Borrelia burgdorferi Complement Regulator-Acquiring Surface Protein 2 Does Not Contribute to Complement Resistance or Host Infectivity

Coleman, Adam S.; Yang, Xiuli; Kumar, Manish; Zhang, Xinyue; Promnares, Kamoltip; Shroder, Deborah Y.; Kenedy, Melisha R.; Anderson, John F.; Akins, Darrin R.; Pal, Utpal

doi:10.1371/journal.pone.0003010

Cited by 60 publications

(100 citation statements)

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“…The protective role of OspA appears to be enhanced by lipidation (for a review, see reference 10). Although CspZ likely contributes to pathogenesis, it does not appear to be absolutely essential for infectivity and virulence (9). In spite of the potential and theoretical promise of vaccines based on FH binding proteins, this study, coupled with earlier analyses, does not elicit optimism regarding the utility of recombinant Borrelia FH binding proteins in development of a vaccine and/or diagnostic assay.…”

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

confidence: 75%

“…In panels B and C, the triangles and circles show the results for individual vaccinated and control mice, respectively, and the bars indicate the averages. determinant of dissemination (9). Lastly, it is important to note that Kraiczy et al also recently determined several cspZ gene sequences for B. burgdorferi isolates (26).…”

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

confidence: 98%

“…Specific CspZ phyletic types were found to correlate with other markers of dissemination. However, an earlier study suggested that CspZ is not essential for infection and dissemination in mice (9). Since B. burgdorferi encodes several proteins with FH binding ability, it is not surprising that the absence or loss of any one protein in this functional class does not result in an avirulent phenotype.…”

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

confidence: 99%

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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: 75%

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

confidence: 98%

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

confidence: 99%

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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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“…Many of the lipoprotein genes are members of these paralogous families. The loss of one of these lipoproteins of B. burgdorferi can be compensated for by the presence of other paralogous genes in the same family (11,38 …”

Section: Discussionmentioning

confidence: 99%

Characterization of the Highly Regulated Antigen BBA05 in the Enzootic Cycle of Borrelia burgdorferi

Xu¹,

He²,

Pang

et al. 2010

Infect Immun

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Dramatic alteration of surface lipoprotein profiles is a key strategy that Borrelia burgdorferi, the Lyme disease pathogen, has evolved for adapting to the diverse environments of arthropod and mammalian hosts. Several of these differentially expressed lipoproteins have been shown to play important roles in the enzootic cycle of B. burgdorferi. The BBA05 protein is a previously identified putative lipoprotein (P55 or S1 antigen) that elicits antibody responses in mammals. Recent microarray analyses indicate that the BBA05 gene is differentially expressed by many environmental factors, including temperature. However, the role of the BBA05 protein in the life cycle of B. burgdorferi has not been elucidated. Here we show that expression of the BBA05 gene was exclusively induced in feeding nymphal ticks during the spirochetal transmission from ticks to mammals. Upon generating a BBA05 mutant in an infectious strain of B. burgdorferi, we showed that the BBA05 mutant remained capable of establishing infection in mice, being acquired by ticks, persisting through tick molting, and reinfecting new mammalian hosts. These results indicate that, despite being a highly conserved and regulated antigen, the BBA05 protein has a nonessential role in the transmission cycle of B. burgdorferi, at least in the animal model.Borrelia burgdorferi, the causative agent of Lyme disease, has an astonishing number of lipoprotein genes (ϳ150) in its genome (over 10% of the total genome) (9, 21); many of these lipoprotein genes are differentially expressed during the enzootic cycle of B. burgdorferi in the two diverse hosts, an arthropod tick (e.g., Ixodes scapularis) vector and a mammalian host (e.g., white-footed mice) (46,50,54,59). A body of evidences indicates that these differentially regulated lipoproteins are important for B. burgdorferi's maintenance in its natural cycle. For example, OspA, an outer surface lipoprotein that is expressed chiefly in unfed ticks, functions as an adhesin essential for spirochetal survival in the tick vector (12,41,42,47,56,70). The outer surface lipoprotein OspC, on the other hand, is induced when ticks feed, concomitant with the downregulation of OspA (17,24,55,56). OspC is not required for B. burgdorferi replication in the tick vector but is essential for spirochetes to establish infection in the mammalian host (26,51,62,63). Although controversial, it has been proposed that OspC may also contribute to spirochetal transmission from ticks to mice (16,26,48,51,63). In addition to OspA and OspC, several other lipoproteins, such as DbpB/A, BBK32, BB0365, and BBA64, were also shown to play a role in spirochetal colonization either in the tick vector or in the mammalian host (2,18,37,45,57,58,71). Thus, studying the functions and regulation of B. burgdorferi lipoproteins is significant to our understanding of how B. burgdorferi adapts to diverse hosts in its natural cycle.In the past few years, we and others identified a regulatory pathway, the Rrp2-RpoN-RpoS pathway (also called the 54 -S sigma factor casca...

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“…CspA inhibits complement deposition and enhances serum resistance of B. burgdorferi in vitro (8,24). Conversely, CspZ is not surface exposed and is not required for serum resistance or experimental murine infection (12). While Hellwage et al previously reported that a recombinant form of OspE from B. burgdorferi strain N40 can bind FH, the importance of OspE expression on the surface of the organism in relation to serum resistance has yet to be defined (21).…”

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confidence: 99%

The OspE-Related Proteins Inhibit Complement Deposition and Enhance Serum Resistance of Borrelia burgdorferi , the Lyme Disease Spirochete

Kenedy

Akins

2011

Infect Immun

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Borrelia burgdorferi, the Lyme disease spirochete, binds the host complement inhibitors factor H (FH) and FH-like protein 1 (FHL-1). Binding of FH/FHL-1 by the B. burgdorferi proteins CspA and the OspE-related proteins is thought to enhance resistance to serum-mediated killing. While previous reports have shown that CspA confers serum resistance in B. burgdorferi, it is unclear whether the OspE-related proteins are relevant in B. burgdorferi serum resistance when OspE is expressed on the borrelial surface. To assess the role of the OspE-related proteins, we overexpressed them in a serum-sensitive CspA mutant strain. OspE overexpression enhanced serum resistance of the CspA-deficient organisms. Furthermore, FH was more efficiently bound to the B. burgdorferi surface when OspE was overexpressed. Deposition of complement components C3 and C5b-9 (the membrane attack complex), however, was reduced on the surface of the OspE-overexpressing strain compared to that on the CspA mutant strain. These data demonstrate that OspE proteins expressed on the surface of B. burgdorferi bind FH and protect the organism from complement deposition and subsequent serum-mediated destruction.

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Borrelia burgdorferi Complement Regulator-Acquiring Surface Protein 2 Does Not Contribute to Complement Resistance or Host Infectivity

Cited by 60 publications

References 59 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

Characterization of the Highly Regulated Antigen BBA05 in the Enzootic Cycle of Borrelia burgdorferi

The OspE-Related Proteins Inhibit Complement Deposition and Enhance Serum Resistance of Borrelia burgdorferi , the Lyme Disease Spirochete

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