Treponema denticola: FhbB, Dentilisin, Complement Evasion and the Paradox of Factor H Cleavage

McDowell, John V.; Miller, Daniel P.; Mallory, Katherine L.; Marconi, Richard T.

doi:10.1007/978-1-4614-5404-5_3

Cited by 13 publications

(24 citation statements)

References 83 publications

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“…FH, a negative regulator of complement activation, binds to an 11.4 kDa lipoprotein and dominant surface antigen designated as FhbB . Bound FH locally (not systemically) downregulates complement activation at the site of infection by serving as a co‐factor for factor I (FI) mediated cleavage of C3b . H 2 S production is also a key driving force in PD progression.…”

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confidence: 99%

Antimicrobial activity of amixicile against Treponema denticola and other oral spirochetes associated with periodontal disease

Reed

O’Bier

Oliver

et al. 2018

Journal of Periodontology

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confidence: 99%

Antimicrobial activity of amixicile against Treponema denticola and other oral spirochetes associated with periodontal disease

Reed

O’Bier

Oliver

et al. 2018

Journal of Periodontology

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“…The binding of FH to FhbB and its subsequent cleavage by dentilisin have been postulated to play a central role in the pathogenesis of T. denticola (9,10,16,35). As the T. denticola population expands with the development of PD, the rate of FH cleavage in GCF may exceed its rate of replenishment, resulting in localized immune dysregulation (5,35).…”

Section: Discussionmentioning

confidence: 99%

“…As the T. denticola population expands with the development of PD, the rate of FH cleavage in GCF may exceed its rate of replenishment, resulting in localized immune dysregulation (5,35). We have hypothesized that T. denticola mediated complement dysregulation could be blocked using an FhbB-based vaccine or a therapeutic ␣-FhbB Ab cocktail.…”

Section: Discussionmentioning

confidence: 99%

“…The cleavage of FH by T. denticola, a protein required for evasion of complement (at least in vitro in human serum), is somewhat of a paradox since cleavage would counter an important immune evasion mechanism of T. denticola (reviewed in reference 35). McDowell et al demonstrated that the 35405⌬fhbB strain is highly sensitive to complement-mediated killing, whereas the parental 35405 strain is not (9).…”

Section: Discussionmentioning

confidence: 99%

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The Treponema denticola FhbB Protein Is a Dominant Early Antigen That Elicits FhbB Variant-Specific Antibodies That Block Factor H Binding and Cleavage by Dentilisin

et al. 2016

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The Treponema denticola FhbB protein contributes to immune evasion by binding factor H (FH). Cleavage of FH by the T. denticola protease, dentilisin, may contribute to the local immune dysregulation that is characteristic of periodontal disease (PD). Although three FhbB phyletic types have been defined (FhbB1, FhbB2, and FhbB3), the in vivo expression patterns and antigenic heterogeneity of FhbB have not been assessed. Here, we demonstrate that FhbB is a dominant early antigen that elicits FhbB type-specific antibody (Ab) responses. Using the murine skin abscess model, we demonstrate that the presence or absence of FhbB or dentilisin significantly influences Ab responses to infection and skin abscess formation. Competitive binding analyses revealed that ␣-FhbB Ab can compete with FH for binding to T. denticola and block dentilisin-mediated FH cleavage. Lastly, we demonstrate that dentilisin cleavage sites reside within critical functional domains of FH, including the complement regulatory domain formed by CCPs 1 to 4. Analysis of the FH cleavage products revealed that they lack cofactor activity. The data presented here provide insight into the in vivo significance of dentilisin, FhbB and its antigenic diversity, and the potential impact of FH cleavage on the regulation of complement activation. P eriodontal disease (PD) of infectious etiology is a significant human and veterinary health concern. PD is a chronic inflammatory disease that degrades tissue and reabsorbs bone that surrounds and supports teeth, leading to endentulism (1). PD results from a dysbiosis of the polymicrobial community of the subgingival crevice. The transition of the bacterial population from predominantly Gram-positive organisms to destructive anaerobic spirochetes and Gram-negative organisms (2-4) is accompanied by local dysregulation of immunoregulatory mechanisms (5-8). Specific periopathogens, including Treponema denticola and Porphyromonas gingivalis, are thought to play leading roles in this process (8)(9)(10). This study is focused on T. denticola, an anaerobic, proteolytic (tissue degrading) spirochete of humans that is a dominant periopathogen and member of the "red microbial complex" (4, 11). T. denticola and other oral treponemes are also key players in root canal and endodontic infections (12, 13).Periopathogens thrive in the subgingival crevice, an anatomical niche bathed in gingival crevicular fluid (GCF). GCF is derived from serum and local tissue exudate (14) and is rich in immune effectors, including activated complement, C-reactive protein, opsonins (C3b and iC3b), anaphylatoxins, and proinflammatory cytokines (reviewed in references 1 and 15). T. denticola evades complement mediated destruction by binding factor H (FH), a negative regulator of the complement system (9, 16-18). FH, an abundant 150-kDa serum glycoprotein (ϳ300 g ml of serum Ϫ1 ) (19,20), consists of 20 imperfect repeat domains (CCPs) of 50 to 60 amino acids each that comprise different functional domains (21-25).The FH binding protein of T. denticola, Fh...

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“…Several recent reviews have summarized the contribution of factor H (FH) binding in complement evasion by spirochetal pathogens (13,14). FH is a central negative regulator of the alternative complement pathway (15).…”

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The Borrelia hermsii Factor H Binding Protein FhbA Is Not Required for Infectivity in Mice or for Resistance to Human Complement In Vitro

et al. 2014

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The primary causative agent of tick-borne relapsing fever in North America is Borrelia hermsii. It has been hypothesized that B. hermsii evades complement-mediated destruction by binding factor H (FH), a host-derived negative regulator of complement. In vitro, B. hermsii produces a single FH binding protein designated FhbA (FH binding protein A). The properties and ligand binding activity of FhbA suggest that it plays multiple roles in pathogenesis. It binds plasminogen and has been identified as a significant target of a B1b B cell-mediated IgM response in mice. FhbA has also been explored as a potential diagnostic antigen for B. hermsii infection in humans. The ability to test the hypothesis that FhbA is a critical virulence factor in vivo has been hampered by the lack of well-developed systems for the genetic manipulation of the relapsing fever spirochetes. In this report, we have successfully generated a B. hermsii fhbA deletion mutant (the B. hermsii YOR⌬fhbA strain) through allelic exchange mutagenesis. Deletion of fhbA abolished FH binding by the YOR⌬fhbA strain and eliminated cleavage of C3b on the cell surface. However, the YOR⌬fhbA strain remained infectious in mice and retained resistance to killing in vitro by human complement. Collectively, these results indicate that B. hermsii employs an FhbA/FH-independent mechanism of complement evasion that allows for resistance to killing by human complement and persistence in mice.

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Treponema denticola: FhbB, Dentilisin, Complement Evasion and the Paradox of Factor H Cleavage

Cited by 13 publications

References 83 publications

Antimicrobial activity of amixicile against Treponema denticola and other oral spirochetes associated with periodontal disease

Antimicrobial activity of amixicile against Treponema denticola and other oral spirochetes associated with periodontal disease

The Treponema denticola FhbB Protein Is a Dominant Early Antigen That Elicits FhbB Variant-Specific Antibodies That Block Factor H Binding and Cleavage by Dentilisin

The Borrelia hermsii Factor H Binding Protein FhbA Is Not Required for Infectivity in Mice or for Resistance to Human Complement In Vitro

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