{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,15]],"date-time":"2026-07-15T14:27:57Z","timestamp":1784125677476,"version":"3.55.0"},"reference-count":83,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T00:00:00Z","timestamp":1752710400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003593","name":"Conselho Nacional de Desenvolvimento Cient\u00edfico e Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["465678\/2014-9 , 312674\/2021-0, 309551\/2021-8"],"award-info":[{"award-number":["465678\/2014-9 , 312674\/2021-0, 309551\/2021-8"]}],"id":[{"id":"10.13039\/501100003593","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e1 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","award":["2022\/02742-3, 2020\/16462-7, 2022\/07724-3 , 2023\/07831-7, 2019\/03779-5, 2024\/22525-2"],"award-info":[{"award-number":["2022\/02742-3, 2020\/16462-7, 2022\/07724-3 , 2023\/07831-7, 2019\/03779-5, 2024\/22525-2"]}],"id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002322","name":"Coordena\u00e7\u00e3o de Aperfei\u00e7oamento de Pessoal de N\u00edvel Superior","doi-asserted-by":"publisher","award":["Finance code 001"],"award-info":[{"award-number":["Finance code 001"]}],"id":[{"id":"10.13039\/501100002322","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100008530","name":"European Regional Development Fund","doi-asserted-by":"publisher","award":["CZ.02.1.01\/0.0\/0.0\/15_003\/0000441, CZ.02.01.01\/00\/23_020\/0008499"],"award-info":[{"award-number":["CZ.02.1.01\/0.0\/0.0\/15_003\/0000441, CZ.02.01.01\/00\/23_020\/0008499"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["Z01 AI001337-01"],"award-info":[{"award-number":["Z01 AI001337-01"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>The Neotropical tick <jats:italic>Amblyomma sculptum<\/jats:italic> is the primary vector of <jats:italic>Rickettsia rickettsii<\/jats:italic>, the causative agent of Brazilian spotted fever, a disease associated with high fatality rates. Tick saliva, a complex mixture of bioactive molecules essential for successful blood feeding, facilitates pathogen transmission and modulates host immune responses. A comprehensive evaluation of the salivary gland transcriptome database reveals that protease inhibitors are abundantly expressed molecules in tick saliva during feeding. Thus, this study aims to describe and characterize the most expressed member of the cystatin family identified in <jats:italic>Amblyomma sculptum<\/jats:italic> salivary transcriptome, named Amblyostatin-1. <\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Bioinformatic tools were employed for <jats:italic>in silico<\/jats:italic> analysis of the Amblyostatin-1 sequence and structure. A recombinant version of Amblyostatin-1 was expressed in an <jats:italic>Escherichia coli<\/jats:italic> system, evaluated against a panel of cysteine proteases in biochemical assays, and used to generate antibodies in immunized mice. The biological activities of Amblyostatin-1 were assessed by its effects on dendritic cell maturation <jats:italic>in vitro<\/jats:italic> and in a carrageenan-induced inflammation model <jats:italic>in vivo<\/jats:italic>.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Based on its sequence and predicted three-dimensional structure, Amblyostatin-1 is classified as an I25B cystatin, and its recombinant form selectively inhibits cathepsins L, C, and S at different rates, with a low nanomolar <jats:italic>Ki<\/jats:italic> value of 0.697 \u00b1 0.22 nM against cathepsin L. Regarding its biological activities, recombinant Amblyostatin-1 partially affects LPS-induced dendritic cell maturation by downmodulating the costimulatory molecules CD80 and CD86 at higher micromolar concentrations (3 \u00b5M) while promoting IL-10 production at nanomolar concentrations (100 nM). The apparent lack of Amblyostatin-1-specific antibody responses in immunized mice suggests an impairment of antigen processing and presentation <jats:italic>in vivo<\/jats:italic>. Furthermore, in a carrageenan-induced inflammation model, Amblyostatin-1 decreased edema formation and neutrophil infiltration into the skin without affecting other myeloid cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>These findings establish Amblyostatin-1 as a novel salivary cystatin with immunomodulatory and anti-inflammatory properties, highlighting its potential as an immunobiological agent.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1585703","type":"journal-article","created":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:24:45Z","timestamp":1752729885000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Amblyostatin-1, the first salivary cystatin with host immunomodulatory and anti-inflammatory properties from the Neotropical tick Amblyomma sculptum, vector of Brazilian spotted fever"],"prefix":"10.3389","volume":"16","author":[{"given":"Wilson Santos","family":"Molari","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamed Amine","family":"Jmel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Josiane Betim","family":"Assis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Fraz\u00e3o-Silva","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00falia Moura","family":"Bernardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gretta","family":"Huamanrayme","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 Mar\u00eda","family":"Medina","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eliane","family":"Esteves","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solange Cristina","family":"Ant\u00e3o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel Cerqueira Alves","family":"Costa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparecida Sadae","family":"Tanaka","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andr\u00e9a Cristina","family":"Foga\u00e7a","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zdenek","family":"Franta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucas","family":"Tirloni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michalis","family":"Kotsyfakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anderson","family":"S\u00e1-Nunes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,7,17]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1007\/s00508-019-1500-y","article-title":"Tick saliva and its role in pathogen transmission","volume":"1","author":"Nuttall","year":"2019","journal-title":"Wien Klin Wochenschr"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2021.05.005","article-title":"Tick host immunity: vector immunomodulation and acquired tick resistance","volume":"42","author":"Kitsou","year":"2021","journal-title":"Trends Immunol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2741\/3363","article-title":"The role of saliva in tick feeding","volume":"14","author":"Francischetti","year":"2009","journal-title":"Front Biosci (Landmark Ed)"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jprot.2015.07.005","article-title":"Modulation of host immunity by tick saliva","volume":"128","author":"Kot\u00e1l","year":"2015","journal-title":"J Proteomics"},{"key":"B5","doi-asserted-by":"publisher","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":"\u0160imo","year":"2017","journal-title":"Front Cell Infect Microbiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.ento.53.103106.093429","article-title":"Prevention of tick-borne diseases","volume":"53","author":"Piesman","year":"2008","journal-title":"Annu Rev Entomol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.ttbdis.2013.11.004","article-title":"Reassessment of the taxonomic status of Amblyomma cajennense () with the description of three new species, Amblyomma tonelliae n. sp., Amblyomma interandinum n. sp. and Amblyomma patinoi n. sp., and reinstatement of Amblyomma mixtum, and Amblyomma sculptum (Ixodida: Ixodidae)","volume":"5","author":"Nava","year":"2014","journal-title":"Ticks Tick Borne Dis"},{"key":"B8","doi-asserted-by":"publisher","first-page":"P. 106598","DOI":"10.1016\/j.actatropica.2022.106598","article-title":"Soft and hard ticks (Parasitiformes: ixodida) on humans: A review of Brazilian biomes and the impact of environmental change","volume":"234","author":"Nogueira","year":"2022","journal-title":"Acta Trop"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/j.idc.2008.03.008","article-title":"What\u2019s new in rocky mountain spotted fever","volume":"22","author":"Chen","year":"2008","journal-title":"Infect Dis Clin North Am"},{"key":"B10","unstructured":"\u00d3bitos confirmados de Febre Maculosa. Brasil, Regi\u00f5es e Unidades Federadas (Infec\u00e7\u00e3o) \u2013 2007 a 2025. Sa\u00fade de A a Z, Bras\u00edlia, DF (sede do Minist\u00e9rio da Sa\u00fade)\n          \n          2025"},{"key":"B11","doi-asserted-by":"publisher","first-page":"P. 140336","DOI":"10.1016\/j.bbapap.2019.140336","article-title":"Small protease inhibitors in tick saliva and salivary glands and their role in tick-host-pathogen interactions","volume":"1868","author":"Martins","year":"2020","journal-title":"Biochim Biophys Acta Proteins Proteom"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3390\/ijms24021556","article-title":"Tick salivary Kunitz-type inhibitors: targeting host hemostasis and immunity to mediate successful blood feeding","volume":"24","author":"Jmel","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/bs.apar.2024.09.001","article-title":"Proteases and protease inhibitors in saliva of hard ticks: biological role and pharmacological potential","volume":"126","author":"\u010cern\u00fd","year":"2024","journal-title":"Adv Parasitol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2020.00374","article-title":"TickSialoFam (TSFam): A database that helps to classify tick salivary proteins, A review on tick salivary protein function and evolution, with considerations on the tick sialome switching phenomenon","volume":"10","author":"Ribeiro","year":"2020","journal-title":"Front Cell Infect Microbiol"},{"key":"B15","doi-asserted-by":"publisher","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":"Chmela\u0159","year":"2017","journal-title":"Front Cell Infect Microbiol"},{"key":"B16","doi-asserted-by":"publisher","first-page":"P. 122","DOI":"10.1186\/s13071-015-0743-3","article-title":"Rhipicephalus microplus and Ixodes ovatus cystatins in tick blood digestion and evasion of host immune response","volume":"8","author":"Parizi","year":"2015","journal-title":"Parasit Vectors"},{"key":"B17","doi-asserted-by":"publisher","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":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.ttbdis.2012.03.004","article-title":"The role of cystatins in tick physiology and blood feeding","volume":"3","author":"Schwarz","year":"2012","journal-title":"Ticks Tick Borne Dis"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M513010200","article-title":"Antiinflammatory and immunosuppressive activity of Sialostatin L, A salivary cystatin from the tick Ixodes scapularis","volume":"281","author":"Kotsyfakis","year":"2006","journal-title":"J Biol Chem"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1242\/jeb.205.18.2843","article-title":"Exploring the sialome of the tick Ixodes scapularis","volume":"205","author":"Valenzuela","year":"2002","journal-title":"J Exp Biol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01156-3","article-title":"Signalp 6.0 predicts all five types of signal peptides using protein language models","volume":"40","author":"Teufel","year":"2022","journal-title":"Nat Biotechnol"},{"key":"B22","article-title":"Prediction of glycosylation across the human proteome and the correlation to protein function","volume":"7","author":"Gupta","year":"2002","journal-title":"Pac Symp Biocomput"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2013.79","article-title":"Precision mapping of the human O-galnac glycoproteome through simplecell technology","volume":"32","author":"Steentoft","year":"2013","journal-title":"EMBO J"},{"key":"B24","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1385\/1-59259-890-0:571","article-title":"Protein identification and analysis tools on the expasy server","volume-title":"The Proteomics Protocols Handbook","author":"Gasteiger","year":"2005"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-021-03819-2","article-title":"Highly accurate protein structure prediction with alphafold","volume":"596","author":"Jumper","year":"2021","journal-title":"Nature"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt458","article-title":"Galaxyrefine: protein structure refinement driven by side-chain repacking","volume":"41","author":"Heo","year":"2013","journal-title":"Nucleic Acids Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1002\/prot.24858","article-title":"Effective protein model structure refinement by loop modeling and overall relaxation","author":"Lee","year":"2016","journal-title":"Proteins"},{"key":"B28","doi-asserted-by":"publisher","first-page":"P. 102090","DOI":"10.1016\/j.ttbdis.2022.102090","article-title":"A draft of the genome of the gulf coast tick, Amblyomma maculatum","volume":"14","author":"Ribeiro","year":"2023","journal-title":"Ticks Tick Borne Dis"},{"key":"B29","doi-asserted-by":"publisher","first-page":"P. 17","DOI":"10.1186\/s12915-025-02121-1","article-title":"Genome sequences of four Ixodes species expands understanding of tick evolution","volume":"23","author":"Cerqueira De Araujo","year":"2025","journal-title":"BMC Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1038\/s41588-022-01275-w","article-title":"A high-quality Ixodes scapularis genome advances tick science","volume":"55","author":"De","year":"2023","journal-title":"Nat Genet"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-2836(05)80360-2","article-title":"Basic local alignment search tool","volume":"215","author":"Altschul","year":"1990","journal-title":"J Mol Biol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkac1052","article-title":"Uniprot: the universal protein knowledgebase in 2023","volume":"51","author":"Consortium","year":"2023","journal-title":"Nucleic Acids Res"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btu031","article-title":"Interproscan 5: genome-scale protein function classification","volume":"30","author":"Jones","year":"2014","journal-title":"Bioinformatics"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkae241","article-title":"The embl-ebi job dispatcher sequence analysis tools framework in 2024","volume":"52","author":"Madeira","year":"2024","journal-title":"Nucleic Acids Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp348","article-title":"Trimal: A tool for automated alignment trimming in large-scale phylogenetic analyses","volume":"25","author":"Capella-Guti\u00e9rrez","year":"2009","journal-title":"Bioinformatics"},{"key":"B36","doi-asserted-by":"publisher","first-page":"E96","DOI":"10.1002\/cpbi.96","article-title":"Using ggtree to visualize data on tree-like structures","volume":"69","author":"Yu","year":"2020","journal-title":"Curr Protoc Bioinf"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703143200","article-title":"Selective cysteine protease inhibition contributes to blood-feeding success of the tick Ixodes scapularis","volume":"282","author":"Kotsyfakis","year":"2007","journal-title":"J Biol Chem"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03034-3","article-title":"The structure and function of iristatin, a novel immunosuppressive tick salivary cystatin","volume":"76","author":"Kot\u00e1l","year":"2019","journal-title":"Cell Mol Life Sci"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22105371","article-title":"Mialostatin, a novel midgut cystatin from Ixodes ricinus ticks: Crystal structure and regulation of host blood digestion","volume":"22","author":"Kot\u00e1l","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B40","doi-asserted-by":"publisher","first-page":"P. 339","DOI":"10.1007\/s00018-023-04993-4","article-title":"Protease-bound structure of ricistatin provides insights into the mechanism of action of tick salivary cystatins in the vertebrate host","volume":"80","author":"Martins","year":"2023","journal-title":"Cell Mol Life Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/0014-5793(91)80804-C","article-title":"The cystatins: protein inhibitors of cysteine proteinases","volume":"285","author":"Turk","year":"1991","journal-title":"FEBS Lett"},{"key":"B42","doi-asserted-by":"publisher","first-page":"111003","DOI":"10.1016\/j.cbpb.2024.111003","article-title":"Functional characterization of a cystatin A from the bat Myotis davidii","volume":"274","author":"Costa","year":"2024","journal-title":"Comp Biochem Physiol B Biochem Mol Biol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1042\/bj1870909","article-title":"Fluorimetric assays for cathepsin B and cathepsin H with methylcoumarylamide substrates","volume":"187","author":"Barrett","year":"1980","journal-title":"Biochem J"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/0005-2744(69)90420-3","article-title":"Kinetics of the reversible inhibition of enzyme-catalysed reactions by tight-binding inhibitors","volume":"185","author":"Morrison","year":"1969","journal-title":"Biochim Biophys Acta"},{"key":"B45","doi-asserted-by":"publisher","first-page":"P. 329","DOI":"10.1186\/1756-3305-6-329","article-title":"Effects of Aedes aegypti salivary components on dendritic cell and lymphocyte biology","volume":"6","author":"Bizzarro","year":"2013","journal-title":"Parasit Vectors"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00118","article-title":"Amblyomma sculptum salivary PGE2 modulates the dendritic cell-Rickettsia rickettsii interactions in vitro and in vivo","author":"Esteves","year":"2019","journal-title":"Front Immunol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"E0155454","DOI":"10.1371\/journal.pone.0155454","article-title":"Exposure to Aedes aegypti bites induces A mixed-type allergic response following salivary antigens challenge in mice","volume":"11","author":"Barros","year":"2016","journal-title":"PloS One"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.611104","article-title":"Salivary protease inhibitors as potential anti-tick vaccines","volume":"11","author":"Costa","year":"2020","journal-title":"Front Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.68167","article-title":"Aemope-1, a novel salivary peptide from Aedes aegypti, selectively modulates activation of murine macrophages and ameliorates experimental colitis","volume":"12","author":"Lara","year":"2021","journal-title":"Front Immunol"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00476","article-title":"Analysis of the salivary gland transcriptome of unfed and partially fed Amblyomma sculptum ticks and descriptive proteome of the saliva","volume":"7","author":"Esteves","year":"2017","journal-title":"Front Cell Infect Microbiol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2014.07.012","article-title":"Rmcystatin3, A cysteine protease inhibitor from Rhipicephalus microplus hemocytes involved in immune response","volume":"106","author":"Lu","year":"2014","journal-title":"Biochimie"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1016\/j.biochi.2017.07.005","article-title":"Characterization of A novel cystatin type 2 from Rhipicephalus microplus midgut","volume":"140","author":"Cardoso","year":"2017","journal-title":"Biochimie"},{"key":"B53","doi-asserted-by":"publisher","first-page":"P. 101374","DOI":"10.1016\/j.ttbdis.2020.101374","article-title":"A novel type 1 cystatin involved in the regulation of Rhipicephalus microplus midgut cysteine proteases","volume":"11","author":"Lu","year":"2020","journal-title":"Ticks Tick Borne Dis"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1515\/BC.2006.204","article-title":"Two secreted cystatins of the soft tick Ornithodoros moubata: differential expression pattern and inhibitory specificity","volume":"387","author":"Grunclov\u00e1","year":"2006","journal-title":"Biol Chem"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1292\/jvms.09-0561","article-title":"Hlcyst-1 and Hlcyst-2 are potential inhibitors of hlcpl-A in the midgut of the ixodid tick Haemaphysalis longicornis","volume":"72","author":"Yamaji","year":"2010","journal-title":"J Vet Med Sci"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1988.tb03109.x","article-title":"The 2.0 A X-ray crystal structure of chicken egg white cystatin and its possible mode of interaction with cysteine proteinases","volume":"7","author":"Bode","year":"1988","journal-title":"EMBO J"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1042\/bss0700179","article-title":"Cystatins","volume":"70","author":"Abrahamson","year":"2003","journal-title":"Biochem Soc Symp"},{"key":"B58","article-title":"Mechanism of interaction of cysteine proteinases and their protein inhibitors as compared to the serine proteinase-inhibitor interaction","author":"Bode","year":"1990","journal-title":"Biol Chem Hoppe Seyler"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0900075","article-title":"The immunomodulatory action of Sialostatin L on dendritic cells reveals its potential to interfere with autoimmunity","volume":"182","author":"S\u00e1-Nunes","year":"2009","journal-title":"J Immunol"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2017.00288","article-title":"Salivary tick cystatin Omc2 targets lysosomal cathepsins S and C in human dendritic cells","volume":"7","author":"Zava\u0161nik-Bergant","year":"2017","journal-title":"Front Cell Infect Microbiol"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.1016\/j.pt.2020.11.004","article-title":"Dendritic cells as A disputed fortress on the tick-host battlefield","volume":"37","author":"S\u00e1-Nunes","year":"2021","journal-title":"Trends Parasitol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1111\/j.0105-2896.2005.00310.x","article-title":"The lysosomal cysteine proteases in mhc class ii antigen presentation","volume":"207","author":"Hsing","year":"2005","journal-title":"Immunol Rev"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1038\/nri3818","article-title":"The ins and outs of MHC class ii-mediated antigen processing and presentation","volume":"15","author":"Roche","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.8.5209","article-title":"Cutting edge: immunity against A \u201cSilent\u201d Salivary antigen of the lyme vector Ixodes scapularis impairs its ability to feed","volume":"181","author":"Kotsyfakis","year":"2008","journal-title":"J Immunol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.179.3.1497","article-title":"Prostaglandin E2 is a major inhibitor of dendritic cell maturation and function in Ixodes scapularis saliva","volume":"179","author":"S\u00e1-Nunes","year":"2007","journal-title":"J Immunol"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M110.205047","article-title":"Deconstructing tick saliva: non-protein molecules with potent immunomodulatory properties","volume":"286","author":"Oliveira","year":"2011","journal-title":"J Biol Chem"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.11.040193.001121","article-title":"Interleukin-10","volume":"11","author":"Moore","year":"1993","journal-title":"Annu Rev Immunol"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-immunol-031210-101312","article-title":"Regulation and functions of the IL-10 family of cytokines in inflammation and disease","volume":"29","author":"Ouyang","year":"2011","journal-title":"Annu Rev Immunol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1002\/eji.1830270920","article-title":"A filarial cysteine protease inhibitor down-regulates T cell proliferation and enhances interleukin-10 production","volume":"27","author":"Hartmann","year":"1997","journal-title":"Eur J Immunol"},{"key":"B70","doi-asserted-by":"publisher","first-page":"E1001248","DOI":"10.1371\/journal.ppat.1001248","article-title":"A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages","volume":"7","author":"Klotz","year":"2011","journal-title":"PloS Pathog"},{"key":"B71","doi-asserted-by":"publisher","first-page":"E0161885","DOI":"10.1371\/journal.pone.0161885","article-title":"The helminth-derived immunomodulator avcystatin reduces virus enhanced inflammation by induction of regulatory IL-10+ T cells","volume":"11","author":"Schuijs","year":"2016","journal-title":"PloS One"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.167.6.3207","article-title":"Modulation of human T cell responses and macrophage functions by onchocystatin, A secreted protein of the filarial nematode Onchocerca volvulus","volume":"167","author":"Sch\u00f6nemeyer","year":"2001","journal-title":"J Immunol"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.3347\/kjp.2011.49.3.245","article-title":"Parasitic helminth cystatin inhibits dss-induced intestinal inflammation via IL-10(+)F4\/80(+) macrophage recruitment","volume":"49","author":"Jang","year":"2011","journal-title":"Korean J Parasitol"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.3389\/fcimb.2021.617461","article-title":"Cystatin alleviates sepsis through activating regulatory macrophages","volume":"11","author":"Xie","year":"2021","journal-title":"Front Cell Infect Microbiol"},{"key":"B75","doi-asserted-by":"publisher","first-page":"P. 108907","DOI":"10.1016\/j.intimp.2022.108907","article-title":"Trichinella spiralis cystatin alleviates polymicrobial sepsis through activating regulatory macrophages","volume":"109","author":"Li","year":"2022","journal-title":"Int Immunopharmacol"},{"key":"B76","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2024.1344878","article-title":"Tick cysteine protease inhibitors suppress immune responses in mannan-induced psoriasis-like inflammation","volume":"15","author":"Wu","year":"2024","journal-title":"Front Immunol"},{"key":"B77","doi-asserted-by":"publisher","DOI":"10.1126\/science.167.3920.1002","article-title":"Neutrophils: their role in the formation of a tick feeding lesion","volume":"167","author":"Tatchell","year":"1970","journal-title":"Science"},{"key":"B78","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4894(80)90116-2","article-title":"Amblyomma americanum: sequential histological analysis of larval and nymphal feeding sites on Guinea pigs","volume":"49","author":"Brown","year":"1980","journal-title":"Exp Parasitol"},{"key":"B79","doi-asserted-by":"publisher","DOI":"10.4269\/ajtmh.1982.31.1285","article-title":"Antibody- and cell-mediated immune resistance by Guinea pigs to adult Amblyomma americanum ticks","volume":"31","author":"Brown","year":"1982","journal-title":"Am J Trop Med Hyg"},{"key":"B80","doi-asserted-by":"publisher","DOI":"10.1016\/0014-4894(83)90004-8","article-title":"Rhipicaphalus appendiculatus: larval feeding sites in Guinea pigs actively sensitized and receiving immune serum","volume":"55","author":"Brown","year":"1983","journal-title":"Exp Parasitol"},{"key":"B81","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxicon.2010.04.019","article-title":"A new tick kunitz type inhibitor, Amblyomin-X, induces tumor cell death by modulating genes related to the cell cycle and targeting the ubiquitin-proteasome system","volume":"56","author":"Chudzinski-Tavassi","year":"2010","journal-title":"Toxicon"},{"key":"B82","doi-asserted-by":"publisher","DOI":"10.1016\/j.toxrep.2018.11.014","article-title":"Preclinical evaluation of Amblyomin-X, A Kunitz-type protease inhibitor with antitumor activity","volume":"6","author":"Maria","year":"2019","journal-title":"Toxicol Rep"},{"key":"B83","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2000605117","article-title":"Semisynthesis of an evasin from tick saliva reveals a critical role of tyrosine sulfation for chemokine binding and inhibition","volume":"117","author":"Franck","year":"2020","journal-title":"Proc Natl Acad Sci U.S.A"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1585703\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,17]],"date-time":"2025-07-17T05:24:48Z","timestamp":1752729888000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1585703\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7,17]]},"references-count":83,"alternative-id":["10.3389\/fimmu.2025.1585703"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1585703","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7,17]]},"article-number":"1585703"}}