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BioscienceHorizons Volume 10 2017 10.1093/biohorizons/hzw015 ................................................................................................................................................................. Review article Evolution of salivary secretions in haematophagous animals Francesca L. Ware* and Martin R. Luck School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicester LE12 5RD, UK *Corresponding author: 27 Braishfield Gardens, Bournemouth, Dorset BH8 0QA, UK. Email: [email protected] Supervisor: Prof. Martin Luck, School of Biosciences, University of Nottingham, Sutton Bonington Campus, Loughborough, Leicester LE12 5RD, UK. ................................................................................................................................................................. Haemostasis is the prevention of blood fluidity in vertebrates and is the first stage of wound healing. Haematophagous animals use the blood of vertebrates as their sole source of nutrition and have evolved many salivary constituents to counteract the haemostatic response of their prey. These animals and their saliva have been studied for many years, with some applications in medicine. The purpose of this study is to compare the salivary constituents of leeches (Hirudinae), ticks (Argasidae and Ixodidae) and vampire bats (Desmodontinae) and to consider their evolutionary origin. Salivary constituents include plasminogen activa- tors (PAs), anticoagulants (activated factor X, FXa; inhibitors), vasodilators, platelet aggregation inhibitors (PAgI) and thrombin inhibitors. The animals studied all tend to possess an anticoagulant and a form of apyrase (PAgI) to assist with blood feeding. Ticks and vampire bats have a form of PA but the leech does not. The vampire bat has a PAgI but no vasodilator. The animals studied are from taxonomically unrelated groups but exploit similar mechanisms of action to facilitate their haematophagy. Given that the haematophagous lifestyle of these animals developed much later than their common ancestors, we conclude that their mechanisms for haematophagy have arisen by convergent evolution. Some molecules, e.g. serine proteases found in invertebrate saliva, are probably derived from a common ancestral gene. The possible paths that have led to evolution of vampire bat salivary components are considered. Further research into the homology of these salivary constituents is required to give insight into how these animals adapted to haematophagy and their further therapeutic potential. Key words: haematophagous, saliva, evolution, leech, tick, vampire bat Submitted on 21 September 2015; editorial decision on 28 November 2016 ................................................................................................................................................................. number of species, we have chosen to examine examples Introduction representing distinctly different phyla. We describe and com- Haematophagous animals are those which rely on blood from pare the range of active components in the saliva of haema- other animals as their only source of nutrition. These parasitic tophagous animals in the following three groups: leeches creatures have evolved highly specific salivary molecules that (Hirudinae), ticks (Ixodidae and Argasidae) and vampire bats counteract the haemostatic response of the host and also exert (Desmodontinae). We then consider whether these components limited behavioural control. Whilst considerable research has may have arisen through convergent or divergent evolution. been carried out on the salivary components and their poten- Haemostasis (Fig. 1) is the process by which blood flow stops tial for the treatment of human disease, few papers have at the site of an injury. It is one of the first responses to vascular explored their evolution. Because this unusual feeding method damage and initiates further processes including wound repair. is displayed across the animal kingdom but in a limited Briefly, coagulation (reviewed by Palta, Saroa and Palta, 2014) ................................................................................................................................................................. © The Author 2017. Published by Oxford University Press. 1 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/ licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. Downloaded from https://academic.oup.com/biohorizons/article-abstract/doi/10.1093/biohorizons/hzw015/2962556For commercial re-use, please contact [email protected] by guest on 23 January 2018 Review article Bioscience Horizons • Volume 10 2017 ................................................................................................................................................................. serine proteases). Plasmin is the active component of the plasminogen (fibrinolytic) system (reviewed by Chapin and Hajjar, 2015), responsible for the eventual breakdown of fibrin fibres, fibrinogen, FV, FVIII, FXII and prothrombin at the start of the wound repair process (Tellgren-Roth et al., 2009; Hall, 2011; Barrett et al., 2012). Leeches Leeches are invertebrate, segmented worms from the phylum Annelida, class Clitellata, subclass Hirudinae (reviewed by Abdualkader et al., 2013). Leeches live in slow flowing streams and fresh water ponds (reviewed by Hildebrandt and Lemke, 2011). Young leeches, having left the safety of the cocoon, feed on amphibians. When their mouth parts have matured, they move on to feed on animals with thicker skin and more nutritious blood, including birds and mammals (Hildebrandt and Lemke, 2011). Leeches, specifically the medicinal leech Hirudo medicinalis, have been used by physicians as a medicinal therapy for various diseases since early civilization (reviewed by Munshi et al., 2008). Haycraft (1884) reported that the H. medicinalis produced a substance with anticoagulant properties. In fact, Figure 1. Haemostasis in vertebrates. A simplified account of haemostasis in vertebrates, including mammals, identifying possible the leech produces several anticoagulants and thrombolytics, targets for the salivary molecules of haematophagous animals. stored in the salivary glands (Chopin et al., 2000). Adapted from Law, Ribeiro and Wells (1992, review article) and Barrett The leech attaches to its prey using the anterior portion of et al. (2012). Dashed arrows indicate inhibition. 5-HT, serotonin; TXA2, thromboxane A2. its sucker. It begins periodic tilting movements of its three jaws, in order to slice open the skin. The pumping action of the pharyngeal muscles sucks the blood from the destroyed blood ves- ’ involves the formation of a loose haemostatic plug, which is sels and lymph of the host into the leech scrop(Lent et al., then converted into a definitive clot (thrombus) containing 1988). These jaw movements also initiate the secretion of saliva fibrin. The formation of fibrin is initiated by a cascade of from its unicellular salivary gland cells, located anteriorly in enzymic reactions (clotting factors of the intrinsic and extrinsic segments three and nine (Hildebrandt and Lemke, 2011). The pathways), the last element of which is a complex of activated mechanism of protein release from gland cells and the biochem- substances, collectively termed the prothrombin activator. This ical events needed to synthesize salivary proteins are unknown complex catalyses the conversion of prothrombin to thrombin (Hildebrandt and Lemke, 2011). Serotonin may stimulate sal- and is considered to be the rate limiting step in blood coagula- iva excretion (Marshall and Lent, 1988; Hildebrandt and tion (Hall, 2011; Barrett et al., 2012). Lemke, 2011) and pharyngeal peristalsis (Lent et al.,1988). Thrombin is a serine protease, which activates and poly- The ingestion of blood lasts roughly 25 min (Lent et al., merizes fibrinogen to form fibrin. Fibrin stabilizing factor 1988). Only the red blood cells and plasma proteins are of (Factor XIII or FXIII; we use this system of abbreviation nutritious value to the leech. Plasma and haem derivatives are – fi throughout), released from platelets within the developing excreted over the following 4 6days,ensuringef cient diges- thrombus, is activated by thrombin and produces a stable tion. Table 1 shows the haematophagy-relevant components of cross-linked fibrin meshwork containing trapped blood cells, saliva in various leech species and their function in the host. platelets and plasma. After the clot has formed (3–6 min), it begins to contract due to the release of pro-coagulant (clot- Anticoagulants encouraging) substances, which cross-link more adjacent The majority of the anticoagulants found in leeches are inhibi- fibrin fibres. The retracting fibrin meshwork pulls the edges of tors of FXa preventing the conversion of prothrombin to the damaged blood vessel together, assisting haemostasis thrombin of the vertebrate coagulation cascade (common path- (Hall, 2011; Barrett et al., 2012). way). Examples are Therostatin (isolated from Theromyzon A euglobulin called plasminogen (profibrinolysin) is found tessulatum; Chopin et al., 2000) and Antistatin. Antistatin within the plasma proteins trapped in the clot. Plasminogen is has also been proposed to have anti-metastatic properties converted into plasmin (fibrinolysin)

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