Abstract
Arthropod saliva regulates proteolysis in the sites of bite(s). Secreted salivary inhibitors target different proteolytic enzymes (proteases) that have a pivotal role in vertebrate hemostasis, immunity and inflammation. The aim of this chapter is to give an overview of the salivary protease inhibitors that affect the latter two physiological procedures. Functional studies, mainly in ticks, have demonstrated many potent arthropod salivary inhibitors of cysteine proteases (cathepsins) and serine proteases (elastase and tryptase). Emphasis is given to the function of these inhibitors and more specifically to the mechanism by which they facilitate hematophagy.
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References
Azzolini, S.S., Santos, J.M., Souza, A.F., Torquato, R.J., Hirata, I.Y., Andreotti, R., Tanaka, A.S., 2004. Purification, characterization, and cloning of a serine proteinase inhibitor from the ectoparasite Haematobia irritans irritans (Diptera: Muscidae). Exp. Parasitol. 106, 103–109.
Belaaouaj, A., McCarthy, R., Baumann, M., Gao, Z., Ley, T.J., Abraham, S.N., Shapiro, S.D., 1998. Mice lacking neutrophil elastase reveal impaired host defense against gram negative bacterial sepsis. Nat. Med. 4, 615–618.
Blair, R.J., Meng, H., Marchese, M.J., Ren, S., Schwartz, L.B., Tonnesen, M.G., Gruber, B.L., 1997. Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor. J. Clin. Invest. 99, 2691–2700.
Corral-Rodriguez, M.A., Macedo-Ribeiro, S., Barbosa Pereira, P.J., Fuentes-Prior, P., 2009. Tick-derived Kunitz-type inhibitors as antihemostatic factors. Insect Biochem. Mol. Biol. 39, 579–595.
Corvera, C.U., Dery, O., McConalogue, K., Bohm, S.K., Khitin, L.M., Caughey, G.H., Payan, D.G., Bunnett, N.W., 1997. Mast cell tryptase regulates rat colonic myocytes through proteinase-activated receptor 2. J. Clin. Invest. 100, 1383–1393.
Coussens, L.M., Raymond, W.W., Bergers, G., Laig-Webster, M., Behrendtsen, O., Werb, Z., Caughey, G.H., Hanahan, D., 1999. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 13, 1382–1397.
Dainichi, T., Maekawa, Y., Ishii, K., Zhang, T., Nashed, B.F., Sakai, T., Takashima, M., Himeno, K., 2001. Nippocystatin, a cysteine protease inhibitor from Nippostrongylus brasiliensis, inhibits antigen processing and modulates antigen-specific immune response. Infect. Immun. 69, 7380–7386.
Felbor, U., Dreier, L., Bryant, R.A., Ploegh, H.L., Olsen, B.R., Mothes, W., 2000. Secreted cathepsin L generates endostatin from collagen XVIII. EMBO J. 19, 1187–1194.
Francischetti, I.M., Mather, T.N., Ribeiro, J.M., 2005. Tick saliva is a potent inhibitor of endothelial cell proliferation and angiogenesis. Thromb. Haemost. 94, 167–174.
Francischetti, I.M., Sá-Nunes, A., Mans, B.J., Santos, I.M., Ribeiro, J.M., 2009. The role of saliva in tick feeding. Front. Biosci. 14, 2051–2088.
Gadher, S.J., Eyre, D.R., Duance, V.C., Wotton, S.F., Heck, L.W., Schmid, T.M., Woolley, D.E., 1988. Susceptibility of cartilage collagens type II, IX, X, and XI to human synovial collagenase and neutrophil elastase. Eur. J. Biochem. 175, 1–7.
Ganz, T., Metcalf, J.A., Gallin, J.I., Boxer, L.A., Lehrer, R.I., 1988. Microbicidal/cytotoxic proteins of neutrophils are deficient in two disorders: Chediak-Higashi syndrome and “specific” granule deficiency. J. Clin. Invest. 82, 552–556.
Goto, S.G., Denlinger, D.L., 2002. Genes encoding two cystatins in the flesh fly Sarcophaga crassipalpis and their distinct expression patterns in relation to pupal diapause. Gene 292, 121–127.
Gruber, B.L., Marchese, M.J., Suzuki, K., Schwartz, L.B., Okada, Y., Nagase, H., Ramamurthy, N.S., 1989. Synovial procollagenase activation by human mast cell tryptase dependence upon matrix metalloproteinase 3 activation. J. Clin. Invest. 84, 1657–1662.
Grunclova, L., Horn, M., Vancova, M., Sojka, D., Franta, Z., Mares, M., Kopacek, P., 2006. Two secreted cystatins of the soft tick Ornithodoros moubata: differential expression pattern and inhibitory specificity. Biol. Chem. 387, 1635–1644.
He, S., Aslam, A., Gaca, M.D., He, Y., Buckley, M.G., Hollenberg, M.D., Walls, A.F., 2004. Inhibitors of tryptase as mast cell-stabilizing agents in the human airways: effects of tryptase and other agonists of proteinase-activated receptor 2 on histamine release. J. Pharmacol. Exp. Ther. 309, 119–126.
Heck, L.W., Blackburn, W.D., Irwin, M.H., Abrahamson, D.R., 1990. Degradation of basement membrane laminin by human neutrophil elastase and cathepsin G. Am. J. Pathol. 136, 1267–1274.
Honey, K., Rudensky, A.Y., 2003. Lysosomal cysteine proteases regulate antigen presentation. Nat. Rev. Immunol. 3, 472–482.
Huang, C., De Sanctis, G.T., O’Brien, P.J., Mizgerd, J.P., Friend, D.S., Drazen, J.M., Brass, L.F., Stevens, R.L., 2001. Evaluation of the substrate specificity of human mast cell tryptase beta I and demonstration of its importance in bacterial infections of the lung. J. Biol. Chem. 276, 26276–26284.
Ide, H., Itoh, H., Yoshida, E., Kobayashi, T., Tomita, M., Maruyama, H., Osada, Y., Nakahata, T., Nawa, Y., 1999. Immunohistochemical demonstration of inter-alpha-trypsin inhibitor light chain (bikunin) in human mast cells. Cell Tissue Res. 297, 149–154.
Kaminska, R., Helisalmi, P., Harvima, R.J., Naukkarinen, A., Horsmanheimo, M., Harvima, I.T., 1999. Focal dermal-epidermal separation and fibronectin cleavage in basement membrane by human mast cell tryptase. J. Invest. Dermatol. 113, 567–573.
Karim, S., Miller, N.J., Valenzuela, J., Sauer, J.R., Mather, T.N., 2005. RNAi-mediated gene silencing to assess the role of synaptobrevin and cystatin in tick blood feeding. Biochem. Biophys. Res. Commun. 334, 1336–1342.
Kido, H., Fukusen, N., Katunuma, N., 1988. Antibodies and inhibitor of chymase are incorporated into mast cell granules and inhibit histamine release. Biol. Chem. Hoppe-Seyler. 369(Suppl), 95–100.
Koh, C.Y., Kini, R.M., 2009. Molecular diversity of anticoagulants from haematophagous animals. Thromb. Haemost. 102, 437–453.
Kotsyfakis, M., Anderson, J.M., Andersen, J.F., Calvo, E., Francischetti, I.M., Mather, T.N., Valenzuela, J.G., Ribeiro, J.M., 2008. Cutting edge: immunity against a "silent" salivary antigen of the Lyme vector Ixodes scapularis impairs its ability to feed. J. Immunol. 181, 5209–5212.
Kotsyfakis, M., Karim, S., Andersen, J.F., Mather, T.N., Ribeiro, J.M., 2007. Selective cysteine protease inhibition contributes to blood-feeding success of the tick Ixodes scapularis. J. Biol. Chem. 282, 29256–29263.
Kotsyfakis, M., Sá-Nunes, A., Francischetti, I.M., Mather, T.N., Andersen, J.F., Ribeiro, J.M., 2006. Antiinflammatory and immunosuppressive activity of sialostatin L, a salivary cystatin from the tick Ixodes scapularis. J. Biol. Chem. 281, 26298–26307.
Kozik, A., Moore, R.B., Potempa, J., Imamura, T., Rapala-Kozik, M., Travis, J., 1998. A novel mechanism for bradykinin production at inflammatory sites. Diverse effects of a mixture of neutrophil elastase and mast cell tryptase versus tissue and plasma kallikreins on native and oxidized kininogens. J. Biol. Chem. 273, 33224–33229.
Leboulle, G., Crippa, M., Decrem, Y., Mejri, N., Brossard, M., Bollen, A., Godfroid, E., 2002a. Characterization of a novel salivary immunosuppressive protein from Ixodes ricinus ticks. J. Biol. Chem. 277, 10083–10089.
Leboulle, G., Rochez, C., Louahed, J., Ruti, B., Brossard, M., Bollen, A., Godfroid, E., 2002b. Isolation of Ixodes ricinus salivary gland mRNA encoding factors induced during blood feeding. Am. J. Trop. Med. Hyg. 66, 225–233.
Lima, C.A., Sasaki, S.D., Tanaka, A.S., 2006. Bmcystatin, a cysteine proteinase inhibitor characterized from the tick Boophilus microplus. Biochem. Biophys. Res. Commun. 347, 44–50.
Lombardi, G., Burzyn, D., Mundinano, J., Berguer, P., Bekinschtein, P., Costa, H., Castillo, L.F., Goldman, A., Meiss, R., Piazzon, I., Nepomnaschy, I., 2005. Cathepsin-L influences the expression of extracellular matrix in lymphoid organs and plays a role in the regulation of thymic output and of peripheral T cell number. J. Immunol. 174, 7022–7032.
Molinari, J.F., Moore, W.R., Clark, J., Tanaka, R., Butterfield, J.H., Abraham, W.M., 1995. Role of tryptase in immediate cutaneous responses in allergic sheep. J. Appl. Physiol. 79, 1966–1970.
Molinari, J.F., Scuri, M., Moore, W.R., Clark, J., Tanaka, R., Abraham, W.M., 1996. Inhaled tryptase causes bronchoconstriction in sheep via histamine release. Am. J. Respir. Crit. Care Med. 154, 649–653.
Paesen, G.C., Siebold, C., Harlos, K., Peacey, M.F., Nuttall, P.A., Stuart, D.I., 2007. A tick protein with a modified Kunitz fold inhibits human tryptase. J. Mol. Biol. 368, 1172–1186.
Prevot, P.P., Adam, B., Boudjeltia, K.Z., Brossard, M., Lins, L., Cauchie, P., Brasseur, R., Vanhaeverbeek, M., Vanhamme, L., Godfroid, E., 2006. Anti-hemostatic effects of a serpin from the saliva of the tick Ixodes ricinus. J. Biol. Chem. 281, 26361–26369.
Prevot, P.P., Beschin, A., Lins, L., Beaufays, J., Grosjean, A., Bruys, L., Adam, B., Brossard, M., Brasseur, R., Zouaoui Boudjeltia, K., Vanhamme, L., Godfroid, E., 2009. Exosites mediate the anti-inflammatory effects of a multifunctional serpin from the saliva of the tick Ixodes ricinus. FEBS J. 276, 3235–3246.
Prevot, P.P., Couvreur, B., Denis, V., Brossard, M., Vanhamme, L., Godfroid, E., 2007. Protective immunity against Ixodes ricinus induced by a salivary serpin. Vaccine 25, 3284–3292.
Reddy, V.Y., Zhang, Q.Y., Weiss, S.J., 1995. Pericellular mobilization of the tissue-destructive cysteine proteinases, cathepsins B, L, and S, by human monocyte-derived macrophages. Proc. Natl. Acad. Sci. U.S.A. 92, 3849–3853.
Reinheckel, T., Hagemann, S., Dollwet-Mack, S., Martinez, E., Lohmuller, T., Zlatkovic, G., Tobin, D.J., Maas-Szabowski, N., Peters, C., 2005. The lysosomal cysteine protease cathepsin L regulates keratinocyte proliferation by control of growth factor recycling. J. Cell Sci. 118, 3387–3395.
Ribeiro, J.M., Arca, B., Lombardo, F., Calvo, E., Phan, V.M., Chandra, P.K., Wikel, S.K., 2007. An annotated catalogue of salivary gland transcripts in the adult female mosquito, Aedes aegypti. BMC Genomics 8, 6.
Ribeiro, J.M., Francischetti, I.M., 2003. Role of arthropod saliva in blood feeding: sialome and post-sialome perspectives. Annu. Rev. Entomol. 48, 73–88.
Rice, A., Banda, M.J., 1995. Neutrophil elastase processing of gelatinase A is mediated by extracellular matrix. Biochemistry 34, 9249–9256.
Sá-Nunes, A., Bafica, A., Antonelli, L.R., Choi, E.Y., Francischetti, I.M., Andersen, J.F., Shi, G.P., Chavakis, T., Ribeiro, J.M., Kotsyfakis, M., 2009. The immunomodulatory action of sialostatin L on dendritic cells reveals its potential to interfere with autoimmunity. J. Immunol. 182, 7422–7429.
Sakai, K., Long, S.D., Pettit, D.A., Cabral, G.A., Schwartz, L.B., 1996. Expression and purification of recombinant human tryptase in a baculovirus system. Protein Expr. Purif. 7, 67–73.
Sant’Anna Azzolini, S., Sasaki, S.D., Torquato, R.J., Andreotti, R., Andreotti, E., Tanaka, A.S., 2003. Rhipicephalus sanguineus trypsin inhibitors present in the tick larvae: isolation, characterization, and partial primary structure determination. Arch. Biochem. Biophys. 417, 176–182.
Sasaki, S.D., Azzolini, S.S., Hirata, I.Y., Andreotti, R., Tanaka, A.S., 2004. Boophilus microplus tick larvae, a rich source of Kunitz type serine proteinase inhibitors. Biochimie 86:643–649.
Sasaki, S.D., de Lima, C.A., Lovato, D.V., Juliano, M.A., Torquato, R.J., Tanaka, A.S., 2008. BmSI-7, a novel subtilisin inhibitor from Boophilus microplus, with activity toward Pr1 proteases from the fungus Metarhizium anisopliae. Exp. Parasitol. 118, 214–220.
Serveau-Avesque, C., Martino, M.F., Herve-Grepinet, V., Hazouard, E., Gauthier, F., Diot, E., Lalmanach, G., 2006. Active cathepsins B, H, K, L and S in human inflammatory bronchoalveolar lavage fluids. Biol. Cell 98, 15–22.
Shamamian, P., Schwartz, J.D., Pocock, B.J., Monea, S., Whiting, D., Marcus, S.G., Mignatti, P., 2001. Activation of progelatinase A (MMP-2) by neutrophil elastase, cathepsin G, and proteinase-3: a role for inflammatory cells in tumor invasion and angiogenesis. J. Cell. Physiol. 189, 197–206.
Stack, M.S., Johnson, D.A., 1994. Human mast cell tryptase activates single-chain urinary-type plasminogen activator (pro-urokinase). J. Biol. Chem. 269, 9416–9419.
Tanaka, A.S., Andreotti, R., Gomes, A., Torquato, R.J., Sampaio, M.U., Sampaio, C.A., 1999. A double headed serine proteinase inhibitor--human plasma kallikrein and elastase inhibitor—from Boophilus microplus larvae. Immunopharmacology 45, 171–177.
Turk, B., Turk, D., Turk, V., 2000. Lysosomal cysteine proteases: more than scavengers. Biochim. Biophys. Acta 1477, 98–111.
Yamaji, K., Tsuji, N., Miyoshi, T., Islam, M.K., Hatta, T., Alim, M.A., Anisuzzaman, M., Kushibiki, S., Fujisaki, K., 2009. A salivary cystatin, HlSC-1, from the ixodid tick Haemaphysalis longicornis play roles in the blood-feeding processes. Parasitol. Res. 106(1), 61–68.
Zavasnik-Bergant, T., Turk, B., 2007. Cysteine proteases: destruction ability versus immunomodulation capacity in immune cells. Biol. Chem. 388, 1141–1149.
Zhou, J., Liao, M., Ueda, M., Gong, H., Xuan, X., Fujisaki, K., 2009. Characterization of an intracellular cystatin homolog from the tick Haemaphysalis longicornis. Vet. Parasitol. 160, 180–183.
Zhou, J., Ueda, M., Umemiya, R., Battsetseg, B., Boldbaatar, D., Xuan, X., Fujisaki, K., 2006. A secreted cystatin from the tick Haemaphysalis longicornis and its distinct expression patterns in relation to innate immunity. Insect Biochem. Mol. Biol. 36, 527–535.
Acknowledgements
This work was supported by the Intramural Research Program of the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, by the grant No. IAA600960811 from the Grant Agency of the Academy of Sciences of the Czech Republic and by the Research Center No. LC06009 from the Ministry of Education, Youth and Sports of the Czech Republic. We thank Professor R. Manjunatha Kini for the fruitful discussions and comments on the manuscript, Dr. Koh Cho Yeow for preparing the figure and NIAID intramural editor Brenda Rae Marshall for assistance.
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Chmelař, J., Francischetti, I.M., Kotsyfakis, M. (2010). Salivary Protease Inhibitors with Non Anti-Hemostatic Functions. In: Kini, R., Clemetson, K., Markland, F., McLane, M., Morita, T. (eds) Toxins and Hemostasis. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-9295-3_10
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