Factor H Binding to PspC of<i>Streptococcus pneumoniae</i>Increases Adherence to Human Cell Lines In Vitro and Enhances Invasion of Mouse Lungs In Vivo

Quin, Lisa R.; Onwubiko, Chinwendu; Moore, Quincy C.; Mills, Megumi Fujioka; McDaniel, Larry S.; Carmicle, Stephanie

doi:10.1128/iai.00474-07

Cited by 43 publications

(42 citation statements)

References 45 publications

(76 reference statements)

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“…As one example, a clear correlation of FH binding, complement sensitivity, and persistence has been established for the relapsing-fever spirochetes (29,49,65). Regarding a role in adherence, it has been demonstrated for the pneumococci that the binding of FHL-1 is important in the interaction with epithelial and endothelial cells (23,60). We previously demonstrated that T. denticola produces a unique 11.4-kDa protein designated FhbB that binds one or more members of the FH protein family (43,44).…”

Section: Discussionmentioning

confidence: 98%

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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Section: Discussionmentioning

confidence: 98%

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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“…PspC promotes pneumococcal adherence and invasion of epithelial cells by binding to the pIgR, but also the interaction with FH was shown recently to mediate pneumococcal adherence to epithelial cells in vitro and to enhance invasion of mouse lungs in vivo (66,67). C4BP binding was shown to enhance the adhesion of the yeast Candida albicans to host endothelial cells (68).…”

Section: Discussionmentioning

confidence: 99%

Clinical Isolates of Streptococcus pneumoniae Bind the Complement Inhibitor C4b-Binding Protein in a PspC Allele-Dependent Fashion

Dieudonne‐Vatran¹,

Krentz²,

Blom

et al. 2009

The Journal of Immunology

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The complement system constitutes an important component of the innate immune system. To colonize their host and/or to cause disease, many pathogens have evolved strategies to avoid complement-mediated bacterial lysis and opsonophagocytosis. In this study, using a collection of 55 clinical isolates of Streptococcus pneumoniae, we demonstrate for the first time that pneumococci bind the complement inhibitor C4b-binding protein (C4BP). C4BP binding seems to be restricted to certain serotypes such as serotype 4, 6B, 7F, and 14, of which the strains of serotype 14 are the strongest binders. We show that bacteria-bound C4BP retains its functional activity and down-regulates the activation of the classical pathway. Thus, this major respiratory pathogen may escape immune recognition and eradication by the complement system. Furthermore, we show that C4BP binding varies between strains but is dependent on the expression of pneumococcal surface protein C, PspC of group 4. The study of the distribution of group 4 pspC locus shows that most of high-binder serotype 14 isolates harbor an allelic variant of group 4 pspC. Using PspC-negative mutant strains, we identified a new allelic variant of PspC (PspC4.4) as a major ligand for C4BP, revealing a new function for this important pneumococcal virulence factor. Thus pneumococci exploit host C4BP for complement evasion in a PspC allele-dependent manner.

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“…These regulators may limit complement activation on the fungal surface and reduce the amount of pathogenbound opsonins, thus influencing opsonophagocytosis. Less attention is paid to the possibility that the pathogen-bound complement regulators function as adhesion molecules, facilitating host-pathogen interactions (18,(20)(21)(22).…”

mentioning

confidence: 99%

Factor H and Factor H-Related Protein 1 Bind to Human Neutrophils via Complement Receptor 3, Mediate Attachment to Candida albicans, and Enhance Neutrophil Antimicrobial Activity

Losse¹,

Zipfel

Józsi³

2009

The Journal of Immunology

124

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The host complement system plays an important role in protection against infections. Several human-pathogenic microbes were shown to acquire host complement regulators, such as factor H (CFH), that downregulate complement activation at the microbial surface and protect the pathogens from the opsonic and lytic effects of complement. Because CFH can also bind to host cells, we addressed the role of CFH and CFH-related proteins as adhesion ligands in host-pathogen interactions. We show that the CFH family proteins CFH, CFH-like protein 1 (CFHL1), CFH-related protein (CFHR) 1, and CFHR4 long isoform bind to human neutrophil granulocytes and to the opportunistic human-pathogenic yeast Candida albicans. Two major binding sites, one within the N-terminus and one in the C-terminus of CFH, were found to mediate binding to neutrophils. Complement receptor 3 (CD11b/CD18; αMβ2 integrin) was identified as the major cellular receptor on neutrophils for CFH, CFHL1, and CFHR1, but not for CFHR4 long isoform. CFH and CFHR1 supported cell migration. Furthermore, CFH, CFHL1, and CFHR1 increased attachment of neutrophils to C. albicans. Adhesion of neutrophils to plasma-opsonized yeasts was reduced when CFH binding was inhibited by specific Abs or when using CFH-depleted plasma. Yeast-bound CFH and CFHR1 enhanced the generation of reactive oxygen species and the release of the antimicrobial protein lactoferrin by human neutrophils, and resulted in a more efficient killing of the pathogen. Thus, CFH and CFHR1, when bound on the surface of C. albicans, enhance antimicrobial activity of human neutrophils.

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Factor H Binding to PspC ofStreptococcus pneumoniaeIncreases Adherence to Human Cell Lines In Vitro and Enhances Invasion of Mouse Lungs In Vivo

Cited by 43 publications

References 45 publications

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

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

Clinical Isolates of Streptococcus pneumoniae Bind the Complement Inhibitor C4b-Binding Protein in a PspC Allele-Dependent Fashion

Factor H and Factor H-Related Protein 1 Bind to Human Neutrophils via Complement Receptor 3, Mediate Attachment to Candida albicans, and Enhance Neutrophil Antimicrobial Activity

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