Identification of an Antiparallel Coiled-Coil/Loop Domain Required for Ligand Binding by the<i>Borrelia hermsii</i>FhbA Protein: Additional Evidence for the Role of FhbA in the Host-Pathogen Interaction

Hovis, Kelley M.; Freedman, John C.; Zhang, Hongming; Forbes, Jonathan L.; Marconi, Richard T.

doi:10.1128/iai.01266-07

Cited by 27 publications

(25 citation statements)

References 63 publications

(87 reference statements)

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“…Based on this finding and the data described above, we postulate that an antiparallel hydrophobic interaction between CspZ alpha helices 1 and 2 may present a loop domain that serves as one of the critical interaction sites for FH. Similarly, FH binding loop domains dependent on coiled-coil interactions for their formation have been demonstrated in the Borrelia hermsii FH binding protein FhbA (17).…”

Section: Vol 77 2009 Analysis Of the Cspz Protein Of B Burgdorferimentioning

confidence: 99%

Comparative Analysis of the Properties and Ligand Binding Characteristics of CspZ, a Factor H Binding Protein, Derived fromBorrelia burgdorferiIsolates of Human Origin

et al. 2009

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Borrelia burgdorferi CspZ (BBH06/BbCRASP-2) binds the complement regulatory protein factor H (FH) and additional unidentified serum proteins. The goals of this study were to assess the ligand binding capability of CspZ orthologs derived from an extensive panel of human Lyme disease isolates and to further define the molecular basis of the interaction between FH and CspZ. While most B. burgdorferi CspZ orthologs analyzed bound FH, specific, naturally occurring polymorphisms, most of which clustered in a specific loop domain of CspZ, prevented FH binding in some orthologs. Sequence analyses also revealed the existence of CspZ phyletic groups that correlate with FH binding and with the relationships inferred from ribosomal spacer types (RSTs). CspZ type 1 (RST1) and type 3 (RST3) strains bind FH, while CspZ type 2 (RST2) strains do not. Antibody responses to CspZ were also assessed. Anti-CspZ antibodies were detected in mice by week 2 of infection, indicating that there was expression during early-stage infection. Analyses of sera collected from infected mice suggested that CspZ production continued over the course of long-term infection as the antibody titer increased over time. While antibody to CspZ was detected in several human Lyme disease serum samples, the response was not universal, and the titers were generally low. Vaccination studies with mice demonstrated that while CspZ is immunogenic, it does not elicit an antibody that is protective or that inhibits dissemination. The data presented here provide significant new insight into the interaction between CspZ and FH and suggest that there is a correlation between CspZ production and dissemination. However, in spite of its possible contributory role in pathogenesis, the immunological analyses indicated that CspZ is likely to have limited potential as a diagnostic marker and vaccine candidate for Lyme disease.

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Section: Vol 77 2009 Analysis Of the Cspz Protein Of B Burgdorferimentioning

confidence: 99%

Comparative Analysis of the Properties and Ligand Binding Characteristics of CspZ, a Factor H Binding Protein, Derived fromBorrelia burgdorferiIsolates of Human Origin

et al. 2009

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“…FhbB shows little or no homology with other FH binding proteins but harbors a centrally located coiled-coil element which has been identified in several spirochetes as an important determinant of FH binding (29,43,44,47,63). The molecular basis of the interactions between complement regulators and pathogen-produced binding proteins has been an area of intensive investigation in terms of both pathogenesis and vaccine development (69,76).…”

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Analysis of a Unique Interaction between the Complement Regulatory Protein Factor H and the Periodontal PathogenTreponema denticola

McDowell¹,

Huang²,

Fenno

et al. 2009

Infect Immun

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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 ϳ50 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.Adult periodontitis, the most common infection of middleaged adults, affects approximately 116 million adults in the United States (3). Periodontal disease is a multifactorial process involving alterations of the overall composition of the oral flora coupled with host-determined susceptibility factors (73). The process is initiated by the formation and spread of polymicrobial biofilms that ultimately progress to plaque formation. The human oral cavity may contain up to 700 bacterial species (58), with the subgingival plaque estimated to consist of up to 415 species (57). Treponema denticola is one of the dominant spirochete species at the leading edge of plaque, and a clear correlation has been demonstrated between its abundance and the occurrence and severity of periodontal disease (reviewed in reference 15).We previously reported that T. denticola binds at least one member of the factor H (FH) protein family (43). In humans, the FH protein family consists of FH, FH-like protein 1 (FHL-1), and five FH-related proteins designated FHR1 through FHR5 (35). FH and FHL-1 serve as cofactors in the factor I-mediated cleavage of C3b, a key opsonin, and accelerate the decay of the C3 convertase complex, leading to downregulation of C3b production (56,66,67,74). Evasion of complement by oral bacteria such as T. denticola is essential as complement proteins are present in gingival fluid at levels as high as 85% of that reported for serum (68). In addition, there is evidence that complement is more active in saliva than in serum (8, 9). The binding to cell-anchored FH family proteins by some microbial pathogens has also been demonstrated to be an important adherence-and-invasion mechanism (5, 23, 55).The interacti...

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“…B. hermsii strain YOR is a well-characterized genomic group II isolate (9,18,26). B. hermsii YOR and all derivative strains were cultivated in Barbour-Stoenner-Kelly (BSK)-H complete medium supplemented with 12% rabbit serum (37°C; 5% CO 2 ) in sealed bottles.…”

Section: Methodsmentioning

confidence: 99%

“…Phylogenetic analyses of FhbA have revealed the existence of two distinct FhbA variants (FhbA1 and FhbA2), both of which bind FH (24,25). The molecular basis of the FhbA-FH interaction has been investigated using truncation analyses and site-directed mutagenesis (19,24,26). In light of the universal distribution of fhbA among low-passage-number B. hermsii isolates, its expression during infection in humans (23), and its ability to bind serum and complement regulatory proteins, we and others have hypothesized that FhbA is an important virulence factor that plays an essential role in B. hermsii's ability to survive and thrive in blood (18,19,25,27).…”

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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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Identification of an Antiparallel Coiled-Coil/Loop Domain Required for Ligand Binding by theBorrelia hermsiiFhbA Protein: Additional Evidence for the Role of FhbA in the Host-Pathogen Interaction

Cited by 27 publications

References 63 publications

Comparative Analysis of the Properties and Ligand Binding Characteristics of CspZ, a Factor H Binding Protein, Derived fromBorrelia burgdorferiIsolates of Human Origin

Comparative Analysis of the Properties and Ligand Binding Characteristics of CspZ, a Factor H Binding Protein, Derived fromBorrelia burgdorferiIsolates of Human Origin

Analysis of a Unique Interaction between the Complement Regulatory Protein Factor H and the Periodontal PathogenTreponema denticola

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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