Kunitz domain-containing proteins are ubiquitous serine protease inhibitors with promising therapeutic potential. They target key proteases involved in major cellular processes such as inflammation or hemostasis through competitive inhibition in a substrate-like manner. Protease inhibitors from the Kunitz superfamily have a low molecular weight (18-24 kDa) and are characterized by the presence of one or more Kunitz motifs consisting of α-helices and antiparallel β-sheets stabilized by three disulfide bonds. Kunitz-type inhibitors are an important fraction of the protease inhibitors found in tick saliva. Their roles in inhibiting and/or suppressing host homeostatic responses continue to be shown to be additive or synergistic with other protease inhibitors such as cystatins or serpins, ultimately mediating successful blood feeding for the tick. In this review, we discuss the biochemical features of tick salivary Kunitz-type protease inhibitors. We focus on their various effects on host hemostasis and immunity at the molecular and cellular level and their potential therapeutic applications. In doing so, we highlight that their pharmacological properties can be exploited for the development of novel therapies and vaccines.

• Klíčová slova
• Kunitz-type, hemostasis, immunomodulation, parasite-host interactions, protease inhibitors, ticks,
• MeSH
• cystatiny * metabolismus   MeSH
• inhibitory serinových proteinas farmakologie   terapeutické užití   metabolismus   MeSH
• klíšťata * MeSH
• serpiny * metabolismus   MeSH
• sliny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• cystatiny * MeSH
• inhibitory serinových proteinas MeSH
• serpiny * MeSH

Protease inhibitors (PIs) are ubiquitous regulatory proteins present in all kingdoms. They play crucial tasks in controlling biological processes directed by proteases which, if not tightly regulated, can damage the host organism. PIs can be classified according to their targeted proteases or their mechanism of action. The functions of many PIs have now been characterized and are showing clinical relevance for the treatment of human diseases such as arthritis, hepatitis, cancer, AIDS, and cardiovascular diseases, amongst others. Other PIs have potential use in agriculture as insecticides, anti-fungal, and antibacterial agents. PIs from tick salivary glands are special due to their pharmacological properties and their high specificity, selectivity, and affinity to their target proteases at the tick-host interface. In this review, we discuss the structure and function of PIs in general and those PI superfamilies abundant in tick salivary glands to illustrate their possible practical applications. In doing so, we describe tick salivary PIs that are showing promise as drug candidates, highlighting the most promising ones tested in vivo and which are now progressing to preclinical and clinical trials.

• Klíčová slova
• drug discovery, protease inhibitors, proteases, tick saliva,
• MeSH
• inhibitory proteas izolace a purifikace   terapeutické užití   MeSH
• interakce hostitele a parazita genetika   imunologie   MeSH
• klíšťata metabolismus   MeSH
• lidé MeSH
• slinné žlázy metabolismus   MeSH
• sliny chemie   metabolismus   MeSH
• transkriptom genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• inhibitory proteas MeSH

Immunodeficiency disorders and autoimmune diseases are common, but a lack of effective targeted drugs and the side-effects of existing drugs have stimulated interest in finding therapeutic alternatives. Naturally derived substances are a recognized source of novel drugs, and tick saliva is increasingly recognized as a rich source of bioactive molecules with specific functions. Ticks use their saliva to overcome the innate and adaptive host immune systems. Their saliva is a rich cocktail of molecules including proteins, peptides, lipid derivatives, and recently discovered non-coding RNAs that inhibit or modulate vertebrate immune reactions. A number of tick saliva and/or salivary gland molecules have been characterized and shown to be promising candidates for drug development for vertebrate immune diseases. However, further validation of these molecules at the molecular, cellular, and organism levels is now required to progress lead candidates to clinical testing. In this paper, we review the data on the immuno-pharmacological aspects of tick salivary compounds characterized in vitro and/or in vivo and present recent findings on non-coding RNAs that might be exploitable as immunomodulatory therapies.

• Klíčová slova
• drug discovery, host immunity, immunomodulation, salivary glands, tick saliva,
• MeSH
• autoimunitní nemoci imunologie   terapie   MeSH
• imunomodulace imunologie   MeSH
• klíšťata imunologie   MeSH
• lidé MeSH
• nemoci imunitního systému imunologie   terapie   MeSH
• proteiny členovců imunologie   MeSH
• sliny imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• proteiny členovců MeSH

Epigenetic mechanisms have not been characterized in ticks despite their importance as vectors of human and animal diseases worldwide. The objective of this study was to characterize the histones and histone modifying enzymes (HMEs) of the tick vector Ixodes scapularis and their role during Anaplasma phagocytophilum infection. We first identified 5 histones and 34 HMEs in I. scapularis in comparison with similar proteins in model organisms. Then, we used transcriptomic and proteomic data to analyze the mRNA and protein levels of I. scapularis histones and HMEs in response to A. phagocytophilum infection of tick tissues and cultured cells. Finally, selected HMEs were functionally characterized by pharmacological studies in cultured tick cells. The results suggest that A. phagocytophilum manipulates tick cell epigenetics to increase I. scapularis p300/CBP, histone deacetylase, and Sirtuin levels, resulting in an inhibition of cell apoptosis that in turn facilitates pathogen infection and multiplication. These results also suggest that a compensatory mechanism might exist by which A. phagocytophilum manipulates tick HMEs to regulate transcription and apoptosis in a tissue-specific manner to facilitate infection, but preserving tick fitness to guarantee survival of both pathogens and ticks. Our study also indicates that the pathogen manipulates arthropod and vertebrate cell epigenetics in similar ways to inhibit the host response to infection. Epigenetic regulation of tick biological processes is an essential element of the infection by A. phagocytophilum and the study of the mechanisms and principal actors involved is likely to provide clues for the development of anti-tick drugs and vaccines.

• Klíčová slova
• Anaplasma, epigenetics, histone, histone modifying enzyme, pathogen, tick,
• MeSH
• Anaplasma phagocytophilum genetika   MeSH
• apoptóza genetika   MeSH
• buněčné linie MeSH
• epigeneze genetická * MeSH
• histonový kód genetika   MeSH
• histony genetika   metabolismus   MeSH
• hmyz - vektory genetika   MeSH
• interakce hostitele a patogenu genetika   MeSH
• klíště genetika   MeSH
• lidé MeSH
• messenger RNA biosyntéza   genetika   MeSH
• transkripční faktory p300-CBP biosyntéza   genetika   MeSH
• transkriptom genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• histony MeSH
• messenger RNA MeSH
• transkripční faktory p300-CBP MeSH

INTRODUCTION: As an ecological adaptation venoms have evolved independently in several species of Metazoa. As haematophagous arthropods ticks are mainly considered as ectoparasites due to directly feeding on the skin of animal hosts. Ticks are of major importance since they serve as vectors for several diseases affecting humans and livestock animals. Ticks are rarely considered as venomous animals despite that tick saliva contains several protein families present in venomous taxa and that many Ixodida genera can induce paralysis and other types of toxicoses. Tick saliva was previously proposed as a special kind of venom since tick venom is used for blood feeding that counteracts host defense mechanisms. As a result, the present study provides evidence to reconsider the venomous properties of tick saliva. RESULTS: Based on our extensive literature mining and in silico research, we demonstrate that ticks share several similarities with other venomous taxa. Many tick salivary protein families and their previously described functions are homologous to proteins found in scorpion, spider, snake, platypus and bee venoms. This infers that there is a structural and functional convergence between several molecular components in tick saliva and the venoms from other recognized venomous taxa. We also highlight the fact that the immune response against tick saliva and venoms (from recognized venomous taxa) are both dominated by an allergic immunity background. Furthermore, by comparing the major molecular components of human saliva, as an example of a non-venomous animal, with that of ticks we find evidence that ticks resemble more venomous than non-venomous animals. Finally, we introduce our considerations regarding the evolution of venoms in Arachnida. CONCLUSIONS: Taking into account the composition of tick saliva, the venomous functions that ticks have while interacting with their hosts, and the distinguishable differences between human (non-venomous) and tick salivary proteins, we consider that ticks should be referred to as venomous ectoparasites.

• Klíčová slova
• Convergence, Pathogens, Secreted proteins, Ticks, Toxicoses, Venom,
• Publikační typ
• časopisecké články MeSH

BACKGROUND: Ticks are blood-sucking arthropods and a primary function of tick salivary proteins is to counteract the host's immune response. Tick salivary Kunitz-domain proteins perform multiple functions within the feeding lesion and have been classified as venoms; thereby, constituting them as one of the important elements in the arms race with the host. The two main mechanisms advocated to explain the functional heterogeneity of tick salivary Kunitz-domain proteins are gene sharing and gene duplication. Both do not, however, elucidate the evolution of the Kunitz family in ticks from a structural dynamic point of view. The Red Queen hypothesis offers a fruitful theoretical framework to give a dynamic explanation for host-parasite interactions. Using the recent salivary gland Ixodes ricinus transcriptome we analyze, for the first time, single Kunitz-domain encoding transcripts by means of computational, structural bioinformatics and phylogenetic approaches to improve our understanding of the structural evolution of this important multigenic protein family. RESULTS: Organizing the I. ricinus single Kunitz-domain peptides based on their cysteine motif allowed us to specify a putative target and to relate this target specificity to Illumina transcript reads during tick feeding. We observe that several of these Kunitz peptide groups vary in their translated amino acid sequence, secondary structure, antigenicity, and intrinsic disorder, and that the majority of these groups are subject to a purifying (negative) selection. We finalize by describing the evolution and emergence of these Kunitz peptides. The overall interpretation of our analyses discloses a rapidly emerging Kunitz group with a distinct disulfide bond pattern from the I. ricinus salivary gland transcriptome. CONCLUSIONS: We propose a model to explain the structural and functional evolution of tick salivary Kunitz peptides that we call target-oriented evolution. Our study reveals that combining analytical approaches (transcriptomes, computational, bioinformatics and phylogenetics) improves our understanding of the biological functions of important salivary gland mediators during tick feeding.

• MeSH
• fylogeneze MeSH
• klíště chemie   klasifikace   genetika   metabolismus   MeSH
• molekulární evoluce * MeSH
• proteiny členovců chemie   genetika   metabolismus   MeSH
• sekvence aminokyselin MeSH
• sekvenční seřazení MeSH
• slinné proteiny a peptidy chemie   genetika   metabolismus   MeSH
• terciární struktura proteinů MeSH
• transkriptom * MeSH
• výpočetní biologie MeSH
• zvířata MeSH
• Check Tag
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• proteiny členovců MeSH
• slinné proteiny a peptidy MeSH