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Tick Histamine Release Factor Is Critical for Ixodes scapularis Engorgement and Transmission of the Lyme Disease Agent

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      Abstract

      Ticks are distributed worldwide and affect human and animal health by transmitting diverse infectious agents. Effective vaccines against most tick-borne pathogens are not currently available. In this study, we characterized a tick histamine release factor (tHRF) from Ixodes scapularis and addressed the vaccine potential of this antigen in the context of tick engorgement and B. burgdorferi transmission. Results from western blotting and quantitative Reverse Transcription-PCR showed that tHRF is secreted in tick saliva, and upregulated in Borrelia burgdorferi-infected ticks. Further, the expression of tHRF was coincident with the rapid feeding phase of the tick, suggesting a role for tHRF in tick engorgement and concomitantly, for efficient B. burgdorferi transmission. Silencing tHRF by RNA interference (RNAi) significantly impaired tick feeding and decreased B. burgdorferi burden in mice. Interfering with tHRF by actively immunizing mice with recombinant tHRF, or passively transferring tHRF antiserum, also markedly reduced the efficiency of tick feeding and B. burgdorferi burden in mice. Recombinant tHRF was able to bind to host basophils and stimulate histamine release. Therefore, we speculate that tHRF might function in vivo to modulate vascular permeability and increase blood flow to the tick bite-site, facilitating tick engorgement. These findings suggest that blocking tHRF might offer a viable strategy to complement ongoing efforts to develop vaccines to block tick feeding and transmission of tick-borne pathogens.

      Author Summary

      Ticks are distributed worldwide and affect human and animal health by transmitting diverse infectious agents. Safe and effective vaccines against most tick-borne pathogens are not currently available. Typical vaccines target microbes directly, using extracts of the organism, or recombinant antigens as the immunogen; the transmission of tick-borne pathogens can also theoretically be prevented by interfering with the ability of ticks to feed on a mammalian host. In this study, we have characterized a putative histamine release factor (tHRF) from I. scapularis ticks, the predominant vector of B. burgdorferi, the agent of Lyme disease in North America. Our results suggested that tHRF is presented in tick saliva and critical for tick feeding; blocking tHRF markedly reduced the efficiency of tick feeding, and reduced the B. burgdorferi burden in mice. This finding provides novel insights into the molecular mechanisms of tick feeding and provides a potential vaccine target to block tick feeding and pathogen transmission.

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      Most cited references 37

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      An annotated catalog of salivary gland transcripts from Ixodes scapularis ticks.

      Over 8000 expressed sequence tags from six different salivary gland cDNA libraries from the tick Ixodes scapularis were analyzed. These libraries derive from feeding nymphs infected or not with the Lyme disease agent, Borrelia burgdorferi, from unfed adults, and from adults feeding on a rabbit for 6-12 h, 18-24 h, and 3-4 days. Comparisons of the several libraries led to identification of several significantly differentially expressed transcripts. Additionally, over 500 new predicted protein sequences are described, including several novel gene families unique to ticks; no function can be presently ascribed to most of these novel families. Among the housekeeping-associated transcripts, we highlight those enzymes associated with post translation modification of amino acids, particularly those forming sulfotyrosine, hydroxyproline, and carboxyl-glutamic acid. Results support the hypothesis that gene duplication, most possibly including genome duplications, is a major player in tick evolution.
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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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          The translationally controlled tumour protein (TCTP).

          The translationally controlled tumour protein (TCTP) is a highly conserved protein that is widely expressed in all eukaryotic organisms. Based on its sequence, TCTP was listed as a separate protein family in protein databases but the recent elucidation of the solution structure of the fission yeast orthologue places it close to a family of small chaperone proteins. The molecular functions determined so far, Ca(2+)- and microtubule-binding, have been mapped to an alpha-helical region of the molecule. TCTP expression is highly regulated both at the transcriptional and translational level and by a wide range of extracellular signals. TCTP has been implicated in important cellular processes, such as cell growth, cell cycle progression, malignant transformation and in the protection of cells against various stress conditions and apoptosis. In addition, an extracellular, cytokine-like function has been established for TCTP, and the protein has been implicated in various medically relevant processes.
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            Author and article information

            Affiliations
            [1 ]Section of Infectious Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
            [2 ]Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America
            Medical College of Wisconsin, United States of America
            Author notes

            Conceived and designed the experiments: JD SN EF. Performed the experiments: JD SN. Analyzed the data: JD SN LZ LL PW. Contributed reagents/materials/analysis tools: LZ LL PW. Wrote the paper: JD SN EF.

            Contributors
            Role: Editor
            Journal
            PLoS Pathog
            plos
            plospath
            PLoS Pathogens
            Public Library of Science (San Francisco, USA )
            1553-7366
            1553-7374
            November 2010
            November 2010
            24 November 2010
            : 6
            : 11
            2991271
            21124826
            10-PLPA-RA-3741R3
            10.1371/journal.ppat.1001205
            (Editor)
            Dai 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.
            Counts
            Pages: 10
            Categories
            Research Article
            Immunology/Immunity to Infections
            Infectious Diseases/Bacterial Infections
            Microbiology/Cellular Microbiology and Pathogenesis
            Microbiology/Immunity to Infections
            ScienceOpen disciplines:

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