FtlA and FtlB Are Candidates for Inclusion in a Next-Generation Multiantigen Subunit Vaccine for Lyme Disease

Camire, Andrew C.; O’Bier, Nathaniel S.; Patel, Dhara T; Cramer, Nicholas A.; Straubinger, Reinhard K.; Breitschwerdt, Edward B.; Funk, Rebecca A.; Marconi, Richard T.

doi:10.1128/iai.00364-22

Cited by 3 publications

(3 citation statements)

References 44 publications

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“…However, after covalent modification by a fatty acid at its N-terminal Cys residue, the protein can be targeted into the periplasmic side of the cytoplasmic membrane, the periplasmic side of the outer membrane, or the external side of the outer membrane [ 12 ]. To clarify the exact location of the PFam12 proteins, prior experimental evidence indicated that FtlE is most likely a periplasmic inner membrane-attached protein, while FtlA, FtlB and FtlCare surface-exposed lipoproteins [ 23 , 24 , 27 ]. Since the lipoprotein signal sequence region in spirochetes may exhibit comparatively high variability, the PFam12 member FtlD was not included in any of the previous studies for lipoprotein localization [ 12 ].…”

Section: Resultsmentioning

confidence: 99%

“…In the current study we focused on the paralogous gene family 12 (PFam12), which contains five members (BB0844, BBG01, BBH37, BBJ08, and BBK01) that do not demonstrate meaningful sequence identity with proteins from any other organism which would allow us to judge the functions of these proteins. It is known that PFam12 members are surface-exposed and highly immunogenic lipoproteins that are upregulated as the tick starts the blood meal [ 8 , 13 , 14 , 23 – 27 ]. In a recent article studying the antigenicity and immunogenicity of PFam12 members, it was suggested to rename the proteins as f amily t welve l ipoproteins (Ftl) FtlA (BBK01), FtlB (BBG01), FtlC (BBH37), and FtlD (BBJ08) [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

“…It is known that PFam12 members are surface-exposed and highly immunogenic lipoproteins that are upregulated as the tick starts the blood meal [ 8 , 13 , 14 , 23 – 27 ]. In a recent article studying the antigenicity and immunogenicity of PFam12 members, it was suggested to rename the proteins as f amily t welve l ipoproteins (Ftl) FtlA (BBK01), FtlB (BBG01), FtlC (BBH37), and FtlD (BBJ08) [ 27 ].…”

Section: Introductionmentioning

confidence: 99%

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Members of the paralogous gene family 12 from the Lyme disease agent Borrelia burgdorferi are non-specific DNA-binding proteins

Brangulis,

Akopjana,

Drunka

et al. 2024

PLoS ONE

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Lyme disease is the most prevalent vector-borne infectious disease in Europe and the USA. Borrelia burgdorferi, as the causative agent of Lyme disease, is transmitted to the mammalian host during the tick blood meal. To adapt to the different encountered environments, Borrelia has adjusted the expression pattern of various, mostly outer surface proteins. The function of most B. burgdorferi outer surface proteins remains unknown. We determined the crystal structure of a previously uncharacterized B. burgdorferi outer surface protein BBK01, known to belong to the paralogous gene family 12 (PFam12) as one of its five members. PFam12 members are shown to be upregulated as the tick starts its blood meal. Structural analysis of BBK01 revealed similarity to the coiled coil domain of structural maintenance of chromosomes (SMC) protein family members, while functional studies indicated that all PFam12 members are non-specific DNA-binding proteins. The residues involved in DNA binding were identified and probed by site-directed mutagenesis. The combination of SMC-like proteins being attached to the outer membrane and exposed to the environment or located in the periplasm, as observed in the case of PFam12 members, and displaying the ability to bind DNA, represents a unique feature previously not observed in bacteria.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Members of the paralogous gene family 12 from the Lyme disease agent Borrelia burgdorferi are non-specific DNA-binding proteins

Brangulis,

Akopjana,

Drunka

et al. 2024

PLoS ONE

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Borreliella burgdorferi factor H-binding proteins are not required for serum resistance and infection in mammals

Cramer,

Socarras,

Earl

et al. 2024

Infect Immun

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The causative agent of Lyme disease (LD), Borreliella burgdorferi , binds factor H (FH) and other complement regulatory proteins to its surface. B. burgdorferi B31 (type strain) encodes five FH-binding proteins (FHBPs): CspZ, CspA, and the OspE paralogs OspE BBN38 , OspE BBL39 , and OspE BBP38 . This study assessed potential correlations between the production of individual FHBPs, FH-binding ability, and serum resistance using a panel of infectious B. burgdorferi clonal populations recovered from dogs. FHBP production was assessed in cultivated spirochetes and by antibody responses in naturally infected humans, dogs, and eastern coyotes (wild canids). FH binding specificity and sensitivity to dog and human serum were also assessed and compared. No correlation was observed between the production of individual FHBPs and FH binding with serum resistance, and CspA was determined to not be produced in animals. Notably, one or more clones isolated from dogs lacked CspZ or the OspE proteins (a finding confirmed by genome sequence determination) and did not bind FH derived from canines. The data presented do not support a correlation between FH binding and the production of individual FHBPs with serum resistance and infectivity. In addition, the limited number and polymorphic nature of cp32s in B. burgdorferi clone DRI85A that were identified through genome sequencing suggest no strict requirement for a defined set of these replicons for infectivity. This study reveals that the immune evasion mechanisms employed by B. burgdorferi are diverse, complex, and yet to be fully defined.

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Development of novel multi-protein chimeric immunogens that protect against infection with the Lyme disease agent, Borreliella burgdorferi

O’Bier,

Camire,

Patel

et al. 2024

mBio

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Lyme disease is the most common tick-borne disease in North America. A vaccine for use in humans is not available. Here, we detail the development of two chimeric vaccine antigens, BAF and Chv2M. BAF elicits Abs that target proteins and protein variants produced by Borreliella species in ticks (OspB and OspA) and mammals (FtlA/B). OspB serves as the backbone structure for the BAF chimeric. Two OspA 221-240 epitope-containing domain (ECD) variants (#A1 and #A15) were inserted into a loop in OspB. The N-terminal region of the FtlA protein was joined to the C-terminus of the chimeric. The second chimeric, Chv2M, consists of L5 (loop 5) and H5 (helix 5) ECDs derived from diverse OspC proteins. Borreliella species produce OspC upon exposure to the bloodmeal and during early infection in mammals. Here, we demonstrate that BAF and Chv2M are potent immunogens that elicit Abs that bind to each component protein (FtlA, FtlB, OspB, and multiple OspA and OspC variants). Anti-BAF and anti-Chv2M Abs kill Borreliella burgdorferi strains through Ab-mediated complement-dependent and complement-independent mechanisms. Eighty percent (32/40) of mice that received a three-dose vaccine regimen were protected from infection with B. burgdorferi B31. Efficacy increased to 90% (18/20) when the amount of Chv2M was increased in the third vaccine dose. Readouts for infection were flaB PCR and seroconversion to VlsE. This study establishes proof of principle for a chimeric immunogen vaccine formulation that elicits Abs to multiple targets on the B. burgdorferi cell surface produced during tick and mammalian stages of the enzootic cycle. IMPORTANCE Lyme disease is a growing public health threat across parts of the Northern Hemisphere. Regions that can support sustained tick populations are expanding, and the incidence of tick-borne diseases is increasing. In light of the increasing risk of Lyme disease, effective preventive strategies are needed. Most vaccine development efforts have focused on outer surface protein A, a Borreliella burgdorferi protein produced only in ticks. Herein, we describe the development of a novel vaccine formulation consisting of two multivalent chimeric proteins that are immunogenic and elicit antibodies with bactericidal activity that target several cell surface proteins produced by the Lyme disease spirochetes in feeding ticks and mammals. In a broader sense, this study advances efforts to develop custom-designed vaccinogens comprised of epitope-containing domains from multiple proteins.

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FtlA and FtlB Are Candidates for Inclusion in a Next-Generation Multiantigen Subunit Vaccine for Lyme Disease

Cited by 3 publications

References 44 publications

Members of the paralogous gene family 12 from the Lyme disease agent Borrelia burgdorferi are non-specific DNA-binding proteins

Members of the paralogous gene family 12 from the Lyme disease agent Borrelia burgdorferi are non-specific DNA-binding proteins

Borreliella burgdorferi factor H-binding proteins are not required for serum resistance and infection in mammals

Development of novel multi-protein chimeric immunogens that protect against infection with the Lyme disease agent, Borreliella burgdorferi

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