Tick Bioactive Molecules as Novel Therapeutics: Beyond Vaccine Targets

Murfin, Kristen E.; Fikrig, Erol

doi:10.3389/fcimb.2017.00222

Cited by 13 publications

(14 citation statements)

References 60 publications

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“…Regulating DC differentiation and function may be a potential strategy for ticks to promote blood-feeding and pathogen transmission. More effort is being done to study the critical roles of biologically important tick bioactive molecules in tick-pathogen-hosts [34–36]. RHcyst-1 may be a promising target for tick control in the future.…”

Section: Discussionmentioning

confidence: 99%

Immunosuppressive effects of tick protein RHcyst-1 on murine bone marrow-derived dendritic cells

Wei

Wang

et al. 2019

Parasites Vectors

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Background Ticks, as blood-feeding arthropod vectors, have evolved their own unique mechanism to suppress host immune responses and evade immune defenses in order to complete blood-feeding. The immunoregulatory effect of tick bioactive molecules on hosts has been widely reported, and the cystatin family has been identified as one of the major immunomodulators. In previous studies, we obtained a novel tick salivary bioactive protein named RHcyst-1, which belongs to the type 1 cystatin family. Here, we demonstrated the effects of RHcyst-1 on the host immune response mainly on dendritic cell (DC) function. Understanding the function of tick-derived bioactive molecule may help to clarify the mechanisms of how ticks escape the host immune response and help to control ticks and tick-borne disease transmission. Methods Bone marrow-derived DCs (BMDCs) were generated and induced by GM-CSF and IL-4 with or without RHcyst-1 addition. Flow cytometry was used to analyze the differentiation and maturation of BMDCs and T cell cytokine production. Quantitative real-time PCR (qRT-PCR) and western blot were used to measure changes in expression within STAT and p38 MAPK signaling pathways. Results Flow cytometry analysis revealed that RHcyst-1 inhibited the differentiation of BMDCs, but had no effect on the maturation of BMDCs. T cells co-cultured with DCs treated with RHcyst-1 produced significantly less TNF-α, IFN-γ and IL-2 than the control group. Further analysis showed that the mRNA level and phosphorylation of p38, ERK and STAT were significantly changed after RHcyst-1 added to bone marrow monocytes during the differentiation stage. Conclusions Our results suggest that RHcyst-1 is one of the major immunosuppressive proteins of BMDC function from blood-feeding ticks. Electronic supplementary material The online version of this article (10.1186/s13071-019-3411-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Immunosuppressive effects of tick protein RHcyst-1 on murine bone marrow-derived dendritic cells

Wei

Wang

et al. 2019

Parasites Vectors

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“…Similar protein families are found in ixodid and argasid ticks, and in Nuttalliella namaqua, suggesting they were present in the ancestral tick lineage (Mans et al, 2016). Reviews on the discovery of proteins in tick saliva and their characterisation include: Steen et al, 2006;Murfin and Fikrig, 2017;Šimo et al, 2017. Many studies involve tick feeding on laboratory hosts that the particular tick species would not encounter naturally, hence limiting interpretation of the results as host species affects expression of saliva proteins and feeding success (Wang et al, 2001b;Anderson et al, 2017;Tirloni et al, 2017).…”

Section: Composition Of Tick Salivamentioning

confidence: 99%

Wonders of tick saliva

Nuttall

2019

Ticks and Tick-borne Diseases

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The NERC and CEH trademarks and logos ('the Trademarks') are registered trademarks of NERC in the UK and other countries, and may not be used without the prior written consent of the Trademark owner. AbstractSaliva of ticks is arguably the most complex saliva of any animal. This is particularly the case for ixodid species that feed for many days firmly attached to the same skin site of their obliging host. Sequencing and spectrometry technologies combined with bioinformatics are enumerating ingredients in the saliva cocktail. The dynamic and expanding saliva recipe is helping decipher the wonderous activities of tick saliva, revealing how ticks stealthily hide from their hosts while satisfying their gluttony and sharing their individual resources. This review takes a tick perspective on the composition and functions of tick saliva, covering water balance, gasket and holdfast, control of host responses, dynamics, individuality, mate guarding, saliva-assisted transmission, and redundancy. It highlights areas sometimes overlookedfeeding aggregation and sharing of sialomes, and the contribution of salivary gland storage granulesand questions whether the huge diversity of tick saliva molecules is 'redundant' or more a reflection on the enormous adaptability wonderous saliva confers on ticks.

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“…Lipocalins are promising new therapy candidates based on their natural ligand-binding functions to store and transport small compounds, which together with their structure (small polypeptide chain) led to design of artificial binding proteins “anticalins” with novel specificities, for example as transporters for pharmaceuticals. In general, it is a very long way from basic research to translation to the clinical praxis and, according to Murfin and Fikrig (2017), with many gaps and lacks. It is known that arthropod molecules are unstable, have a short half-life (for example OmCI mentioned in this review) or are cytotoxic, thus they require improved pharmacokinetics, optimization of dosage, delivery way, etc.…”

Section: Resultsmentioning

confidence: 99%

“…Ticks are blood feeders and bioactive compounds in their saliva have a promising therapeutic potential for treatment of some human diseases associated with hemostatic and immunological disorders (Mans, 2005; Hovius et al, 2008; Francischetti, 2010; Štibrániová et al, 2013; Sousa et al, 2015; Bonvin et al, 2016; Chudzinski-Tavassi et al, 2016, 2018; Chmelar et al, 2017; Murfin and Fikrig, 2017; Parizi et al, 2018). Tick salivary glands, a paired organ consisting of acini in grape-like clusters, produce saliva secreted by the feeding tick into the host primarily to enable blood feeding by suppressing local hemostatic and host immune responses (Francischetti et al, 2009; Kazimírová and Štibrániová, 2013; Wikel, 2013; Kotal et al, 2015; Šimo et al, 2017; Nuttall, 2018).…”

Section: Ticks and Pharmacological Properties Of Their Salivamentioning

confidence: 99%

Deciphering Biological Processes at the Tick-Host Interface Opens New Strategies for Treatment of Human Diseases

et al. 2019

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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.

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Tick Bioactive Molecules as Novel Therapeutics: Beyond Vaccine Targets

Cited by 13 publications

References 60 publications

Immunosuppressive effects of tick protein RHcyst-1 on murine bone marrow-derived dendritic cells

Immunosuppressive effects of tick protein RHcyst-1 on murine bone marrow-derived dendritic cells

Wonders of tick saliva

Deciphering Biological Processes at the Tick-Host Interface Opens New Strategies for Treatment of Human Diseases

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