{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T09:45:04Z","timestamp":1768470304363,"version":"3.49.0"},"reference-count":97,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T00:00:00Z","timestamp":1630368000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001824","name":"Grantov\u00e1 Agentura \u010cesk\u00e9 Republiky","doi-asserted-by":"publisher","award":["19-14704Y"],"award-info":[{"award-number":["19-14704Y"]}],"id":[{"id":"10.13039\/501100001824","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["384 CZ.02.1.01\/0.0\/0.0\/16_019\/0000759"],"award-info":[{"award-number":["384 CZ.02.1.01\/0.0\/0.0\/16_019\/0000759"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Tick saliva is a rich source of antihemostatic, anti-inflammatory, and immunomodulatory molecules that actively help the tick to finish its blood meal. Moreover, these molecules facilitate the transmission of tick-borne pathogens. Here we present the functional and structural characterization of Iripin-8, a salivary serpin from the tick Ixodes ricinus, a European vector of tick-borne encephalitis and Lyme disease. Iripin-8 displayed blood-meal-induced mRNA expression that peaked in nymphs and the salivary glands of adult females. Iripin-8 inhibited multiple proteases involved in blood coagulation and blocked the intrinsic and common pathways of the coagulation cascade in vitro. Moreover, Iripin-8 inhibited erythrocyte lysis by complement, and Iripin-8 knockdown by RNA interference in tick nymphs delayed the feeding time. Finally, we resolved the crystal structure of Iripin-8 at 1.89 \u00c5 resolution to reveal an unusually long and rigid reactive center loop that is conserved in several tick species. The P1 Arg residue is held in place distant from the serpin body by a conserved poly-Pro element on the P\u2032 side. Several PEG molecules bind to Iripin-8, including one in a deep cavity, perhaps indicating the presence of a small-molecule binding site. This is the first crystal structure of a tick serpin in the native state, and Iripin-8 is a tick serpin with a conserved reactive center loop that possesses antihemostatic activity that may mediate interference with host innate immunity.<\/jats:p>","DOI":"10.3390\/ijms22179480","type":"journal-article","created":{"date-parts":[[2021,8,31]],"date-time":"2021-08-31T21:59:45Z","timestamp":1630447185000},"page":"9480","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":26,"title":["Ixodes ricinus Salivary Serpin Iripin-8 Inhibits the Intrinsic Pathway of Coagulation and Complement"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5644-1468","authenticated-orcid":false,"given":"Jan","family":"Kot\u00e1l","sequence":"first","affiliation":[{"name":"Department of Medical Biology, Faculty of Science, University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice, Brani\u0161ovsk\u00e1 1760c, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"},{"name":"Laboratory of Genomics and Proteomics of Disease Vectors, Institute of Parasitology, Biology Center CAS, Brani\u0161ovsk\u00e1 1160\/31, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4210-6677","authenticated-orcid":false,"given":"St\u00e9phanie G. I.","family":"Polderdijk","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, Department of Haematology, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Helena","family":"Langhansov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Science, University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice, Brani\u0161ovsk\u00e1 1760c, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Monika","family":"Ederov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Science, University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice, Brani\u0161ovsk\u00e1 1760c, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8127-6276","authenticated-orcid":false,"given":"Larissa A.","family":"Martins","sequence":"additional","affiliation":[{"name":"Laboratory of Genomics and Proteomics of Disease Vectors, Institute of Parasitology, Biology Center CAS, Brani\u0161ovsk\u00e1 1160\/31, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zuzana","family":"Ber\u00e1nkov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Science, University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice, Brani\u0161ovsk\u00e1 1760c, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0277-140X","authenticated-orcid":false,"given":"Ad\u00e9la","family":"Chlast\u00e1kov\u00e1","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Science, University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice, Brani\u0161ovsk\u00e1 1760c, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ond\u0159ej","family":"Hajdu\u0161ek","sequence":"additional","affiliation":[{"name":"Laboratory of Vector Immunology, Institute of Parasitology, Biology Center CAS, Brani\u0161ovsk\u00e1 1160\/31, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7526-1876","authenticated-orcid":false,"given":"Michail","family":"Kotsyfakis","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Science, University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice, Brani\u0161ovsk\u00e1 1760c, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"},{"name":"Laboratory of Genomics and Proteomics of Disease Vectors, Institute of Parasitology, Biology Center CAS, Brani\u0161ovsk\u00e1 1160\/31, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James A.","family":"Huntington","sequence":"additional","affiliation":[{"name":"Cambridge Institute for Medical Research, Department of Haematology, University of Cambridge, The Keith Peters Building, Hills Road, Cambridge CB2 0XY, UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7089-6143","authenticated-orcid":false,"given":"Jind\u0159ich","family":"Chmela\u0159","sequence":"additional","affiliation":[{"name":"Department of Medical Biology, Faculty of Science, University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice, Brani\u0161ovsk\u00e1 1760c, 37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1289\/ehp.00108119","article-title":"Impact of climatic change on the northern latitude limit and population density of the disease-transmitting European tick Ixodes ricinus","volume":"108","author":"Lindgren","year":"2000","journal-title":"Environ. Health Perspect."},{"key":"ref_2","unstructured":"Sonenshine, D.E. (2014). Biology of Ticks, Oxford University Press. [2nd ed.]."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3842","DOI":"10.1016\/j.jprot.2012.04.026","article-title":"Tick salivary secretion as a source of antihemostatics","volume":"75","author":"Chmelar","year":"2012","journal-title":"J Proteom."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.jprot.2015.07.005","article-title":"Modulation of host immunity by tick saliva","volume":"128","author":"Kotal","year":"2015","journal-title":"J. Proteom."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3389\/fcimb.2013.00043","article-title":"Tick salivary compounds: Their role in modulation of host defences and pathogen transmission","volume":"3","author":"Kazimirova","year":"2013","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3389\/fcimb.2017.00281","article-title":"The Essential Role of Tick Salivary Glands and Saliva in Tick Feeding and Pathogen Transmission","volume":"7","author":"Simo","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"830","DOI":"10.3389\/fphys.2019.00830","article-title":"Deciphering Biological Processes at the Tick-Host Interface Opens New Strategies for Treatment of Human Diseases","volume":"10","author":"Stibraniova","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1002\/ps.1293","article-title":"An in vitro feeding assay to test acaricides for control of hard ticks","volume":"63","author":"Krober","year":"2007","journal-title":"Pest Manag. Sci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1016\/j.ibmb.2016.11.010","article-title":"A mutation in the PSST homologue of complex I (NADH:ubiquinone oxidoreductase) from Tetranychus urticae is associated with resistance to METI acaricides","volume":"80","author":"Bajda","year":"2017","journal-title":"Insect Biochem. Mol. Biol."},{"key":"ref_10","first-page":"71","article-title":"Interaction between the coagulation and complement system","volume":"632","author":"Amara","year":"2008","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Manning, J.E., and Cantaert, T. (2019). Time to Micromanage the Pathogen-Host-Vector Interface: Considerations for Vaccine Development. Vaccines, 7.","DOI":"10.3390\/vaccines7010010"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1016\/j.pt.2017.04.003","article-title":"Mosquito Biting Modulates Skin Response to Virus Infection","volume":"33","author":"Pingen","year":"2017","journal-title":"Trends Parasitol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"216","DOI":"10.3389\/fcimb.2017.00216","article-title":"Protease Inhibitors in Tick Saliva: The Role of Serpins and Cystatins in Tick-host-Pathogen Interaction","volume":"7","author":"Chmelar","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"337","DOI":"10.3389\/fmicb.2013.00337","article-title":"Ticks and tick-borne pathogens at the cutaneous interface: Host defenses, tick countermeasures, and a suitable environment for pathogen establishment","volume":"4","author":"Wikel","year":"2013","journal-title":"Front. Microbiol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1016\/j.dci.2008.07.010","article-title":"Subversion of complement by hematophagous parasites","volume":"33","author":"Schroeder","year":"2009","journal-title":"Dev. Comp. Immunol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.4049\/jimmunol.174.4.2084","article-title":"Complement inhibitor of C5 activation from the soft tick Ornithodoros moubata","volume":"174","author":"Nunn","year":"2005","journal-title":"J. Immunol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1111\/j.1538-7836.2011.04360.x","article-title":"Serpin structure, function and dysfunction","volume":"9","author":"Huntington","year":"2011","journal-title":"J. Thromb. Haemost. JTH"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/gb-2006-7-5-216","article-title":"An overview of the serpin superfamily","volume":"7","author":"Law","year":"2006","journal-title":"Genome Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"24299","DOI":"10.1074\/jbc.R110.112771","article-title":"Serpins flex their muscle: I. Putting the clamps on proteolysis in diverse biological systems","volume":"285","author":"Silverman","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"24307","DOI":"10.1074\/jbc.R110.141408","article-title":"Serpins flex their muscle: II. Structural insights into target peptidase recognition, polymerization, and transport functions","volume":"285","author":"Whisstock","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"D624","DOI":"10.1093\/nar\/gkx1134","article-title":"The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database","volume":"46","author":"Rawlings","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1016\/j.sbi.2006.10.005","article-title":"Molecular gymnastics: Serpin structure, folding and misfolding","volume":"16","author":"Whisstock","year":"2006","journal-title":"Curr. Opin. Struct. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1016\/j.semcdb.2016.09.001","article-title":"Serpins in arthropod biology","volume":"62","author":"Meekins","year":"2017","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.ttbdis.2014.08.002","article-title":"Bioinformatic analyses of male and female Amblyomma americanum tick expressed serine protease inhibitors (serpins)","volume":"6","author":"Porter","year":"2015","journal-title":"Ticks Tick-Borne Dis."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Karim, S., and Ribeiro, J.M. (2015). An Insight into the Sialome of the Lone Star Tick, Amblyomma americanum, with a Glimpse on Its Time Dependent Gene Expression. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0131292"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.tibtech.2013.04.004","article-title":"ZFN, TALEN, and CRISPR\/Cas-based methods for genome engineering","volume":"31","author":"Gaj","year":"2013","journal-title":"Trends Biotechnol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"517","DOI":"10.3389\/fcimb.2017.00517","article-title":"Tick-Host Range Adaptation: Changes in Protein Profiles in Unfed Adult Ixodes scapularis and Amblyomma americanum Saliva Stimulated to Feed on Different Hosts","volume":"7","author":"Tirloni","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"10083","DOI":"10.1074\/jbc.M111391200","article-title":"Characterization of a novel salivary immunosuppressive protein from Ixodes ricinus ticks","volume":"277","author":"Leboulle","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"26361","DOI":"10.1074\/jbc.M604197200","article-title":"Anti-hemostatic effects of a serpin from the saliva of the tick Ixodes ricinus","volume":"281","author":"Prevot","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1182\/blood-2010-06-293241","article-title":"A tick salivary protein targets cathepsin G and chymase and inhibits host inflammation and platelet aggregation","volume":"117","author":"Chmelar","year":"2011","journal-title":"Blood"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1128\/IAI.03065-14","article-title":"Ixodes ricinus salivary serpin IRS-2 affects Th17 differentiation via inhibition of the interleukin-6\/STAT-3 signaling pathway","volume":"83","author":"Palenikova","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"626200","DOI":"10.3389\/fimmu.2021.626200","article-title":"Iripin-3, a New Salivary Protein Isolated From Ixodes ricinus Ticks, Displays Immunomodulatory and Anti-Hemostatic Properties In Vitro","volume":"12","author":"Chlastakova","year":"2021","journal-title":"Front. Immunol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.ijpara.2015.03.009","article-title":"Conserved Amblyomma americanum tick Serpin19, an inhibitor of blood clotting factors Xa and XIa, trypsin and plasmin, has anti-haemostatic functions","volume":"45","author":"Kim","year":"2015","journal-title":"Int. J. Parasitol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"109064","DOI":"10.1016\/j.vetpar.2020.109064","article-title":"A serpin from the tick Rhipicephalus haemaphysaloides: Involvement in vitellogenesis","volume":"279","author":"Xu","year":"2020","journal-title":"Vet. Parasitol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"180","DOI":"10.1016\/j.ttbdis.2015.09.007","article-title":"Effective inhibition of thrombin by Rhipicephalus microplus serpin-15 (RmS-15) obtained in the yeast Pichia pastoris","volume":"7","author":"Xu","year":"2016","journal-title":"Ticks Tick-Borne Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1453","DOI":"10.1107\/S1744309110032343","article-title":"Crystallization and diffraction analysis of the serpin IRS-2 from the hard tick Ixodes ricinus","volume":"66 Pt 11","author":"Kovarova","year":"2010","journal-title":"Acta Crystallogr. Sect. F Struct. Biol. Cryst. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ellisdon, A.M., Zhang, Q., Henstridge, M.A., Johnson, T.K., Warr, C.G., Law, R.H., and Whisstock, J.C. (2014). High resolution structure of cleaved Serpin 42 Da from Drosophila melanogaster. BMC Struct. Biol., 14.","DOI":"10.1186\/1472-6807-14-14"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1038\/nsb0194-48","article-title":"The intact and cleaved human antithrombin III complex as a model for serpin-proteinase interactions","volume":"1","author":"Schreuder","year":"1994","journal-title":"Nat. Struct. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1730","DOI":"10.3382\/ps\/pey024","article-title":"Structural change of ovalbumin-related protein X by alkali treatment","volume":"97","author":"Akazawa","year":"2018","journal-title":"Poult. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2121","DOI":"10.1038\/s41598-018-19567-9","article-title":"Probing the folding pathway of a consensus serpin using single tryptophan mutants","volume":"8","author":"Yang","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/0001-706X(96)00007-1","article-title":"Anticoagulant activity of Triatoma infestans and Panstrongylus megistus saliva (Hemiptera\/Triatominae)","volume":"61","author":"Pereira","year":"1996","journal-title":"Acta Trop."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Lestinova, T., Rohousova, I., Sima, M., de Oliveira, C.I., and Volf, P. (2017). Insights into the sand fly saliva: Blood-feeding and immune interactions between sand flies, hosts, and Leishmania. PLoS Negl. Trop. Dis., 11.","DOI":"10.1371\/journal.pntd.0005600"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1023\/B:THRO.0000014588.95061.28","article-title":"Remodeling the blood coagulation cascade","volume":"16","author":"Hoffman","year":"2003","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Kascakova, B., Kotal, J., Martins, L.A., Berankova, Z., Langhansova, H., Calvo, E., Crossley, J.A., Havlickova, P., Dycka, F., and Prudnikova, T. (2021). Structural and biochemical characterization of the novel serpin Iripin-5 from Ixodes ricinus. Acta Crystallogr. Sect. D, 77.","DOI":"10.1107\/S2059798321007920"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1007\/s00018-019-03034-3","article-title":"The structure and function of Iristatin, a novel immunosuppressive tick salivary cystatin","volume":"76","author":"Kotal","year":"2019","journal-title":"Cell. Mol. Life Sci. CMLS"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: A key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"375","DOI":"10.3389\/fimmu.2013.00375","article-title":"Sand-fly saliva-leishmania-man: The trigger trio","volume":"4","author":"Oliveira","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"95","DOI":"10.5455\/OVJ.2012.v2.i0.p95","article-title":"Tsetse fly saliva: Could it be useful in fly infection when feeding in chronically aparasitemic mammalian hosts","volume":"2","author":"Awuoche","year":"2012","journal-title":"Open Vet. J."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1016\/j.ijpara.2006.05.002","article-title":"Tsetse fly saliva biases the immune response to Th2 and induces anti-vector antibodies that are a useful tool for exposure assessment","volume":"36","author":"Caljon","year":"2006","journal-title":"Int. J. Parasitol."},{"key":"ref_50","first-page":"279","article-title":"The kinin-kallikrein system: Physiological roles, pathophysiology and its relationship to cancer biomarkers","volume":"18","author":"Kashuba","year":"2013","journal-title":"Biomark. Biochem. Indic. Expo. Response Susceptibility Chem."},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Caljon, G., De Ridder, K., De Baetselier, P., Coosemans, M., and Van Den Abbeele, J. (2010). Identification of a tsetse fly salivary protein with dual inhibitory action on human platelet aggregation. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0009671"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"530","DOI":"10.3389\/fphys.2019.00530","article-title":"Chemical Equilibrium at the Tick-Host Feeding Interface:A Critical Examination of Biological Relevance in Hematophagous Behavior","volume":"10","author":"Mans","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ibmb.2006.11.005","article-title":"An insight into the sialome of Anopheles funestus reveals an emerging pattern in anopheline salivary protein families","volume":"37","author":"Calvo","year":"2007","journal-title":"Insect Biochem. Mol. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1055\/s-0036-1586227","article-title":"Plasmin: A Modulator of Immune Function","volume":"43","author":"Draxler","year":"2017","journal-title":"Semin. Thromb. Hemost."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1126\/science.1231143","article-title":"Multiplex genome engineering using CRISPR\/Cas systems","volume":"339","author":"Cong","year":"2013","journal-title":"Science"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.molimm.2004.07.001","article-title":"Investigation of the mechanisms of anti-complement activity in Ixodes ricinus ticks","volume":"42","author":"Lawrie","year":"2005","journal-title":"Mol. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1038\/nbt.1755","article-title":"A TALE nuclease architecture for efficient genome editing","volume":"29","author":"Miller","year":"2011","journal-title":"Nat. Biotechnol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"18717","DOI":"10.1074\/jbc.M001486200","article-title":"Purification, cloning, and expression of a novel salivary anticomplement protein from the tick, Ixodes scapularis","volume":"275","author":"Valenzuela","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1111\/j.1365-2583.2007.00742.x","article-title":"Biochemical and functional characterization of Salp20, an Ixodes scapularis tick salivary protein that inhibits the complement pathway","volume":"16","author":"Tyson","year":"2007","journal-title":"Insect Mol. Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3964","DOI":"10.4049\/jimmunol.180.6.3964","article-title":"A novel mechanism of complement inhibition unmasked by a tick salivary protein that binds to properdin","volume":"180","author":"Tyson","year":"2008","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1111\/j.1365-2583.2006.00710.x","article-title":"Ixodes ticks belonging to the Ixodes ricinus complex encode a family of anticomplement proteins","volume":"16","author":"Daix","year":"2007","journal-title":"Insect Mol. Biol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.chom.2011.06.010","article-title":"A tick mannose-binding lectin inhibitor interferes with the vertebrate complement cascade to enhance transmission of the lyme disease agent","volume":"10","author":"Schuijt","year":"2011","journal-title":"Cell Host Microbe"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"368","DOI":"10.1016\/j.pt.2016.01.004","article-title":"All For One and One For All on the Tick-Host Battlefield","volume":"32","author":"Chmelar","year":"2016","journal-title":"Trends Parasitol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1016\/j.pt.2013.04.002","article-title":"New insights into the machinery of blood digestion by ticks","volume":"29","author":"Sojka","year":"2013","journal-title":"Trends Parasitol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1186\/1756-3305-3-119","article-title":"Dynamics of digestive proteolytic system during blood feeding of the hard tick Ixodes ricinus","volume":"3","author":"Franta","year":"2010","journal-title":"Parasites Vectors"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3093","DOI":"10.1242\/jeb.01749","article-title":"Tracing heme in a living cell: Hemoglobin degradation and heme traffic in digest cells of the cattle tick Boophilus microplus","volume":"208 Pt 16","author":"Lara","year":"2005","journal-title":"J. Exp. Biol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"199","DOI":"10.3389\/fcimb.2017.00199","article-title":"Serine Protease Inhibitors in Ticks: An Overview of Their Role in Tick Biology and Tick-Borne Pathogen Transmission","volume":"7","author":"Blisnick","year":"2017","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1016\/S0965-1748(02)00240-0","article-title":"Four serine proteinase inhibitors (serpin) from the brown ear tick, Rhiphicephalus appendiculatus; cDNA cloning and preliminary characterization","volume":"33","author":"Mulenga","year":"2003","journal-title":"Insect Biochem. Mol. Biol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1301","DOI":"10.1016\/j.vaccine.2004.08.041","article-title":"A serine protease inhibitor (serpin) from Haemaphysalis longicornis as an anti-tick vaccine","volume":"23","author":"Imamura","year":"2005","journal-title":"Vaccine"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1016\/j.ttbdis.2012.03.002","article-title":"Differential recognition by tick-resistant cattle of the recombinantly expressed Rhipicephalus microplus serine protease inhibitor-3 (RMS-3)","volume":"3","author":"Vance","year":"2012","journal-title":"Ticks Tick-Borne Dis."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/s13071-014-0605-4","article-title":"Rhipicephalus microplus serine protease inhibitor family: Annotation, expression and functional characterisation assessment","volume":"8","author":"Xu","year":"2015","journal-title":"Parasites Vectors"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1089\/thy.2000.10.141","article-title":"The thyroxine-binding proteins","volume":"10","author":"Schussler","year":"2000","journal-title":"Thyroid"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/j.mce.2009.06.015","article-title":"Molecular and structural basis of steroid hormone binding and release from corticosteroid-binding globulin","volume":"316","author":"Lin","year":"2010","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/j.ttbdis.2015.12.017","article-title":"Target validation of highly conserved Amblyomma americanum tick saliva serine protease inhibitor 19","volume":"7","author":"Kim","year":"2016","journal-title":"Ticks Tick-Borne Dis."},{"key":"ref_75","first-page":"1131","article-title":"Tick histamine-binding proteins and related lipocalins: Potential as therapeutic agents","volume":"6","author":"Mans","year":"2005","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1093\/oxfordjournals.molbev.a003992","article-title":"Evolution of hematophagy in ticks: Common origins for blood coagulation and platelet aggregation inhibitors from soft ticks of the genus Ornithodoros","volume":"19","author":"Mans","year":"2002","journal-title":"Mol. Biol. Evol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"8692","DOI":"10.1016\/S0021-9258(18)81848-8","article-title":"Anticoagulant activity of synthetic hirudin peptides","volume":"264","author":"Maraganore","year":"1989","journal-title":"J. Biol. Chem."},{"key":"ref_78","first-page":"797","article-title":"Identification of Borrelia burgdorferi sensu stricto, Borrelia garinii and Borrelia afzelii in Ixodes ricinus ticks from southern Bohemia using monoclonal antibodies","volume":"289","author":"Kopecky","year":"2000","journal-title":"Zent. Bakteriol. Int. J. Med. Microbiol."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"e00896-18","DOI":"10.1128\/IAI.00896-18","article-title":"Tracking of Borrelia afzelii transmission from infected Ixodes ricinus nymphs to mice","volume":"87","author":"Pospisilova","year":"2019","journal-title":"Infect. Immun."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e01004-17","DOI":"10.1128\/JVI.01004-17","article-title":"Mosquito Saliva Reshapes Alphavirus Infection and Immunopathogenesis","volume":"92","author":"Fong","year":"2018","journal-title":"J. Virol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"200","DOI":"10.4149\/av_2013_02_200","article-title":"Immunomodulators in tick saliva and their benefits","volume":"57","author":"Stibraniova","year":"2013","journal-title":"Acta Virol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"407","DOI":"10.3389\/fcimb.2020.00407","article-title":"Aedes Mosquito Salivary Components and Their Effect on the Immune Response to Arboviruses","volume":"10","author":"Guerrero","year":"2020","journal-title":"Front. Cell Infect. Microbiol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"482","DOI":"10.1016\/j.chom.2009.10.006","article-title":"Antibodies against a tick protein, Salp15, protect mice from the Lyme disease agent","volume":"6","author":"Dai","year":"2009","journal-title":"Cell Host Microbe"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/S0965-1748(02)00181-9","article-title":"Molecular cloning, expression and isolation of ferritins from two tick species--Ornithodoros moubata and Ixodes ricinus","volume":"33","author":"Kopacek","year":"2003","journal-title":"Insect Biochem. Mol. Biol."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1093\/jmedent\/43.6.1208","article-title":"Effect of tick saliva on mechanisms of innate immune response against Borrelia afzelii","volume":"43","author":"Kyckova","year":"2006","journal-title":"J. Med. Entomol."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Ribeiro, J.M., Arca, B., Lombardo, F., Calvo, E., Phan, V.M., Chandra, P.K., and Wikel, S.K. (2007). An annotated catalogue of salivary gland transcripts in the adult female mosquito, Aedes aegypti. BMC Genom., 8.","DOI":"10.1186\/1471-2164-8-6"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"16216","DOI":"10.1016\/S0021-9258(19)85408-X","article-title":"A Kazal-type inhibitor with thrombin specificity from Rhodnius prolixus","volume":"268","author":"Friedrich","year":"1993","journal-title":"J. Biol. Chem."},{"key":"ref_88","first-page":"204","article-title":"Biochemical characterization of a thrombin inhibitor from the bloodsucking bug Dipetalogaster maximus","volume":"29","author":"Lange","year":"1999","journal-title":"Haemostasis"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1664","DOI":"10.1016\/j.jprot.2011.06.022","article-title":"Diversity of anti-haemostatic proteins in the salivary glands of Rhodnius species transmitters of Chagas disease in the greater Amazon","volume":"74","author":"Bussacos","year":"2011","journal-title":"J. Proteom."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"475","DOI":"10.4269\/ajtmh.1996.54.475","article-title":"Isolation and characterization of the tsetse thrombin inhibitor: A potent antithrombotic peptide from the saliva of Glossina morsitans morsitans","volume":"54","author":"Cappello","year":"1996","journal-title":"Am. J. Trop. Med. Hyg."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"14290","DOI":"10.1073\/pnas.95.24.14290","article-title":"Tsetse thrombin inhibitor: Bloodmeal-induced expression of an anticoagulant in salivary glands and gut tissue of Glossina morsitans morsitans","volume":"95","author":"Cappello","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_92","doi-asserted-by":"crossref","unstructured":"Chagas, A.C., Oliveira, F., Debrabant, A., Valenzuela, J.G., Ribeiro, J.M., and Calvo, E. (2014). Lundep, a sand fly salivary endonuclease increases Leishmania parasite survival in neutrophils and inhibits XIIa contact activation in human plasma. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1003923"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.biochi.2015.02.011","article-title":"Ayadualin, a novel RGD peptide with dual antihemostatic activities from the sand fly Lutzomyia ayacuchensis, a vector of Andean-type cutaneous leishmaniasis","volume":"112","author":"Kato","year":"2015","journal-title":"Biochimie"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"7095","DOI":"10.1021\/bi00482a021","article-title":"2nd, Design and characterization of hirulogs: A novel class of bivalent peptide inhibitors of thrombin","volume":"29","author":"Maraganore","year":"1990","journal-title":"Biochemistry"},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"USAN Council (1995). List No. 374. New names. Bivalirudin. Desirudin. Clin. Pharmacol. Ther., 58, 241.","DOI":"10.1016\/0009-9236(95)90204-X"},{"key":"ref_96","doi-asserted-by":"crossref","unstructured":"Poulin, R. (2007). Evolutionary Ecology of Parasites, Princeton University Press. [2nd ed.].","DOI":"10.1515\/9781400840809"},{"key":"ref_97","unstructured":"Schrodinger, LLC (2015). The PyMOL Molecular Graphics System, Schrodinger, LLC. Version 1.8."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9480\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:53:49Z","timestamp":1760165629000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/17\/9480"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,8,31]]},"references-count":97,"journal-issue":{"issue":"17","published-online":{"date-parts":[[2021,9]]}},"alternative-id":["ijms22179480"],"URL":"https:\/\/doi.org\/10.3390\/ijms22179480","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,8,31]]}}}