{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T17:58:12Z","timestamp":1780423092237,"version":"3.54.1"},"reference-count":107,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2021,9,26]],"date-time":"2021-09-26T00:00:00Z","timestamp":1632614400000},"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":["20-05736S"],"award-info":[{"award-number":["20-05736S"]}],"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":["CZ.02.1.01\/0.0\/0.0\/16_019\/0000759"],"award-info":[{"award-number":["CZ.02.1.01\/0.0\/0.0\/16_019\/0000759"]}],"id":[{"id":"10.13039\/501100008530","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100010100","name":"Jiho\u010desk\u00e1 Univerzita v \u010cesk\u00fdch Bud\u011bjovic\u00edch","doi-asserted-by":"publisher","award":["120\/2021\/P"],"award-info":[{"award-number":["120\/2021\/P"]}],"id":[{"id":"10.13039\/100010100","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Apicomplexan genomes encode multiple pepsin-family aspartyl proteases (APs) that phylogenetically cluster to six independent clades (A to F). Such diversification has been powered by the function-driven evolution of the ancestral apicomplexan AP gene and is associated with the adaptation of various apicomplexan species to different strategies of host infection and transmission through various invertebrate vectors. To estimate the potential roles of Babesia APs, we performed qRT-PCR-based expressional profiling of Babesia microti APs (BmASP2, 3, 5, 6), which revealed the dynamically changing mRNA levels and indicated the specific roles of individual BmASP isoenzymes throughout the life cycle of this parasite. To expand on the current knowledge on piroplasmid APs, we searched the EuPathDB and NCBI GenBank databases to identify and phylogenetically analyse the complete sets of APs encoded by the genomes of selected Babesia and Theileria species. Our results clearly determine the potential roles of identified APs by their phylogenetic relation to their homologues of known function\u2014Plasmodium falciparum plasmepsins (PfPM I\u2013X) and Toxoplasma\u00a0gondii aspartyl proteases (TgASP1\u20137). Due to the analogies with plasmodial plasmepsins, piroplasmid APs represent valuable enzymatic targets that are druggable by small molecule inhibitors\u2014candidate molecules for the yet-missing specific therapy for babesiosis.<\/jats:p>","DOI":"10.3390\/pathogens10101241","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T21:40:30Z","timestamp":1632778830000},"page":"1241","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Plasmepsin-like Aspartyl Proteases in Babesia"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3277-7001","authenticated-orcid":false,"given":"Pavla","family":"\u0160nebergerov\u00e1","sequence":"first","affiliation":[{"name":"Institute of Parasitology, Biology Centre, Academy of Sciences of the Czech Republic, Brani\u0161ovsk\u00e1 1160\/31, CZ-37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"},{"name":"Faculty of Science, University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice, Brani\u0161ovsk\u00e1 1760c, CZ-37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2370-6981","authenticated-orcid":false,"given":"Pavla","family":"Barto\u0161ov\u00e1-Sojkov\u00e1","sequence":"additional","affiliation":[{"name":"Institute of Parasitology, Biology Centre, Academy of Sciences of the Czech Republic, Brani\u0161ovsk\u00e1 1160\/31, CZ-37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Jaloveck\u00e1","sequence":"additional","affiliation":[{"name":"Faculty of Science, University of South Bohemia in \u010cesk\u00e9 Bud\u011bjovice, Brani\u0161ovsk\u00e1 1760c, CZ-37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9848-9435","authenticated-orcid":false,"given":"Daniel","family":"Sojka","sequence":"additional","affiliation":[{"name":"Institute of Parasitology, Biology Centre, Academy of Sciences of the Czech Republic, Brani\u0161ovsk\u00e1 1160\/31, CZ-37005 \u010cesk\u00e9 Bud\u011bjovice, Czech Republic"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"356","DOI":"10.1016\/j.pt.2019.01.007","article-title":"Babesia life cycle\u2013when phylogeny meets biology","volume":"35","author":"Jalovecka","year":"2019","journal-title":"Trends Parasitol."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Vannier, E., and Krause, P.J. (2020). Babesiosis. Hunter\u2019s Tropical Medicine and Emerging Infectious Diseases, Elsevier.","DOI":"10.1016\/B978-0-323-55512-8.00105-8"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1788","DOI":"10.1016\/j.meegid.2012.07.004","article-title":"Babesia: A world emerging","volume":"12","author":"Schnittger","year":"2012","journal-title":"Infect. Genet. Evol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1563","DOI":"10.1017\/S0031182014000961","article-title":"Vaccines against bovine babesiosis: Where we are now and possible roads ahead","volume":"141","author":"Suarez","year":"2014","journal-title":"Parasitology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1016\/j.ttbdis.2015.10.015","article-title":"Geographical distribution of Dermacentor marginatus and Dermacentor reticulatus in Europe","volume":"7","author":"Rubel","year":"2016","journal-title":"Ticks Tick-Borne Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2397","DOI":"10.1056\/NEJMra1202018","article-title":"Human babesiosis","volume":"366","author":"Vannier","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Lobo, C.A., Cursino-Santos, J.R., Alhassan, A., and Rodrigues, M. (2013). Babesia: An emerging infectious threat in transfusion medicine. PLoS Pathog., 9.","DOI":"10.1371\/journal.ppat.1003387"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"96.e91","DOI":"10.1016\/j.cmi.2014.07.004","article-title":"A retrospective serological survey on human babesiosis in Belgium","volume":"21","author":"Lempereur","year":"2015","journal-title":"Clin. Microbiol. Infect."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1588","DOI":"10.3201\/eid2408.180180","article-title":"Misdiagnosis of babesiosis as malaria, Equatorial Guinea, 2014","volume":"24","author":"Arsuaga","year":"2018","journal-title":"Emerg. Infect. Dis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"622","DOI":"10.1016\/j.pt.2019.06.002","article-title":"Babesiosis vaccines: Lessons learned, challenges ahead, and future glimpses","volume":"35","author":"Rathinasamy","year":"2019","journal-title":"Trends Parasitol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/nmicrobiol.2016.79","article-title":"A global map of genetic diversity in Babesia microti reveals strong population structure and identifies variants associated with clinical relapse","volume":"1","author":"Lemieux","year":"2016","journal-title":"Nat. Microbiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1222","DOI":"10.1093\/cid\/cix477","article-title":"Clinical and molecular evidence of atovaquone and azithromycin resistance in relapsed Babesia microti infection associated with rituximab and chronic lymphocytic leukemia","volume":"65","author":"Simon","year":"2017","journal-title":"Clin. Infect. Dis."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1146\/annurev.pathol.1.110304.100151","article-title":"Proteases in parasitic diseases","volume":"1","author":"McKerrow","year":"2006","journal-title":"Annu. Rev. Pathol. Mech. Dis."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1002\/pro.3948","article-title":"How to use the MEROPS database and website to help understand peptidase specificity","volume":"30","author":"Rawlings","year":"2021","journal-title":"Protein Sci."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Barrett, A.J., Rawlings, N.D., Salvesen, G., and Woessner, J.F. (2012). Handbook of proteolytic enzymes introduction. Handbook of Proteolytic Enzymes, Elsevier. [3rd ed.].","DOI":"10.1016\/B978-0-12-382219-2.00838-3"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"708","DOI":"10.1016\/j.pt.2016.05.015","article-title":"Parasite cathepsin D-like peptidases and their relevance as therapeutic targets","volume":"32","author":"Sojka","year":"2016","journal-title":"Trends Parasitol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1018","DOI":"10.1111\/j.1600-0854.2007.00589.x","article-title":"A family of aspartic proteases and a novel, dynamic and cell-cycle-dependent protease localization in the secretory pathway of Toxoplasma Gondii","volume":"8","author":"Shea","year":"2007","journal-title":"Traffic"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1016\/S1471-4922(01)02037-2","article-title":"Aspartic proteases of Plasmodium falciparum and other parasitic protozoa as drug targets","volume":"17","author":"Coombs","year":"2001","journal-title":"Trends Parasitol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1016\/j.chom.2020.03.015","article-title":"Targeting plasmepsins\u2014an achilles\u2019 heel of the malaria parasite","volume":"27","author":"Burrows","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_20","unstructured":"Jalovecka, M., Urbanova, V., Sojka, D., Malandrin, L., Sima, R., Kopacek, P., and Hajdusek, O. (2017, January 20). Establishment of Babesia microti laboratory model and its experimental application. Proceedings of the 9. Tick and Tick-borne Pathogen Conference and 1st Asia Pacific Rickettsia Conference, Cairns, Australia."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1126\/science.aaf8675","article-title":"A multistage antimalarial targets the plasmepsins IX and X essential for invasion and egress","volume":"358","author":"Pino","year":"2017","journal-title":"Science"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"e27480","DOI":"10.7554\/eLife.27480","article-title":"A druggable secretory protein maturase of Toxoplasma essential for invasion and egress","volume":"6","author":"Dogga","year":"2017","journal-title":"Elife"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-016-1161-5","article-title":"Plasmodium falciparum ookinete expression of plasmepsin VII and plasmepsin X","volume":"15","author":"Li","year":"2016","journal-title":"Malar. J."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/j.1365-2958.2008.06407.x","article-title":"Reverse genetics screen identifies six proteins important for malaria development in the mosquito","volume":"70","author":"Ecker","year":"2008","journal-title":"Mol. Microbiol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"248","DOI":"10.3389\/fcimb.2018.00248","article-title":"The complexity of piroplasms life cycles","volume":"8","author":"Jalovecka","year":"2018","journal-title":"Front. Cell. Infect. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1111\/tra.12053","article-title":"Role of plasmepsin V in export of diverse protein families from the Plasmodium falciparum exportome","volume":"14","author":"Boddey","year":"2013","journal-title":"Traffic"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1038\/nature08726","article-title":"Plasmepsin V licenses Plasmodium proteins for export into the host erythrocyte","volume":"463","author":"Russo","year":"2010","journal-title":"Nature"},{"key":"ref_28","first-page":"e01718","article-title":"Aspartyl protease 5 matures dense granule proteins that reside at the host-parasite interface","volume":"9","author":"Coffey","year":"2018","journal-title":"Toxoplasma Gondii. MBio"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"35284","DOI":"10.1038\/srep35284","article-title":"Genome-wide diversity and gene expression profiling of Babesia microti isolates identify polymorphic genes that mediate host-pathogen interactions","volume":"6","author":"Silva","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e201900382","DOI":"10.26508\/lsa.201900382","article-title":"Evidence for vesicle-mediated antigen export by the human pathogen Babesia Microti","volume":"2","author":"Thekkiniath","year":"2019","journal-title":"Life Sci. Alliance"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1007\/BF00219605","article-title":"An electron microscopic study of Babesia microti invading erythrocytes","volume":"169","author":"Rudzinska","year":"1976","journal-title":"Cell Tissue Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"3796","DOI":"10.1016\/j.celrep.2019.11.073","article-title":"Inhibition of plasmepsin V activity blocks Plasmodium falciparum gametocytogenesis and transmission to mosquitoes","volume":"29","author":"Jennison","year":"2019","journal-title":"Cell Rep."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1432","DOI":"10.1074\/jbc.M409740200","article-title":"The role of Plasmodium falciparum food vacuole plasmepsins","volume":"280","author":"Liu","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_34","first-page":"567","article-title":"Apicomplexa","volume":"2","year":"2017","journal-title":"Handb. Protists"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/srep24461","article-title":"Hemoglobin consumption by P. falciparum in individual erythrocytes imaged via quantitative phase spectroscopy","volume":"6","author":"Rinehart","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12936-016-1097-9","article-title":"Comparative genome-wide analysis and evolutionary history of haemoglobin-processing and haem detoxification enzymes in malarial parasites","volume":"15","author":"Ponsuwanna","year":"2016","journal-title":"Malar. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"8425","DOI":"10.1074\/jbc.REV120.009309","article-title":"Malaria parasite plasmepsins: More than just plain old degradative pepsins","volume":"295","author":"Nasamu","year":"2020","journal-title":"J. Biol. Chem."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/S0166-6851(96)02763-6","article-title":"Hemoglobin catabolism and iron utilization by malaria parasites","volume":"83","author":"Rosenthal","year":"1996","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4189","DOI":"10.1182\/blood-2002-08-2654","article-title":"Excess hemoglobin digestion and the osmotic stability of Plasmodium falciparum\u2013infected red blood cells","volume":"101","author":"Lew","year":"2003","journal-title":"Blood"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"5392","DOI":"10.1073\/pnas.1218412110","article-title":"Protein complex directs hemoglobin-to-hemozoin formation in Plasmodium falciparum","volume":"110","author":"Chugh","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_41","first-page":"1","article-title":"Characterizations of individual mouse red blood cells parasitized by Babesia microti using 3-D holographic microscopy","volume":"5","author":"Park","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1089\/vbz.2016.1955","article-title":"Guidelines for the detection of Babesia and Theileria parasites","volume":"17","author":"Lempereur","year":"2017","journal-title":"Vector-Borne Zoonotic Dis."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.3324\/haematol.2018.214304","article-title":"Altered parasite life-cycle processes characterize Babesia divergens infection in human sickle cell anemia","volume":"104","author":"Singh","year":"2019","journal-title":"Haematologica"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/0040-8166(87)90071-1","article-title":"Ultrastructure of the intra-erythrocytic stage of Theileria species from cattle and waterbuck","volume":"19","author":"Fawcett","year":"1987","journal-title":"Tissue Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1590\/S0100-736X2003000300002","article-title":"Ultrastructure of Babesia equi trophozoites isolated in Minas Gerais, Brazil","volume":"23","author":"Lima","year":"2003","journal-title":"Pesqui. Vet. Bras."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1111\/j.1550-7408.1976.tb03759.x","article-title":"Ultrastructure of intraerythrocytic Babesia microti with emphasis on the feeding mechanism","volume":"23","author":"Rudzinska","year":"1976","journal-title":"J. Protozool."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e00928-20","DOI":"10.1128\/mSphere.00928-20","article-title":"Four-dimensional characterizationof the Babesia divergens asexual life cycle, from the trophozoite to the multiparasite stage","volume":"5","author":"Conesa","year":"2020","journal-title":"MSphere"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1016\/j.exppara.2007.04.009","article-title":"Babesia bovis: Effects of cysteine protease inhibitors on in vitro growth","volume":"117","author":"Okubo","year":"2007","journal-title":"Exp. Parasitol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1016\/j.ttbdis.2015.09.002","article-title":"Characterization of a papain-like cysteine protease essential for the survival of Babesia ovis merozoites","volume":"7","author":"Carletti","year":"2016","journal-title":"Ticks Tick-Borne Dis."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/S1471-4922(01)02030-X","article-title":"Aspartyl proteinase genes from apicomplexan parasites: Evidence for evolution of the gene structure","volume":"17","author":"Jean","year":"2001","journal-title":"Trends Parasitol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1016\/j.ijpara.2016.11.009","article-title":"Plasmodium berghei plasmepsin VIII is essential for sporozoite gliding motility","volume":"47","author":"Mastan","year":"2017","journal-title":"Int. J. Parasitol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"990","DOI":"10.1073\/pnas.022630099","article-title":"Four plasmepsins are active in the Plasmodium falciparum food vacuole, including a protease with an active-site histidine","volume":"99","author":"Banerjee","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"642","DOI":"10.1016\/j.chom.2020.02.005","article-title":"Dual plasmepsin-targeting antimalarial agents disrupt multiple stages of the malaria parasite life cycle","volume":"27","author":"Favuzza","year":"2020","journal-title":"Cell Host Microbe"},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Sojka, D., \u0160nebergerov\u00e1, P., and Robbertse, L. (2021). Protease inhibition\u2014an established strategy to combat infectious diseases. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22115762"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/j.mib.2013.05.002","article-title":"Invasion factors of apicomplexan parasites: Essential or redundant?","volume":"16","author":"Meissner","year":"2013","journal-title":"Curr. Opin. Microbiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"645","DOI":"10.1038\/nrmicro.2017.86","article-title":"Gliding motility powers invasion and egress in Apicomplexa","volume":"15","author":"Dubremetz","year":"2017","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1051\/vetres\/2009020","article-title":"Babesia and its hosts: Adaptation to long-lasting interactions as a way to achieve efficient transmission","volume":"40","author":"Chauvin","year":"2009","journal-title":"Vet. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1128\/IAI.73.1.649-651.2005","article-title":"Babesia divergens and Plasmodium falciparum use common receptors, glycophorins A and B, to invade the human red blood cell","volume":"73","author":"Lobo","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1111\/cmi.12276","article-title":"Malaria adhesins: Structure and function","volume":"16","author":"Malpede","year":"2014","journal-title":"Cell. Microbiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1093\/femsre\/fuw001","article-title":"Merozoite surface proteins in red blood cell invasion, immunity and vaccines against malaria","volume":"40","author":"Beeson","year":"2016","journal-title":"FEMS Microbiol. Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"6448","DOI":"10.1128\/IAI.70.11.6448-6455.2002","article-title":"Babesia bovis merozoite surface antigen 2 proteins are expressed on the merozoite and sporozoite surface, and specific antibodies inhibit attachment and invasion of erythrocytes","volume":"70","author":"Mosqueda","year":"2002","journal-title":"Infect. Immun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"972","DOI":"10.3389\/fcell.2021.662805","article-title":"Theileria\u2019s strategies and effector mechanisms for host cell transformation: From invasion to immortalization","volume":"9","author":"Woods","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1097\/MOH.0b013e328352245a","article-title":"Babesia and red cell invasion","volume":"19","author":"Lobo","year":"2012","journal-title":"Curr. Opin. Hematol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"797","DOI":"10.1111\/j.1462-5822.2011.01597.x","article-title":"The moving junction of apicomplexan parasites: A key structure for invasion","volume":"13","author":"Besteiro","year":"2011","journal-title":"Cell. Microbiol."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"4783","DOI":"10.1128\/IAI.00969-08","article-title":"Babesia divergens apical membrane antigen 1 and its interaction with the human red blood cell","volume":"77","author":"Montero","year":"2009","journal-title":"Infect. Immun."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3890","DOI":"10.1128\/IAI.00168-15","article-title":"Expression, purification, and biological characterization of Babesia microti apical membrane antigen 1","volume":"83","author":"Moitra","year":"2015","journal-title":"Infect. Immun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"2947","DOI":"10.1128\/IAI.72.5.2947-2955.2004","article-title":"Erythrocyte invasion by Babesia bovis merozoites is inhibited by polyclonal antisera directed against peptides derived from a homologue of Plasmodium falciparum apical membrane antigen 1","volume":"72","author":"Gaffar","year":"2004","journal-title":"Infect. Immun."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Gonz\u00e1lez, L.M., Estrada, K., Grande, R., Jim\u00e9nez-Jacinto, V., Vega-Alvarado, L., Sevilla, E., Barrera, J., Cuesta, I., Zaballos, \u00c1., and Bautista, J.M. (2019). Comparative and functional genomics of the protozoan parasite Babesia divergens highlighting the invasion and egress processes. PLoS Negl. Trop. Dis., 13.","DOI":"10.1371\/journal.pntd.0007680"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Buguliskis, J.S., Brossier, F., Shuman, J., and Sibley, L.D. (2010). Rhomboid 4 (ROM4) affects the processing of surface adhesins and facilitates host cell invasion by Toxoplasma gondii. PLoS Pathog., 6.","DOI":"10.1371\/journal.ppat.1000858"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/S1471-4922(02)00015-6","article-title":"Cell invasion by Theileria sporozoites","volume":"19","author":"Shaw","year":"2003","journal-title":"Trends Parasitol."},{"key":"ref_71","doi-asserted-by":"crossref","unstructured":"Shaw, M.K. (2002). Theileria development and host cell invasion. Theileria, Springer.","DOI":"10.1007\/978-1-4615-0903-5_1"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"447","DOI":"10.1038\/s41564-018-0111-0","article-title":"A protease cascade regulates release of the human malaria parasite Plasmodium falciparum from host red blood cells","volume":"3","author":"Thomas","year":"2018","journal-title":"Nat. Microbiol."},{"key":"ref_73","doi-asserted-by":"crossref","unstructured":"Collins, C.R., Hackett, F., Atid, J., Tan, M.S.Y., and Blackman, M.J. (2017). The Plasmodium falciparum pseudoprotease SERA5 regulates the kinetics and efficiency of malaria parasite egress from host erythrocytes. PLoS Pathog., 13.","DOI":"10.1371\/journal.ppat.1006453"},{"key":"ref_74","first-page":"1","article-title":"The malaria parasite egress protease SUB1 is a calcium-dependent redox switch subtilisin","volume":"5","author":"Strath","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.chom.2015.09.007","article-title":"Processing of Plasmodium falciparum merozoite surface protein MSP1 activates a spectrin-binding function enabling parasite egress from RBCs","volume":"18","author":"Das","year":"2015","journal-title":"Cell Host Microbe"},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1038\/emboj.2009.22","article-title":"A multifunctional serine protease primes the malaria parasite for red blood cell invasion","volume":"28","author":"Koussis","year":"2009","journal-title":"EMBO J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"35717","DOI":"10.1074\/jbc.M604344200","article-title":"A conserved subtilisin protease identified in Babesia divergens merozoites","volume":"281","author":"Montero","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Lempereur, L., Larcombe, S.D., Durrani, Z., Karagenc, T., Bilgic, H.B., Bakirci, S., Hacilarlioglu, S., Kinnaird, J., Thompson, J., and Weir, W. (2017). Identification of candidate transmission-blocking antigen genes in Theileria annulata and related vector-borne apicomplexan parasites. BMC Genom., 18.","DOI":"10.1186\/s12864-017-3788-1"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1111\/j.1365-2958.2005.05024.x","article-title":"CelTOS, a novel malarial protein that mediates transmission to mosquito and vertebrate hosts","volume":"59","author":"Kariu","year":"2006","journal-title":"Mol. Microbiol."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"e20621","DOI":"10.7554\/eLife.20621","article-title":"Malaria parasite CelTOS targets the inner leaflet of cell membranes for pore-dependent disruption","volume":"5","author":"Jimah","year":"2016","journal-title":"Elife"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1093\/emboj\/19.11.2435","article-title":"RAP1 controls rhoptry targeting of RAP2 in the malaria parasite Plasmodium Falciparum","volume":"19","author":"Baldi","year":"2000","journal-title":"EMBO J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"e01419","DOI":"10.1128\/mBio.01460-19","article-title":"Deletion of Plasmodium falciparum protein RON3 affects the functional translocation of exported proteins and glucose uptake","volume":"10","author":"Low","year":"2019","journal-title":"MBio"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1016\/j.chom.2016.10.015","article-title":"Plasmodium merozoite TRAP family protein is essential for vacuole membrane disruption and gamete egress from erythrocytes","volume":"20","author":"Bargieri","year":"2016","journal-title":"Cell Host Microbe"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1038\/85064","article-title":"BACE1 is the major \u03b2-secretase for generation of A\u03b2 peptides by neurons","volume":"4","author":"Cai","year":"2001","journal-title":"Nat. Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","unstructured":"Sleebs, B.E., Lopaticki, S., Marapana, D.S., O\u2019Neill, M.T., Rajasekaran, P., Gazdik, M., G\u00fcnther, S., Whitehead, L.W., Lowes, K.N., and Barfod, L. (2014). Inhibition of Plasmepsin V activity demonstrates its essential role in protein export, PfEMP1 display, and survival of malaria parasites. PLoS Biol., 12.","DOI":"10.1371\/journal.pbio.1001897"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1111\/cmi.12498","article-title":"The aspartyl protease TgASP5 mediates the export of the Toxoplasma GRA16 and GRA24 effectors into host cells","volume":"18","author":"Braun","year":"2016","journal-title":"Cell. Microbiol."},{"key":"ref_87","doi-asserted-by":"crossref","unstructured":"Hammoudi, P.-M., Jacot, D., Mueller, C., Di Cristina, M., Dogga, S.K., Marq, J.-B., Romano, J., Tosetti, N., Dubrot, J., and Emre, Y. (2015). Fundamental roles of the Golgi-associated Toxoplasma aspartyl protease, ASP5, at the host-parasite interface. PLoS Pathog., 11.","DOI":"10.1371\/journal.ppat.1005211"},{"key":"ref_88","doi-asserted-by":"crossref","unstructured":"Asada, M., Goto, Y., Yahata, K., Yokoyama, N., Kawai, S., Inoue, N., Kaneko, O., and Kawazu, S.-I. (2012). Gliding motility of Babesia bovis merozoites visualized by time-lapse video microscopy. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0035227"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1111\/cmi.12422","article-title":"The apicomplexan parasite Babesia divergens internalizes band 3, glycophorin A and spectrin during invasion of human red blood cells","volume":"17","author":"Repnik","year":"2015","journal-title":"Cell. Microbiol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1038\/s41579-019-0321-3","article-title":"The parasitophorous vacuole of the blood-stage malaria parasite","volume":"18","author":"Matz","year":"2020","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_91","doi-asserted-by":"crossref","unstructured":"Egea, P.F. (2020). Crossing the vacuolar rubicon: Structural insights into effector protein trafficking in apicomplexan parasites. Microorganisms, 8.","DOI":"10.3390\/microorganisms8060865"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/s41586-018-0469-4","article-title":"Malaria parasite translocon structure and mechanism of effector export","volume":"561","author":"Ho","year":"2018","journal-title":"Nature"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e00819","DOI":"10.1128\/mSphere.00858-19","article-title":"Coimmunoprecipitation with MYR1 identifies three additional proteins within the Toxoplasma gondii parasitophorous vacuole required for translocation of dense granule effectors into host cells","volume":"5","author":"Cygan","year":"2020","journal-title":"Msphere"},{"key":"ref_94","doi-asserted-by":"crossref","unstructured":"Hakimi, H., Templeton, T.J., Sakaguchi, M., Yamagishi, J., Miyazaki, S., Yahata, K., Uchihashi, T., Kawazu, S.-I., Kaneko, O., and Asada, M. (2020). Novel Babesia bovis exported proteins that modify properties of infected red blood cells. PLoS Pathog., 16.","DOI":"10.1371\/journal.ppat.1008917"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1618","DOI":"10.1111\/cmi.12460","article-title":"Shared elements of host-targeting pathways among apicomplexan parasites of differing lifestyles","volume":"17","author":"Jiang","year":"2015","journal-title":"Cell. Microbiol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1016\/j.ijpara.2018.11.002","article-title":"Unravelling the cellular and molecular pathogenesis of bovine babesiosis: Is the sky the limit?","volume":"49","author":"Suarez","year":"2019","journal-title":"Int. J. Parasitol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"7113","DOI":"10.1093\/nar\/gku322","article-title":"The evolutionary dynamics of variant antigen genes in Babesia reveal a history of genomic innovation underlying host\u2013parasite interaction","volume":"42","author":"Jackson","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"9102","DOI":"10.1093\/nar\/gks700","article-title":"Sequencing of the smallest Apicomplexan genome from the human pathogen Babesia microti","volume":"40","author":"Cornillot","year":"2012","journal-title":"Nucleic Acids Res."},{"key":"ref_99","first-page":"1","article-title":"A novel Babesia orientalis 135-kilodalton spherical body protein like: Identification of its secretion into cytoplasm of infected erythrocytes","volume":"11","author":"Guo","year":"2018","journal-title":"Parasites Vectors"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.molbiopara.2014.05.004","article-title":"Gene disruption reveals a dispensable role for plasmepsin VII in the Plasmodium berghei life cycle","volume":"195","author":"Mastan","year":"2014","journal-title":"Mol. Biochem. Parasitol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"454","DOI":"10.1016\/j.exppara.2011.05.003","article-title":"Toxoplasma gondii aspartic protease 1 is not essential in tachyzoites","volume":"128","author":"Polonais","year":"2011","journal-title":"Exp. Parasitol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1038\/nrmicro3184","article-title":"Cell division in apicomplexan parasites","volume":"12","author":"Francia","year":"2014","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1186\/s13071-016-1731-y","article-title":"Stimulation and quantification of Babesia divergens gametocytogenesis","volume":"9","author":"Jalovecka","year":"2016","journal-title":"Parasites Vectors"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"e45","DOI":"10.1093\/nar\/29.9.e45","article-title":"A new mathematical model for relative quantification in real-time RT\u2013PCR","volume":"29","author":"Pfaffl","year":"2001","journal-title":"Nucleic Acids Res."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1647","DOI":"10.1093\/bioinformatics\/bts199","article-title":"Geneious Basic: An integrated and extendable desktop software platform for the organization and analysis of sequence data","volume":"28","author":"Kearse","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"W232","DOI":"10.1093\/nar\/gkw256","article-title":"W-IQ-TREE: A fast online phylogenetic tool for maximum likelihood analysis","volume":"44","author":"Trifinopoulos","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nmeth.4285","article-title":"ModelFinder: Fast model selection for accurate phylogenetic estimates","volume":"14","author":"Kalyaanamoorthy","year":"2017","journal-title":"Nat. Methods"}],"container-title":["Pathogens"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-0817\/10\/10\/1241\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:05:06Z","timestamp":1760166306000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-0817\/10\/10\/1241"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,26]]},"references-count":107,"journal-issue":{"issue":"10","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["pathogens10101241"],"URL":"https:\/\/doi.org\/10.3390\/pathogens10101241","relation":{},"ISSN":["2076-0817"],"issn-type":[{"value":"2076-0817","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,26]]}}}