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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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          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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            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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              A critical appraisal of "chronic Lyme disease".

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                Author and article information

                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
                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.

                Article
                10-PLPA-RA-3741R3
                10.1371/journal.ppat.1001205
                2991271
                21124826
                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.
                Page count
                Pages: 10
                Categories
                Research Article
                Immunology/Immunity to Infections
                Infectious Diseases/Bacterial Infections
                Microbiology/Cellular Microbiology and Pathogenesis
                Microbiology/Immunity to Infections

                Infectious disease & Microbiology

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