Binding of Human Factor H–Related Protein 1 to Serum‐Resistant<i>Borrelia burgdorferi</i>Is Mediated by Borrelial Complement Regulator–Acquiring Surface Proteins

Haupt, Katrin; Kraiczy, Peter; Wallich, Reinhard; Brade, Volker; Skerka, Christine; Zipfel, Peter F.

doi:10.1086/518509

Cited by 89 publications

(58 citation statements)

References 37 publications

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“…The possibility that innate immunity can prevent homologous, but not heterologous, B. burgdorferi infection is surprising considering that the innate system is not thought to be able to differentiate between variations that exist among heterologous bacterial strains. However, as an example, various B. burgdorferi strains may simply differ in their ability to bind host complement negative regulators (e.g., factor H and factor H-like proteins) (66)(67)(68) and/or express their own functional complement inhibitors (e.g., CspA) (69). Thus, a disparate ability of a B. burgdorferi strain to inhibit overall activation of the innate system may ultimately predetermine the partial success of host superinfection.…”

Section: Discussionmentioning

confidence: 99%

Bacterial Heterogeneity Is a Requirement for Host Superinfection by the Lyme Disease Spirochete

Rogovskyy

Bankhead

2014

Infect Immun

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In nature, mixed Borrelia burgdorferi infections are common and possibly can be acquired by either superinfection or coinfection. Superinfection by heterologous B. burgdorferi strains has been established experimentally, although the ability of homologous B. burgdorferi clones to superinfect a host has not been studied in detail. Information regarding any potential immune barriers to secondary infection also currently is unavailable. In the present study, the ability to superinfect various mouse models by homologous wild-type clones was examined and compared to superinfection by heterologous strains. To assess the ability of homologous B. burgdorferi clones to successfully superinfect a mouse host, primary-and secondary-infecting spirochetes were recovered via in vitro cultivation of collected blood or tissue samples. This was accomplished by generating two different antibiotic-resistant versions of the wild-type B31-A3 clone in order to distinguish superinfecting B. burgdorferi from primary-infecting spirochetes. The data demonstrate an inability of homologous B. burgdorferi to superinfect immunocompetent mice as opposed to heterologous strains. Attempts to superinfect different types of immunodeficient mice with homologous B. burgdorferi indicate that the murine innate immune system represents a major barrier to intrastrain superinfection. Consequently, the possibility of innate immunity as a driving force for B. burgdorferi heterogeneity during the enzootic cycle is discussed.

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Section: Discussionmentioning

confidence: 99%

Bacterial Heterogeneity Is a Requirement for Host Superinfection by the Lyme Disease Spirochete

Rogovskyy

Bankhead

2014

Infect Immun

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“…In most cases, FHR-1 binding to microbes and microbial proteins that otherwise bind FH (and in some cases also FHL-1) was demonstrated, such as for several borrelial proteins (48, 69, 70), Leptospira interrogans (71), S. aureus (33), Pseudomonas aeruginosa (72), N. gonorrhoeae (60), Plasmodium falciparum (73), C. albicans (61), and Aspergillus fumigatus (74). So far, in most reports, no functional role for FHR-1 when associated/bound to microbes was demonstrated; in most cases, it was merely assumed that FHR-1 inhibits complement terminal pathway based on the report of Heinen et al (15).…”

Section: Fhrs Binding To Microbesmentioning

confidence: 99%

Factor H Family Proteins in Complement Evasion of Microorganisms

Józsi

2017

Front. Immunol.

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Human-pathogenic microbes possess various means to avoid destruction by our immune system. These include interactions with the host complement system that may facilitate pathogen entry into cells and tissues, expression of molecules that defuse the effector complement components and complexes, and acquisition of host complement inhibitors to downregulate complement activity on the surface of the pathogen. A growing number of pathogenic microorganisms have acquired the ability to bind the complement inhibitor factor H (FH) from body fluids and thus hijack its host protecting function. In addition to FH, binding of FH-related (FHR) proteins was also demonstrated for several microbes. Initial studies assumed that these proteins are complement inhibitors similar to FH. However, recent evidence suggests that FHR proteins may rather enhance complement activation both directly and also by competing with the inhibitor FH for binding to certain ligands and surfaces. This mini review focuses on the role of the main alternative pathway regulator FH in host–pathogen interactions, as well as on the emerging role of the FHR proteins as enhancers of complement activation.

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“…In all probability, the inhibitory capacity of CbiA in the former assay might be overwhelmed by the efficient complement activation through the AP and the resulting amplification loop. Moreover, it is tempting to speculate that binding of other, as yet unidentified serum-derived proteins may counteract binding of CbiA, BpcA and HcpA to FH as shown for the FH/FHR-1 interaction of ErpA, ErpC, and ErpP, in which FH was displaced under physiological conditions by FHR-1 49–51 . More recently, a similar scenario has been reported for BGA71 of B. bavariensis 29 and the complement inhibitors Efb-C and Ecb of Staphylococcus aureus 52 that failed to inhibit complement upon activation of the AP, but efficiently inhibited activation of the terminal sequence (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Complement proteins were either purchased from Complement Technology (Tyler, TX) or their generation has been previously described 51, 56, 57 . Polyclonal antibodies for the detection of complement components were obtained from Complement Technology, Merck (Darmstadt, Germany) or Quidel (San Diego, CA).…”

Section: Methodsmentioning

confidence: 99%

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Immune evasion of Borrelia miyamotoi: CbiA, a novel outer surface protein exhibiting complement binding and inactivating properties

Röttgerding

Wagemakers

Koetsveld

et al. 2017

Sci Rep

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Borrelia (B.) miyamotoi, an emerging tick-borne relapsing fever spirochete, resists complement-mediated killing. To decipher the molecular principles of immune evasion, we sought to identify determinants contributing to complement resistance. Employing bioinformatics, we identified a gene encoding for a putative Factor H-binding protein, termed CbiA (complement binding and inhibitory protein A). Functional analyses revealed that CbiA interacted with complement regulator Factor H (FH), C3, C3b, C4b, C5, and C9. Upon binding to CbiA, FH retained its cofactor activity for Factor I-mediated inactivation of C3b. The Factor H-binding site within CbiA was mapped to domain 20 whereby the C-terminus of CbiA was involved in FH binding. Additionally, CbiA directly inhibited the activation of the classical pathway and the assembly of the terminal complement complex. Of importance, CbiA displayed inhibitory activity when ectopically produced in serum-sensitive B. garinii G1, rendering this surrogate strain resistant to human serum. In addition, long-term in vitro cultivation lead to an incremental loss of the cbiA gene accompanied by an increase in serum susceptibility. In conclusion, our data revealed a dual strategy of B. miyamotoi to efficiently evade complement via CbiA, which possesses complement binding and inhibitory activities.

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Binding of Human Factor H–Related Protein 1 to Serum‐ResistantBorrelia burgdorferiIs Mediated by Borrelial Complement Regulator–Acquiring Surface Proteins

Cited by 89 publications

References 37 publications

Bacterial Heterogeneity Is a Requirement for Host Superinfection by the Lyme Disease Spirochete

Bacterial Heterogeneity Is a Requirement for Host Superinfection by the Lyme Disease Spirochete

Factor H Family Proteins in Complement Evasion of Microorganisms

Immune evasion of Borrelia miyamotoi: CbiA, a novel outer surface protein exhibiting complement binding and inactivating properties

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