Insights into the Role of Tick Salivary Protease Inhibitors during Ectoparasite–Host Crosstalk

Abstract

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.

Host Immune Responses to Salivary Components - A Critical Facet of Tick-Host Interactions

“…Advances in the field of computational biology have substantially improved several PIs and their targeted proteases by using 3D structural information that could be useful in permitting receptor-based design ( Jmel et al., 2021 ). Recently discovered ncRNAs in tick saliva have been proposed to be prompted by the immune modulators of the vertebrate host ( Chen et al., 2019 ).…”

“…During this course, the salivary glands (SGs) yield and secrete a plethora of molecules in non-uniform time-dependent patterns ( Kim et al., 2020 ), either to target-specific or a pleiotropic host’s molecules at the bite site, which initiates a set of mechanisms for disrupting host immune responses ( Ren et al., 2019 ). This results in interference with several complement mediators—including complement cascade components, eicosanoids, chemokines, cytokines, growth factors, cell-signaling molecules, and antibodies ( Aounallah et al., 2020 ) —proteolytic pathways, in particular pro-coagulants (thrombin, coagulation factors), pro-inflammatory enzymes (cathepsins S, C, B, L, and G, chymase, kallikrein, neutrophil elastase, proteinase 3, and tryptase), and complement pathway enzymes (component 2 and factors B, C, and D) ( Tirloni et al., 2014 ; Kim et al, 2015a ; Jmel et al., 2021 ). Meanwhile in this molecular tick–host crosstalk at the tick bite site, the dynamic responses of host hemostasis (first-line host innate immune response comprising platelet aggregation, coagulation, and vasoconstriction) are initiated against tick salivary molecules ( Kim et al., 2020 ).…”

“…The fate of the host’s innate immunity has been observed to be differentially modulated or inhibited by a set of tick salivary protease inhibitors (PIs) ( Martins et al., 2020 ). A particularly notable role of PIs has been detected in tick–host crosstalk, as the host defense mechanisms are highly regulated by specific endogenous inhibitors subsequently inhibited by tick-secreted PIs ( Martins et al., 2020 ; Jmel et al., 2021 ). The salivary PIs of several ticks have been characterized and found to be differentially expressed throughout the blood-feeding process, inducing local immunosuppression by inhibiting platelet aggregation or blocking cascade elements of intrinsic, extrinsic, and common pathways of blood coagulation, tumor development, and angiogenic factors ( Chmelař et al., 2017 ; Costa et al., 2021 ).…”

Serpins in Tick Physiology and Tick-Host Interaction

“…serpins may be involved in development (present in the ovary) and in the regulation of blood digestion (present in the midgut). In addition, their expression and presence in salivary glands and/or saliva suggest that they play a role in tick feeding, possibly influencing host resistance mechanisms and facilitating pathogen transmission ( Jmel et al., 2021 ). Therefore, in order to determine the role of individual serpins, we must not only investigate their capabilities in experimental models in vitro and/or in vivo , but we must also consider developmental stage and tissue specific expression, taking into consideration also the time during tick feeding that gene expression present peak(s).…”

rDromaserpin: A Novel Anti-Hemostatic Serpin, from the Salivary Glands of the Hard Tick Hyalomma dromedarii

“…These species represent an attractive natural source for the development of novel antihemostatic serpins. Particularly, proteins from tick salivary glands have been proven to target several blood coagulation components [26]. Several tick serpins have been described in numerous sequencing projects [27]; however, roughly a dozen of them are functionally described [28].…”