the surface of T. denticola to serve as a cofactor for factor I-mediated cleavage of C3b revealed that C3b is cleaved in an FHL-1/factor I-independent manner, perhaps by an unidentified protease. Based on the data presented here, we hypothesize that the primary function of FHL-1 binding by T. denticola might be to facilitate adherence to FHL-1 present on anchorage-dependent cells and in the extracellular matrix.

scholarly journals Putative Coiled-Coil Structural Elements of the BBA68 Protein of Lyme Disease Spirochetes Are Required for Formation of Its Factor H Binding Site

2005 ◽  
Vol 187 (4) ◽  
pp. 1317-1323 ◽  
Author(s):  
John V. McDowell ◽  
Matthew E. Harlin ◽  
Elizabeth A. Rogers ◽  
Richard T. Marconi
Keyword(s):  
Lyme Disease ◽  
Binding Site ◽  
Immune Evasion ◽  
Coiled Coil ◽  
Factor H ◽  
Regulatory Proteins ◽  
Structural Elements ◽  
Binding Ability ◽  
Complement Regulatory Proteins ◽  
Factor I

ABSTRACT Factor H and factor H like-protein 1 (FHL-1) are complement regulatory proteins that serve as cofactors for the factor I-mediated cleavage of C3b. Some Lyme disease and relapsing fever spirochete species bind factor H to their surface to facilitate immune evasion. The Lyme disease spirochetes produce several factor H binding proteins (FHBPs) that form two distinct classes. Class I FHBPs (OspE orthologs and paralogs) bind only factor H, while class II FHBPs (BBA68) bind both factor H and FHL-1. BBA68 belongs to a large paralogous protein family, and of these paralogs, BBA69 is the member most closely related to BBA68. To determine if BBA69 can also bind factor H, recombinant protein was generated and tested for factor H binding. BBA69 did not exhibit factor H binding ability, suggesting that among family 54 paralogs, factor H binding is unique to BBA68. To identify the determinants of BBA68 that are involved in factor H binding, truncation and site-directed mutational analyses were performed. These analyses revealed that the factor H binding site is discontinuous and provide strong evidence that coiled-coil structural elements are involved in the formation of the binding site.

scholarly journals ATYPICAL HEMOLYTIC-UREMIC SYNDROME IN GENERAL AND IN PREGNANCY

2018 ◽  
Vol 5 (3) ◽  
pp. 132-139
Author(s):  
Aleksandr V. Novikov
Keyword(s):  
Hemolytic Uremic Syndrome ◽  
Renal Damage ◽  
Atypical Hemolytic Uremic Syndrome ◽  
Factor H ◽  
New Drugs ◽  
Factor I ◽  
The Past ◽  
Alternative Complement ◽  
Uremic Syndrome ◽  
The Complement System

Atypical hemolytic-uremic syndrome (aHUS) is an ultra-rare (orphan) disease, a form of thrombotic microangiopathy, which arises from a disturbance of the activation of an alternative complement pathway. Pregnancy is a frequent trigger for the onset of obstetric aHUS. Against the background of the disease in pregnant women, there is a high risk of developing pre-eclampsia, acute renal damage and consequently maternal mortality. In the world over the past 5 years, the number of confirmed cases of aHUS has increased. However, this is due not so much to the increase in the occurence of the disease as to the improvement in the methods of its diagnosis. The genetic nature of the aHUS dictates the need to create modern sensitive tests for the study of the complement system: measurement of the plasma concentration of factor H and factor I, C3, C4, genetic screening of regulatory genes, and others. It is also necessary to develop new drugs that, along with Eculizumabum (Soliris®, Alexion Pharmaceuticals, Cheshire, CT, USA) would be used in the therapy of aHUS.

scholarly journals Analysis of a Unique Interaction between the Complement Regulatory Protein Factor H and the Periodontal Pathogen Treponema denticola

2009 ◽  
Vol 77 (4) ◽  
pp. 1417-1425 ◽  
Author(s):  
John V. McDowell ◽  
Bernice Huang ◽  
J. Christopher Fenno ◽  
Richard T. Marconi
Keyword(s):  
Regulatory Protein ◽  
Coiled Coil ◽  
Alpha Helix ◽  
Leading Edge ◽  
Factor H ◽  
Host Cells ◽  
Periodontal Pathogen ◽  
Treponema Denticola ◽  
Complement Regulatory Proteins ◽  
Protein Factor

ABSTRACT Treponema denticola, a spirochete associated with periodontitis, is abundant at the leading edge of subgingival plaque, where it interacts with gingival epithelia. T. denticola produces a number of virulence factors, including dentilisin, a protease which is cytopathic to host cells, and FhbB, a unique T. denticola lipoprotein that binds complement regulatory proteins. Earlier analyses suggested that FhbB specifically bound to factor H (FH)-like protein 1 (FHL-1). However, by using dentilisin-deficient mutants of T. denticola, we found that T. denticola preferentially binds FH and not FHL-1, and that FH is then cleaved by dentilisin to yield an FH subfragment of ∼50 kDa. FH bound to dentilisin-deficient mutants but was not cleaved and retained its ability to serve as a cofactor for factor I in the cleavage of C3b. To assess the molecular basis of the interaction of FhbB with FH, mutational analyses were conducted. Replacement of specific residues in widely separated domains of FhbB and disruption of a central alpha helix with coiled-coil formation probability attenuated or eliminated FH binding. The data presented here are the first to demonstrate the retention at the cell surface of a proteolytic cleavage product of FH. The precise role of this FH fragment in the host-pathogen interaction remains to be determined.

scholarly journals Identification of the Gene Encoding the FhbB Protein of Treponema denticola, a Highly Unique Factor H-Like Protein 1 Binding Protein

2006 ◽  
Vol 75 (2) ◽  
pp. 1050-1054 ◽  
Author(s):  
John V. McDowell ◽  
Jesse Frederick ◽  
Lola Stamm ◽  
Richard T. Marconi
Keyword(s):  
Periodontal Disease ◽  
Binding Protein ◽  
Factor H ◽  
Sequence Conservation ◽  
Treponema Denticola ◽  
Gene Encoding ◽  
Unique Factor

ABSTRACT The gene encoding the Treponema denticola factor H-like protein 1 (FHL-1) binding protein, FhbB, was recovered and characterized. Sequence conservation, expression, and properties of FhbB were analyzed. The identification of FhbB represents an important step in understanding the contribution of FHL-1 binding in T. denticola pathogenesis and in development of periodontal disease.

scholarly journals The human complement regulatory factor-H-like protein 1, which represents a truncated form of factor H, displays cell-attachment activity

1997 ◽  
Vol 326 (2) ◽  
pp. 321-327 ◽  
Author(s):  
Jens HELLWAGE ◽  
Sabine KÜHN ◽  
Peter F. ZIPFEL
Keyword(s):  
Cell Attachment ◽  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor ◽  
Integrin Receptors ◽  
Short Consensus Repeats ◽  
Dependent Cell ◽  
Alternative Pathway Of Complement ◽  
Regulatory Functions ◽  
Recombinant Fragments

Complement factor H (FH) and factor-H-like protein 1 (FHL-1) are human plasma proteins with regulatory functions in the alternative pathway of complement activation. FH and FHL-1 are organized in repetitive elements termed short consensus repeats (SCRs) and the seven SCRs of FHL-1 are identical with the N-terminal domain of the 20 SCRs of FH. The fourth SCR of both proteins (SCR 4) includes the sequence Arg-Gly-Asp (RGD), a motif that is responsible for the major adhesive activity of matrix proteins like fibronectin. A synthetic hexapeptide with the sequence ERGDAV derived from the RGD domain of FH/FHL-1 interferes with cell attachment to a fibronectin matrix. Although the identical motif is present in both FH and FHL-1, only FHL-1 acts as a matrix for cell spreading and attachment, thus the two proteins differ in function. The adhesive activity of FHL-1 is localized to the RGD-containing SCR 4 by the use of recombinant fragments. All three analysed anchorage-dependent cell lines (CCl64, C32 and MRC-5) adhere to an FHL-1 matrix. The use of synthetic peptides in competition assays, on either FHL-1-derived or fibronectin matrices, shows that the cellular receptors binding to the FH/FHL-1-derived RGD motif are related to or identical with integrin receptors which interact with fibronectin. The identification of a functional adhesive domain in the FH/FHL-1 sequence demonstrates, at least for FHL-1, a role in cell attachment and adhesion.

Comparison of Sampling Techniques For qPCR Quantification of Periodontal Pathogens

2018 ◽  
Vol 68 (12) ◽  
pp. 2853-2856 ◽  
Author(s):  
Igor Jelihovschi ◽  
Cristian Drochioi ◽  
Aida Corina Badescu ◽  
Raoul Vasile Lupusoru ◽  
Alexandra Elena Munteanu ◽  
...  
Keyword(s):  
Periodontal Disease ◽  
Periodontal Diseases ◽  
Pcr Analysis ◽  
Treponema Denticola ◽  
Subgingival Plaque ◽  
Periodontal Pathogens ◽  
Radiographic Evidence ◽  
Gingival Bleeding ◽  
As Species ◽  
Qpcr Quantification

The diagnosis of periodontal disease is mainly based on use of clinical and radiographic evidence. In this study we employed a quantitative PCR analysis of Aggregatibacter actinomycetemcomitans and Treponema denticola as species strongly involved in periodontal diseases, burden in periodontal pockets to detect the main sampling factors that interfere with qPCR results. From 22 patients with advanced periodontal disease, subgingival plaque was comparatively collected by paper points and periodontal Gracey curettes. Samples were collected from the same situs in presence of gingival bleeding and absence of bleeding. The concordance and agreement of results between samples were assessed. The present study demonstrates that subgingival plaque sampling with sterile absorbable paper points is often accompanied by gingival bleeding resulting in quantification biases of periodontal pathogens.

Development of an FhbB based chimeric vaccinogen that elicits antibodies that block Factor H binding and cleavage by the periopathogen Treponema denticola

2020 ◽  
Author(s):  
Nathaniel S. O'Bier ◽  
Dhara T. Patel ◽  
Lee D. Oliver ◽  
Daniel P. Miller ◽  
Richard T. Marconi
Keyword(s):  
Factor H ◽  
Treponema Denticola ◽  
Block Factor

scholarly journals New functional and structural insights from updated mutational databases for complement factor H, Factor I, membrane cofactor protein and C3

2014 ◽  
Vol 34 (5) ◽  
Author(s):  
Elizabeth Rodriguez ◽  
Pavithra M. Rallapalli ◽  
Amy J. Osborne ◽  
Stephen J. Perkins
Keyword(s):  
Alternative Pathway ◽  
Factor H ◽  
Complement Factor H ◽  
Complement C3 ◽  
Complement Factor ◽  
Membrane Cofactor Protein ◽  
Complement Alternative Pathway ◽  
Factor I ◽  
Mutational Hotspots ◽  
Structural Insights

A new compilation of 324 mutations in four major proteins from the complement alternative pathway reveals mutational hotspots in factor H and complement C3, and less so in factor I and membrane cofactor protein. Their associations with function are discussed.

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