Salivary Protease Inhibitors with Non Anti-Hemostatic Functions

  • Jindřich Chmelař
  • Ivo M.B. Francischetti
  • Michalis Kotsyfakis
Chapter

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.

Keywords

Mast Cell Salivary Gland Tick Infestation Hard Tick Bovine Pancreatic Trypsin Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

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.

Because I.M.B.F. is a government employee and this is a government work, the work is in the public domain in the United States. Notwithstanding any other agreements, the NIH reserves the right to provide the work to PubMedCentral for display and use by the public, and PubMedCentral may tag or modify the work consistent with its customary practices. You can establish rights outside of the U.S. subject to a government use license.

References

  1. 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.PubMedCrossRefGoogle Scholar
  2. 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.PubMedCrossRefGoogle Scholar
  3. 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.PubMedCrossRefGoogle Scholar
  4. 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.PubMedCrossRefGoogle Scholar
  5. 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.PubMedCrossRefGoogle Scholar
  6. 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.PubMedCrossRefGoogle Scholar
  7. 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.PubMedCrossRefGoogle Scholar
  8. 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.PubMedCrossRefGoogle Scholar
  9. 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.PubMedGoogle Scholar
  10. 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.PubMedCrossRefGoogle Scholar
  11. 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.PubMedCrossRefGoogle Scholar
  12. 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.PubMedCrossRefGoogle Scholar
  13. 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.PubMedCrossRefGoogle Scholar
  14. 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.PubMedCrossRefGoogle Scholar
  15. 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.PubMedCrossRefGoogle Scholar
  16. 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.PubMedCrossRefGoogle Scholar
  17. 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.PubMedGoogle Scholar
  18. Honey, K., Rudensky, A.Y., 2003. Lysosomal cysteine proteases regulate antigen presentation. Nat. Rev. Immunol. 3, 472–482.PubMedCrossRefGoogle Scholar
  19. 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.PubMedCrossRefGoogle Scholar
  20. 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.PubMedCrossRefGoogle Scholar
  21. 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.PubMedCrossRefGoogle Scholar
  22. 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.PubMedCrossRefGoogle Scholar
  23. 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.PubMedGoogle Scholar
  24. Koh, C.Y., Kini, R.M., 2009. Molecular diversity of anticoagulants from haematophagous animals. Thromb. Haemost. 102, 437–453.PubMedGoogle Scholar
  25. 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.PubMedGoogle Scholar
  26. 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.PubMedCrossRefGoogle Scholar
  27. 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.PubMedCrossRefGoogle Scholar
  28. 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.PubMedCrossRefGoogle Scholar
  29. 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.PubMedCrossRefGoogle Scholar
  30. 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.PubMedGoogle Scholar
  31. 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.PubMedCrossRefGoogle Scholar
  32. 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.PubMedGoogle Scholar
  33. 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.PubMedGoogle Scholar
  34. 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.PubMedCrossRefGoogle Scholar
  35. 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.PubMedCrossRefGoogle Scholar
  36. 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.PubMedCrossRefGoogle Scholar
  37. 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.PubMedCrossRefGoogle Scholar
  38. 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.PubMedCrossRefGoogle Scholar
  39. 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.PubMedCrossRefGoogle Scholar
  40. 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.PubMedCrossRefGoogle Scholar
  41. 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.PubMedCrossRefGoogle Scholar
  42. 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.PubMedCrossRefGoogle Scholar
  43. Rice, A., Banda, M.J., 1995. Neutrophil elastase processing of gelatinase A is mediated by extracellular matrix. Biochemistry 34, 9249–9256.PubMedCrossRefGoogle Scholar
  44. 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.PubMedCrossRefGoogle Scholar
  45. 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.PubMedCrossRefGoogle Scholar
  46. 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.PubMedCrossRefGoogle Scholar
  47. 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.PubMedCrossRefGoogle Scholar
  48. 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.PubMedCrossRefGoogle Scholar
  49. 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.PubMedCrossRefGoogle Scholar
  50. 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.PubMedCrossRefGoogle Scholar
  51. 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.PubMedGoogle Scholar
  52. 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.PubMedCrossRefGoogle Scholar
  53. Turk, B., Turk, D., Turk, V., 2000. Lysosomal cysteine proteases: more than scavengers. Biochim. Biophys. Acta 1477, 98–111.PubMedCrossRefGoogle Scholar
  54. 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.Google Scholar
  55. Zavasnik-Bergant, T., Turk, B., 2007. Cysteine proteases: destruction ability versus immunomodulation capacity in immune cells. Biol. Chem. 388, 1141–1149.PubMedCrossRefGoogle Scholar
  56. 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.PubMedCrossRefGoogle Scholar
  57. 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.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2010

Authors and Affiliations

  • Jindřich Chmelař
    • 1
  • Ivo M.B. Francischetti
    • 2
  • Michalis Kotsyfakis
    • 3
  1. 1.Laboratory of Genomics and Proteomics of Disease VectorsInstitute of Parasitology, Biology Centre, ASCR v.v.i.Ceske BudejoviceCzech Republic
  2. 2.Section of Vector Biology, Laboratory of Malaria and Vector ResearchNational Institute of Allergy and Infectious Diseases, National Institutes of HealthRockvilleUSA
  3. 3.Laboratory of Genomics and Proteomics of Disease VectorsInstitute of Parasitology, Biology Centre, ASCR v.v.i.Ceske BudejoviceCzech Republic

Personalised recommendations