Tick Salivary Compounds for Targeted Immunomodulatory Therapy

Abstract

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.

Keywords: drug discovery; host immunity; immunomodulation; salivary glands; tick saliva.

FIGURE 1

Obstacles faced by ticks at the host-tick interface when taking a blood meal. Ticks initiate feeding by inserting their hypostomes into host skin, resulting in tissue and vascular damage. The host has developed several mechanisms to prevent blood loss including activating hemostasis, innate and adaptive immunity, the complement pathway, and inflammatory responses leading to wound healing and tissue remodeling, all of which disrupt tick feeding. Ticks, in turn, secrete saliva at the bite site that contains proteinaceous molecules (enzymes, lipocalins, protease inhibitors, etc.), non-proteinaceous molecules (prostaglandins, prostacyclins), and ncRNAs (miRNAs and lncRNAs). These molecules display anticoagulatory, antiplatelet, vasodilatory, anti-inflammatory, and immunomodulatory activities to counter host reactions and to guarantee a successful blood meal. DC, dendritic cells; LT, lymphocyte T; LB, lymphocyte T; Mφ, macrophage.

FIGURE 2

Schematic representation of tick salivary molecules implicated in the modulation of the complement system and innate immunity. Activated resident cells in the dermis stimulate host awareness of injury and removal of the feeding ticks. Tick saliva neutralizes itch and pain through salivary components that sequester histamine and/or serotonin (such as SHBP, Ra-HBPs, and HA24) or modulate MC function (such as RmS-3). TdPI and Tryptogalinin inhibit tryptase released by MCs. AAS27, AAS41, and IRS-2 inhibit chymase liberated by MCs. Neutrophil and monocyte recruitment is suppressed by MIF and Ir-LBP. Moreover, ticks manipulate the host cytokine network by inhibiting cytokines and chemokines using Salp16 Iper 1,2; Evasin 1, 3, 4; DsCystatin; Hyalomin-A, –B; Amregulin; PGE₂; Ado; and HlSerpin-a, –b. Several anti-complement molecules have been identified in tick salivary glands including RaCI; Isac; Salp 20; Irac I, II; IxACs; OmCI; TSGP2, 3; and CirpT. AAS: Amblyomma americanum serpin; DC: dendritic cells; IL: interleukin; Irac: I. ricinus anticomplement; IRS-2: I. ricinus Serpin-2; Isac: I. scapularis salivary anticomplement; IxACs: Ixodes anticomplement proteins; MIF: macrophage migration inhibitory factor; Mφ: macrophage; OmCI: O. moubata complement inhibitor; PGE₂: prostaglandin E2; Ra-HBPs: R. appendiculatus histamine-binding proteins; RmS: Rhipicephalus microplus serpin; Salp: salivary protein; SHBP: serotonin- and histamine-binding protein; TdPI: tick-derived protease inhibitor.

FIGURE 3

Schematic representation of tick salivary molecules targeting adaptive immunity. During the primary contact with ticks, dendritic cells present salivary antigens to lymphocytes, which trigger cell- and humoral-mediated responses. Some tick salivary molecules prevent the initiation of adaptive immunity by targeting DCs, including Salp15, PGE₂, RHS2, Japanin, and sialostatin. Other compounds block the proliferation of lymphocytes and/or inhibit the production of T cell cytokines such as p36, RH36, HL-p36, Iristatin, Iris, Ipis-1, IrSPI, Evasins, RmS-3, and RmS-17. However, BIP and BIF disarm humoral host immunity by inhibiting B cell responses, including the production of specific anti-tick antibodies. BCR: B cell receptor; BIF: B cell inhibitory factor; BIP: B cell inhibitory protein; CD: cluster of differentiation; CTL: cytotoxic T lymphocyte; DC: dendritic cells; HL-p36: Haemaphysalis longicornis p-36; IFN-γ: interferon gamma; Ig: immunoglobulin; IL: interleukin; LB: lymphocyte B; MHC: major histocompatibility complex; PGE₂: prostaglandin E2; RmS: Rhipicephalus microplus serpin; Salp: salivary protein; TCR: T cell receptor; TGF-β: transforming growth factor-beta; Th: T helper; TNF: tumor necrosis factor; Treg: regulatory T cell.

FIGURE 4

Possible strategies used by tick ncRNAs in host cells. (A) miR-8-3p, bantam-3p, mir-317-3p, and miR-279a-3p from Ixodes ricinus have been predicted to target gap junctions and inflammatory mediator regulation of TRP channels, which play a role in host homeostatic responses. (B) Host miRNAs regulate protein coding genes through mRNA cleavage and/or direct translational repression and/or mRNA destabilization. Ticks secrete exosomes in their saliva containing lncRNAs, which may compete with host mRNAs for host miRNA binding by acting as “sponge” molecules that inhibit host miRNA interactions with host mRNAs, thus affecting host homeostatic responses to tick feeding.