Ticks are efficient vectors of arboviruses, although less than 10% of tick species are known to be virus vectors. Most tick-borne viruses (TBV) are RNA viruses some of which cause serious diseases in humans and animals world-wide. Several TBV impacting human or domesticated animal health have been found to emerge or re-emerge recently. In order to survive in nature, TBV must infect and replicate in both vertebrate and tick cells, representing very different physiological environments. Information on molecular mechanisms that allow TBV to switch between infecting and replicating in tick and vertebrate cells is scarce. In general, ticks succeed in completing their blood meal thanks to a plethora of biologically active molecules in their saliva that counteract and modulate different arms of the host defense responses (haemostasis, inflammation, innate and acquired immunity, and wound healing). The transmission of TBV occurs primarily during tick feeding and is a complex process, known to be promoted by tick saliva constituents. However, the underlying molecular mechanisms of TBV transmission are poorly understood. Immunomodulatory properties of tick saliva helping overcome the first line of defense to injury and early interactions at the tick-host skin interface appear to be essential in successful TBV transmission and infection of susceptible vertebrate hosts. The local host skin site of tick attachment, modulated by tick saliva, is an important focus of virus replication. Immunomodulation of the tick attachment site also promotes co-feeding transmission of viruses from infected to non-infected ticks in the absence of host viraemia (non-viraemic transmission). Future research should be aimed at identification of the key tick salivary molecules promoting virus transmission, and a molecular description of tick-host-virus interactions and of tick-mediated skin immunomodulation. Such insights will enable the rationale design of anti-tick vaccines that protect against disease caused by tick-borne viruses.

Ticks are obligatory blood-feeding ectoparasites, causing blood loss and skin damage in their hosts. In addition, ticks also transmit a number of various pathogenic microorganisms that cause serious diseases in humans and animals. Ticks evolved a wide array of salivary bioactive compounds that, upon injection into the host skin, inhibit or modulate host reactions such as hemostasis, inflammation and wound healing. Modulation of the tick attachment site in the host skin involves mainly molecules which affect physiological processes orchestrated by cytokines, chemokines and growth factors. Suppressing host defense reactions is crucial for tick survival and reproduction. Furthermore, pharmacologically active compounds in tick saliva have a promising therapeutic potential for treatment of some human diseases connected with disorders in hemostasis and immune system. These disorders are often associated to alterations in signaling pathways and dysregulation or overexpression of specific cytokines which, in turn, affect mechanisms of angiogenesis, cell motility and cytoskeletal regulation. Moreover, tick salivary molecules were found to exert cytotoxic and cytolytic effects on various tumor cells and have anti-angiogenic properties. Elucidation of the mode of action of tick bioactive molecules on the regulation of cell processes in their mammalian hosts could provide new tools for understanding the complex changes leading to immune disorders and cancer. Tick bioactive molecules may also be exploited as new pharmacological inhibitors of the signaling pathways of cytokines and thus help alleviate patient discomfort and increase patient survival. We review the current knowledge about tick salivary peptides and proteins that have been identified and functionally characterized in in vitro and/or in vivo models and their therapeutic perspective.

Tick-borne viruses (TBVs) belong to the largest biological group known as arboviruses with unique mode of transmission by blood-feeding arthropods (ticks, mosquitoes, sand flies, biting midges, etc.) to a susceptible vertebrate host. Taxonomically, it is a heterogenous group of vertebrate viruses found in several viral families. With only one exception, African swine fever virus, all TBVs have a RNA genome. To date, at least 160 tick-borne viruses are known, some of them pose a significant threat to human and animal health worldwide. Recently, a number of established TBVs has re-emerged and spread to new geographic locations due to the influence of anthropogenic activities and few available vaccines. Moreover, new emerging tick-borne diseases are constantly being reported. Major advances in molecular biotechnologies have led to discoveries of new TBVs and further genetic characterization of unclassified viruses resulting in changes in TBVs classification created by the International Committee for the Taxonomy of Viruses. Although TBVs spend over 95% of their life cycle within tick vectors and the role of ticks as vectors has been known for over 100 years, our knowledge about TBVs and molecular processes involved in the virus-tick interactions is scarce.

Herpesviruses are a large group of DNA viruses infecting mainly vertebrates. Murine gammaherpesvirus 68 (MHV68) is often used as a model in studies of the pathogenesis of clinically important human gammaherpesviruses such as Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus. This rodent virus appears to be geographically widespread; however, its natural transmission cycle is unknown. Following detection of MHV68 in field-collected ticks, including isolation of the virus from tick salivary glands and ovaries, we investigated whether MHV68 is a tick-borne virus. Uninfected Ixodes ricinus ticks were shown to acquire the virus by feeding on experimentally infected laboratory mice. The virus survived tick molting, and the molted ticks transmitted the virus to uninfected laboratory mice on which they subsequently fed. MHV68 was isolated from the tick salivary glands, consistent with transmission via tick saliva. The virus survived in ticks without loss of infectivity for at least 120 days, and subsequently was transmitted vertically from one tick generation to the next, surviving more than 500 days. Furthermore, the F1 generation (derived from F0 infected females) transmitted MHV68 to uninfected mice on which they fed, with MHV68 M3 gene transcripts detected in blood, lung, and spleen tissue of mice on which F1 nymphs and F1 adults engorged. These experimental data fulfill the transmission criteria that define an arthropod-borne virus (arbovirus), the largest biological group of viruses. Currently, African swine fever virus (ASFV) is the only DNA virus recognized as an arbovirus. Like ASFV, MHV68 showed evidence of pathogenesis in ticks. Previous studies have reported MHV68 in free-living ticks and in mammals commonly infested with I. ricinus, and neutralizing antibodies to MHV68 have been detected in large mammals (e.g., deer) including humans. Further studies are needed to determine if these reports are the result of tick-borne transmission of MHV68 in nature, and whether humans are at risk of infection.

Ticks, very successful vectors and reservoirs of diverse viruses and other infectious agents, are able to counteract host defence mechanisms and wound healing processes to facilitate blood-feeding. Cutting the epidermis by the tick chelicerae and penetration of the hypostome into the dermis followed by feeding elicit a wound healing response, involving coagulation, inflammation, angiogenesis, synthesis of extracellular matrix and ground substances, as well as tissue remodelling. These repair processes of injured skin are coordinated by a wide array of cytokines, chemokines and growth factors. Tick salivary gland compounds, in addition to their vital anticoagulant and immunomodulatory functions, also possess significant anti-tumour properties and represent very promising sources of novel pharmaceuticals. Among life-threatening cancers, cervical carcinoma is still a high risk. Human transforming growth factor-beta 1 (huTGF-β1) inhibitors are significant in anti-cancer therapy. In this study, we investigated effects of salivary gland extracts (SGE) of females of two ixodid ticks, Dermacentor reticulatus (DR SGE) and Hyalomma anatolicum excavatum (HAE SGE), on signalling pathways triggered by huTGF-β1 in two cervical carcinoma cell lines, SiHa and HeLa, varying in their response to huTGF-β1. By dual luciferase reporter assay we monitored activation/inhibition of canonical SMAD or non-canonical signalling pathways in cells treated with huTGF-β1 and DR SGE/HAE SGE. Using specific monoclonal antibodies we tested effects of SGE on phosphorylation of ERK1/2 and/or AKT-1 molecules. We were the first to detect significant inhibition of huTGF-β1 induced signalling pathways, canonical as well as non-canonical, by DR and HAE SGE. Although the overall effects of both SGE on signalling pathways were similar, we revealed different patterns of effects of the two SGE on phosphorylation of the monitored signal transducers. Further investigations in this field are required. Keywords Ticks . Tick salivary glands . huTGF-β1 . Signalling . Cervical cancer cells . Suppression Abbreviations DR Dermacentor reticulatus females, tick ECM extracellular matrix ERK extracellular signal-regulated kinase FGF-2 fibroblast growth factor 2 HAE Hyalomma anatolicum excavatum females, tick HGF hepatocyte growth factor huTGF-β1 human transforming growth factor beta 1 JNK c-Jun N-terminal kinase MAPK mitogen-activated protein kinase PDGF platelet-derived growth factor PI3K phosphatidylinositol 3-kinase PKB/AKT protein kinase B SG salivary glands SGE salivary gland extract SMAD Sma and Mad proteins from Caenorhabditis elegans and Drosophila, respectively STAT signal transducers and activators of transcription TGF-β1 transforming growth factor beta 1

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