Abstract
Tick saliva is a rich source of pharmacologically and immunologically active molecules. These salivary components are indispensable for successful blood feeding on vertebrate hosts and are believed to facilitate the transmission of tick-borne pathogens. Here we present the functional and structural characterization of Iripin-3, a protein expressed in the salivary glands of the tick Ixodes ricinus, a European vector of tick-borne encephalitis and Lyme disease. Belonging to the serpin superfamily of protease inhibitors, Iripin-3 strongly inhibited the proteolytic activity of serine proteases kallikrein and matriptase. In an in vitro setup, Iripin-3 was capable of modulating the adaptive immune response as evidenced by reduced survival of mouse splenocytes, impaired proliferation of CD4+ T lymphocytes, suppression of the T helper type 1 immune response, and induction of regulatory T cell differentiation. Apart from altering acquired immunity, Iripin-3 also inhibited the extrinsic blood coagulation pathway and reduced the production of pro-inflammatory cytokine interleukin-6 by lipopolysaccharide-stimulated bone marrow-derived macrophages. In addition to its functional characterization, we present the crystal structure of cleaved Iripin-3 at 1.95 Å resolution. Iripin-3 proved to be a pluripotent salivary serpin with immunomodulatory and anti-hemostatic properties that could facilitate tick feeding via the suppression of host anti-tick defenses. Physiological relevance of Iripin-3 activities observed in vitro needs to be supported by appropriate in vivo experiments.
Highlights
The European tick Ixodes ricinus (Acari: Ixodidae) is an obligate blood-sucking ectoparasite that transmits several medically important pathogens such as Lyme disease spirochetes from the Borrelia burgdorferi sensu lato complex and tick-borne encephalitis virus [1]
We presume that ticks employ some of their serpins to modulate host defenses, as evidenced by several tick serpins with anti-platelet, anti-coagulant, anti-inflammatory, and/or immunomodulatory properties that have been shown to be secreted via saliva into the host [34,35,36,37, 72]
Iripin-3 is a pluripotent salivary protein secreted by I. ricinus ticks via saliva into the feeding site, where it might suppress various aspects of host anti-tick defenses
Summary
The European tick Ixodes ricinus (Acari: Ixodidae) is an obligate blood-sucking ectoparasite that transmits several medically important pathogens such as Lyme disease spirochetes from the Borrelia burgdorferi sensu lato complex and tick-borne encephalitis virus [1]. Cutaneous tissue injury and tick antigens are sensed by cells in the vicinity of the tick attachment site, such as keratinocytes, fibroblasts endothelial cells, mast cells, macrophages and dendritic cells [3]. Ticks surpass the host response by secreting hundreds of bioactive molecules via their saliva into the wound [9,10,11] Since these salivary molecules can target hemostasis and almost every branch of the immune response, they might be useful in the development of novel pharmaceuticals for the treatment of immune-mediated inflammatory diseases, hypercoagulable states, diseases associated with excessive complement activation, or even cancer [11,12,13,14]. Tick salivary proteins represent potential targets for the development of anti-tick and/or transmission blocking vaccines [15]
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