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      Oral Immunization with OspC Does Not Prevent Tick-Borne Borrelia burgdorferi Infection

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          Abstract

          Oral vaccination strategies are of interest to prevent transmission of Lyme disease as they can be used to deliver vaccines to humans, pets, and to natural wildlife reservoir hosts of Borrelia burgdorferi. We developed a number of oral vaccines based in E. coli expressing recombinant OspC type K, OspB, BBK32 from B. burgdorferi, and Salp25, Salp15 from Ixodes scapularis. Of the five immunogenic candidates only OspC induced significant levels of antigen-specific IgG and IgA when administered to mice via the oral route. Antibodies to OspC did not prevent dissemination of B. burgdorferi as determined by the presence of spirochetes in ear, heart and bladder tissues four weeks after challenge. Next generation sequencing of genomic DNA from ticks identified multiple phyletic types of B. burgdorferi OspC (A, D, E, F, I, J, K, M, Q, T, X) in nymphs that engorged on vaccinated mice. PCR amplification of OspC types A and K from flat and engorged nymphal ticks, and from heart and bladder tissues collected after challenge confirmed sequencing analysis. Quantification of spirochete growth in a borreliacidal assay shows that both types of spirochetes (A and K) survived in the presence of OspC-K specific serum whereas the spirochetes were killed by OspA specific serum. We show that oral vaccination of C3H-HeN mice with OspC-K induced significant levels of antigen-specific IgG. However, these serologic antibodies did not protect mice from infection with B. burgdorferi expressing homologous or heterologous types of OspC after tick challenge.

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          Most cited references 44

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          Induction of an outer surface protein on Borrelia burgdorferi during tick feeding.

          Lyme disease spirochetes, Borrelia burgdorferi sensu lato, are maintained in zoonotic cycles involving ticks and small mammals. In unfed ticks, the spirochetes produce one outer surface protein, OspA, but not OspC. During infection in mammals, immunological data suggest that the spirochetes have changed their surface, now expressing OspC but little or no OspA. We find by in vitro growth experiments that this change is regulated in part by temperature; OspC is produced by spirochetes at 32-37 degrees C but not at 24 degrees C. Furthermore, spirochetes in the midgut of ticks that have fully engorged on mice now have OspC on their surface. Thus two environmental cues, an increase in temperature and tick feeding, trigger a major alteration of the spirochetal outer membrane. This rapid synthesis of OspC by spirochetes during tick feeding may play an essential role in the capacity of these bacteria to successfully infect mammalian hosts, including humans, when transmitted by ticks.
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            The Lyme disease agent exploits a tick protein to infect the mammalian host.

            The Lyme disease agent, Borrelia burgdorferi, is maintained in a tick-mouse cycle. Here we show that B. burgdorferi usurps a tick salivary protein, Salp15 (ref. 3), to facilitate the infection of mice. The level of salp15 expression was selectively enhanced by the presence of B. burgdorferi in Ixodes scapularis, first indicating that spirochaetes might use Salp15 during transmission. Salp15 was then shown to adhere to the spirochaete, both in vitro and in vivo, and specifically interacted with B. burgdorferi outer surface protein C. The binding of Salp15 protected B. burgdorferi from antibody-mediated killing in vitro and provided spirochaetes with a marked advantage when they were inoculated into naive mice or animals previously infected with B. burgdorferi. Moreover, RNA interference-mediated repression of salp15 in I. scapularis drastically reduced the capacity of tick-borne spirochaetes to infect mice. These results show the capacity of a pathogen to use a secreted arthropod protein to help it colonize the mammalian host.
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              Vaccination against Lyme disease with recombinant Borrelia burgdorferi outer-surface lipoprotein A with adjuvant. Lyme Disease Vaccine Study Group.

              The risk of acquiring Lyme disease is high in areas in which the disease is endemic, and the development of a safe and effective vaccine is therefore important. We conducted a multicenter, double-blind, randomized trial involving 10,936 subjects who lived in areas of the United States in which Lyme disease is endemic. Participants received an injection of either recombinant Borrelia burgdorferi outer-surface lipoprotein A (OspA) with adjuvant or placebo at enrollment and 1 and 12 months later. In cases of suspected Lyme disease, culture of skin lesions, polymerase-chain-reaction testing, or serologic testing was done. Serologic testing was performed 12 and 20 months after study entry to detect asymptomatic infections. In the first year, after two injections, 22 subjects in the vaccine group and 43 in the placebo group contracted definite Lyme disease (P=0.009); vaccine efficacy was 49 percent (95 percent confidence interval, 15 to 69 percent). In the second year, after the third injection, 16 vaccine recipients and 66 placebo recipients contracted definite Lyme disease (P<0.001); vaccine efficacy was 76 percent (95 percent confidence interval, 58 to 86 percent). The efficacy of the vaccine in preventing asymptomatic infection was 83 percent in the first year and 100 percent in the second year. Injection of the vaccine was associated with mild-to-moderate local or systemic reactions lasting a median of three days. Three injections of vaccine prevented most definite cases of Lyme disease or asymptomatic B. burgdorferi infection.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 March 2016
                2016
                : 11
                : 3
                Affiliations
                [1 ]Department of Microbiology, Immunology and Biochemistry, College of Medicine, University of Tennessee Health Sciences Center, Memphis, Tennessee, United States of America
                [2 ]Immuno Technologies Inc., Memphis, Tennessee, United States of America
                [3 ]Molecular Resource Center, University of Tennessee Health Sciences Center, Memphis, Tennessee, United States of America
                University of Kentucky College of Medicine, UNITED STATES
                Author notes

                Competing Interests: The authors have the following interests: Luciana Richer and Maria Gomes-Solecki are employed by Immuno Technologies, Inc. MGS holds more than 5% financial interest in Immuno Technologies, Inc. and in US Biologic, Inc. LR holds 5% financial interest in Immuno Technologies, Inc. MGS advises US Biologic on development of reservoir targeted vaccines for Lyme borreliosis. MGS holds several relevant patents (Recombinant constructs of Borrelia burgdorferi, US 7,605,248; Groups of Borrelia burgdorferi and Borrelia afzelii that cause Lyme Disease in humans, US 7,582,304; Oral vaccine for Borrelia, US 2009/0297560 A1). This did not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: RM LR MGS. Performed the experiments: RM DLJ LR. Analyzed the data: RM DLJ MGS. Wrote the paper: MGS.

                Article
                PONE-D-15-47195
                10.1371/journal.pone.0151850
                4798528
                26990760
                © 2016 Melo et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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                Figures: 7, Tables: 0, Pages: 17
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                Funding
                The authors thank the National Institutes of Health, National Institute of Allergy and Infectious Diseases for funding support (R44 AI096551) to MGS via Immuno Technologies, Inc. Immuno Technologies, Inc. provided support in the form of salaries for authors [LR, MGS], but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The specific roles of these authors are articulated in the Author Contributions section.
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                Custom metadata
                Deep-sequencing dataset files are available from the NIH Sequence Read Archive (SRA) accession Nr. SRP071080.

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