Although apicomplexan parasites of the group Piroplasmida represent commonly identified global risks to both animals and humans, detailed knowledge of their life cycles is surprisingly limited. Such a discrepancy results from incomplete literature reports, nomenclature disunity and recently, from large numbers of newly described species. This review intends to collate and summarize current knowledge with respect to piroplasm phylogeny. Moreover, it provides a comprehensive view of developmental events of Babesia, Theileria, and Cytauxzoon representative species, focusing on uniform consensus of three consecutive phases: (i) schizogony and merogony, asexual multiplication in blood cells of the vertebrate host; (ii) gamogony, sexual reproduction inside the tick midgut, later followed by invasion of kinetes into the tick internal tissues; and (iii) sporogony, asexual proliferation in tick salivary glands resulting in the formation of sporozoites. However, many fundamental differences in this general consensus occur and this review identifies variables that should be analyzed prior to further development of specific anti-piroplasm strategies, including the attractive targeting of life cycle stages of Babesia or Theileria tick vectors.

BIOEPAR INRA Oniris Université Bretagne Loire Nantes France

Faculty of Science University of South Bohemia České Budějovice Czechia

Institute of Parasitology Biology Centre of the Czech Academy of Sciences České Budějovice Czechia

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Ahmed J. S., Schnittger L., Mehlhorn H. (1999). Review: Theileria schizonts induce fundamental alterations in their host cells. Parasitol. Res. 85, 527–538. 10.1007/s004360050592 PubMed DOI

Alzan H. F., Knowles D. P., Suarez C. E. (2016). Comparative bioinformatics analysis of transcription factor genes indicates conservation of key regulatory domains among Babesia bovis, Babesia microti, and Theileria equi. PLoS Negl. Trop. Dis. 10:e0004983. 10.1371/journal.pntd.0004983 PubMed DOI PMC

Arisue N., Hashimoto T. (2014). Phylogeny and evolution of apicoplasts and apicomplexan parasites. Parasitol. Int. 64, 254–259. 10.1016/j.parint.2014.10.005 PubMed DOI

Asada M., Goto Y., Yahata K., Yokoyama N., Kawai S., Inoue N., et al. . (2012). Gliding motility of Babesia bovis merozoites visualized by time-lapse video microscopy. PLoS ONE 7:e35227. 10.1371/journal.pone.0035227 PubMed DOI PMC

Baneth G., Florin-Christensen M., Cardoso L., Schnittger L. (2015). Reclassification of Theileria annae as Babesia vulpes sp. nov. Parasit. Vectors 8:207. 10.1186/s13071-015-0830-5 PubMed DOI PMC

Bastos R. G., Suarez C. E., Laughery J. M., Johnson W. C., Ueti M. W., Knowles D. P. (2013). Differential expression of three members of the multidomain adhesion CCp family in Babesia bigemina, Babesia bovis and Theileria equi. PLoS ONE 8:e67765. 10.1371/journal.pone.0067765 PubMed DOI PMC

Becker C. A., Malandrin L., Depoix D., Larcher T., David P. H., Chauvin A., et al. . (2010). Identification of three CCp genes in Babesia divergens: novel markers for sexual stages parasites. Mol. Biochem. Parasitol. 174, 36–43. 10.1016/j.molbiopara.2010.06.011 PubMed DOI

Becker C. A., Malandrin L., Larcher T., Chauvin A., Bischoff E., Bonnet S. I. (2013). Validation of BdCCp2 as a marker for Babesia divergens sexual stages in ticks. Exp. Parasitol. 133, 51–56. 10.1016/j.exppara.2012.10.007 PubMed DOI

Binnington K. C. (1978). Sequential changes in salivary gland structure during attachment and feeding of the cattle tick, Boophilus microplus. Int. J. Parasitol. 8, 97–115. 10.1016/0020-7519(78)90004-8 PubMed DOI

Bishop R., Musoke A., Morzaria S., Gardner M., Nene V. (2004). Theileria: intracellular protozoan parasites of wild and domestic ruminants transmitted by ixodid ticks. Parasitology 129, 271–283. 10.1017/S0031182003004748 PubMed DOI

Bishop R. P., Hemmink J. D., Morrison W. I., Weir W., Toye P. G., Sitt T., et al. . (2015). The African buffalo parasite Theileria. sp. (buffalo) can infect and immortalize cattle leukocytes and encodes divergent orthologues of Theileria parva antigen genes. Int. J. Parasitol. Parasites Wildl. 4, 333–342. 10.1016/j.ijppaw.2015.08.006 PubMed DOI PMC

Blouin E. F., De Waal D. T. (1989). The fine structure of developmental stages of Babesia caballiin the salivary glands of Hyalomma truncatum. Onderstepoort J. Vet. Res. 56, 189–193. PubMed

Blouin E. F., Kocan A. A., Kocan K. M., Hair J. (1987). Evidence of a limited schizogonous cycle for Cytauxzoon felis in bobcats following exposure to infected ticks. J. Wildl. Dis. 23, 499–501. 10.7589/0090-3558-23.3.499 PubMed DOI

Blouin E. F., van Rensburg L. (1988). An ultrastructural study of the development of Babesia occultans in the salivary glands of adult Hyalomma marginatum rufipes. Onderstepoort J. Vet. Res. 55, 93–100. PubMed

Bock R., Jackson L., de Vos A., Jorgensen W. (2004). Babesiosis of cattle. Parasitol. 129(Suppl.) S247–S269. 10.1017/S0031182004005190 PubMed DOI

Boldbaatar D., Battsetseg B., Matsuo T., Hatta T., Umemiya-Shirafuji R., Xuan X., et al. . (2008). Tick vitellogenin receptor reveals critical role in oocyte development and transovarial transmission of Babesia parasite. Biochem. Cell Biol. 86, 331–344. 10.1139/O08-071 PubMed DOI

Boldbaatar D., Umemiya-Shirafuji R., Liao M., Tanaka T., Xuan X., Fujisaki K. (2010). Multiple vitellogenins from the Haemaphysalis longicornis tick are crucial for ovarian development. J. Insect Physiol. 56, 1587–1598. 10.1016/j.jinsphys.2010.05.019 PubMed DOI

Bonnet S., Jouglin M., Malandrin L., Becker C., Agoulon A., L'hostis M., et al. . (2007). Transstadial and transovarial persistence of Babesia divergens DNA in Ixodes ricinus ticks fed on infected blood in a new skin-feeding technique. Parasitology 134, 197–207. 10.1017/S0031182006001545 PubMed DOI

Burki F., Inagaki Y., Bråte J., Archibald J. M., Keeling P. J., Cavalier-Smith T., et al. . (2009). Large-scale phylogenomic analyses reveal that two enigmatic protist lineages, telonemia and centroheliozoa, are related to photosynthetic chromalveolates. Genome Biol. Evol. 1, 231–238. 10.1093/gbe/evp022 PubMed DOI PMC

Christophers S. R. (1907). Preliminary note on the development of Piroplasma canis in the tick. Br. Med. J. 1, 76–78. 10.1136/bmj.1.2402.76 PubMed DOI PMC

Clancey N., Horney B., Burton S., Birkenheuer A., McBurney S., Tefft K. (2010). Babesia (Theileria) annae in a red fox (Vulpes vulpes) from Prince Edward Island, Canada. J. Wildl. Dis. 46, 615–621. 10.7589/0090-3558-46.2.615 PubMed DOI

Conrad P. A., Denham D., Brown C. G. (1986). Intraerythrocytic multiplication of Theileria parva in vitro: an ultrastructural study. Int. J. Parasitol. 16, 223–229. 10.1016/0020-7519(86)90047-0 PubMed DOI

Conrad P. A., Kelly B. G., Brown C. G. (1985). Intraerythrocytic schizogony of Theileria annulata. Parasitology 91, 67–82. 10.1017/S0031182000056523 PubMed DOI

Coons L. B., Roshdy M. A. (1973). Fine structure of the salivary glands of unfed male Dermacentor variabilis (Say) (Ixodoidea: Ixodidae). J. Parasitol. 59, 900–912. 10.2307/3278433 PubMed DOI

de la Fuente J., Antunes S., Bonnet S., Cabezas-Cruz A., Domingos A. G., Estrada-Peña A., et al. . (2017). Tick-pathogen interactions and vector competence: identification of molecular drivers for tick-borne diseases. Front. Cell. Infect. Microbiol. 7:114. 10.3389/fcimb.2017.00114 PubMed DOI PMC

Del Carmen Terrón M., González-Camacho F., González L. M., Luque D., Montero E. (2016). Ultrastructure of the Babesia divergens free merozoite. Ticks Tick Borne Dis. 7, 1274–1279. 10.1016/j.ttbdis.2016.07.001 PubMed DOI

Dobbelaere D., Heussler V. (1999). Transformation of leukocytes by Theileria parva and T. annulata. Annu. Rev. Microbiol. 53, 1–42. 10.1146/annurev.micro.53.1.1 PubMed DOI

Dobbelaere D. A., Küenzi P. (2004). The strategies of the Theileria parasite: a new twist in host-pathogen interactions. Curr. Opin. Immunol. 16, 524–530. 10.1016/j.coi.2004.05.009 PubMed DOI

Dobbelaere D. A., Rottenberg S. (2003). Theileria-induced leukocyte transformation. Curr. Opin. Microbiol. 6, 377–382. 10.1016/S1369-5274(03)00085-7 PubMed DOI

Dobbelaere D. A., Webster P., Leitch B. L., Voigt W. P., Irvin A. D. (1985). Theileria parva: expression of a sporozoite surface coat antigen. Exp. Parasitol. 60, 90–100. 10.1016/S0014-4894(85)80026-6 PubMed DOI

Donnelly J., Peirce M. A. (1975). Experiments on the transmission of Babesia divergens to cattle by the tick Ixodes ricinus. Int. J. Parasitol. 5, 363–367. 10.1016/0020-7519(75)90085-5 PubMed DOI

Dubremetz J. F., Garcia-Réguet N., Conseil V., Fourmaux M. N. (1998). Apical organelles and host-cell invasion by Apicomplexa. Int. J. Parasitol. 28, 1007–1013. 10.1016/S0020-7519(98)00076-9 PubMed DOI

Fawcett D., Musoke A., Voigt W. (1984). Interaction of sporozoites of Theileria parva with bovine lymphocytes in vitro. I. Early events after invasion. Tissue Cell 16, 873–884. 10.1016/0040-8166(84)90068-5 PubMed DOI

Fawcett D. W., Büscher G., Doxsey S. (1982a). Salivary gland of the tick vector of East Coast fever. III. The ultrastructure of sporogony in Theileria parva. Tissue Cell 14, 183–206. 10.1016/0040-8166(82)90017-9 PubMed DOI

Fawcett D. W., Büscher G., Doxsey S. (1982b). Salivary gland of the tick vector of East Coast fever. IV. Cell type selectivity and host cell responses to Theileria parva. Tissue Cell 14, 397–414. 10.1016/0040-8166(82)90035-0 PubMed DOI

Fawcett D. W., Conrad P. A., Grootenhuis J. G., Morzaria S. P. (1987). Ultrastructure of the intra-erythrocytic stage of Theileria species from cattle and waterbuck. Tissue Cell 19, 643–655. 10.1016/0040-8166(87)90071-1 PubMed DOI

Fawcett D. W., Doxsey S., Stagg D. A., Young A. S. (1982c). The entry of sporozoites of Theileria parva into bovine lymphocytes in vitro. Electron microscopic observations. Eur. J. Cell Biol. 27, 10–21. PubMed

Florin-Christensen M., Suarez C. E., Rodriguez A. E., Flores D. A., Schnittger L. (2014). Vaccines against bovine babesiosis: where we are now and possible roads ahead. Parasitology 28, 1–30. 10.1017/S0031182014000961 PubMed DOI

Friedhoff K., Scholtyseck E., Weber G. (1972). Fine structure of the merozoites of Babesia ovis in the salivary glands of female ticks. Z. Parasitenkd. 38, 132–140. 10.1007/BF00329024 PubMed DOI

Friedhoff K. T., Büscher G. (1976). Rediscovery of Koch's “strahlenörper” of Babesia bigemina. Z. Parasitenkd. 50, 345–347. 10.1007/BF02462979 PubMed DOI

Gauer M., Mackenstedt U., Mehlhorn H., Schein E., Zapf F., Njenga E., et al. . (1995). DNA measurements and ploidy determination of developmental stages in the life cycles of Theileria annulata and T. parva. Parasitol. Res. 81, 565–574. 10.1007/BF00932023 PubMed DOI

Gohil S., Herrmann S., Günther S., Cooke B. M. (2013). Bovine babesiosis in the 21st century: advances in biology and functional genomics. Int. J. Parasitol. 43, 125–132. 10.1016/j.ijpara.2012.09.008 PubMed DOI

Gorenflot A., Brasseur P., Precigout E., L'Hostis M., Marchand A., Schrevel J. (1991). Cytological and immunological responses to Babesia divergens in different hosts: ox, gerbil, man. Parasitol. Res. 77, 3–12. 10.1007/BF00934377 PubMed DOI

Gorenflot A., Precigout E., Valentin A., Bissuel G., Carcy B., Brasseur P., et al. . (1992). Babesia divergens vaccine. Mem. Inst. Oswaldo Cruz. 87, 279–281. 10.1590/S0074-02761992000700047 PubMed DOI

Gough J. M., Jorgensen W. K., Kemp D. H. (1998). Development of tick gut forms of Babesia bigemina in vitro. J. Eukaryot. Microbiol. 45, 298–306. 10.1111/j.1550-7408.1998.tb04540.x PubMed DOI

Guimarães A. M., Lima J. D., Ribeiro M. F. B. (1998a). Sporogony and experimental transmission of Babesia equi by Boophilus microplus. Parasitol. Res. 84, 323–327. 10.1007/s004360050404 PubMed DOI

Guimarães A. M., Lima J. D., Ribeiro M. F. B., Camargos E. R. S., Bozzi I. A. (1998b). Ultrastructure of sporogony in Babesia equi in salivary glands of adult female Boophilus microplus ticks. Parasitol. Res. 84, 69–74. PubMed

Guimarães A. M., Lima J. D., Ribeiro M. F. B. (2003). Ultrastructure of Babesia equi trophozoites isolated in Minas Gerais, Brazil. Pesq. Vet. Bras. 23, 101–104. 10.1590/S0100-736X2003000300002 DOI

Hagiwara K., Takahashi K., Taniyama H., Kawamoto S., Kurosawa T., Ikuta K., et al. . (1997). Detection of Theileria sergenti schizonts in bovine lymph node. Int. J. Parasitol. 27, 1375–1378. 10.1016/S0020-7519(97)00092-1 PubMed DOI

Hajdušek O., Síma R., Ayllón N., Jalovecká M., Perner J., de la Fuente J., et al. . (2013). Interaction of the tick immune system with transmitted pathogens. Front. Cell. Infect. Microbiol. 3:26. 10.3389/fcimb.2013.00026 PubMed DOI PMC

Hazen-Karr C. G., Kocan A. A., Kocan K. M., Hair J. A. (1987). The ultrastructure of sporogony in Theileria cervi (Bettencourt et al., 1907) in salivary glands of female Amblyomma americanum (L.) ticks. J. Parasitol. 73, 1182–1188. 10.2307/3282304 PubMed DOI

Higuchi S., Izumitani M., Hoshi H., Kawamura S., Yasuda Y. (1999a). Development of Babesia gibsoni in the midgut of larval tick, Rhipicephalus sanguineus. J. Vet. Med. Sci. 61, 689–691. 10.1292/jvms.61.689 PubMed DOI

Higuchi S., Konno H., Hoshi F., Kawamura S., Yasuda Y. (1993). Observations of Babesia gibsoni in the ovary of the tick, Haemaphysalis longicornis. Kitasato. Arch. Exp. Med. 65, 153–158. PubMed

Higuchi S., Kuroda H., Hoshi H., Kawamura S., Yasuda Y. (1999b). Development of Babesia gibsoni in the midgut of the nymphal stage of the tick, Rhipicephalus sanguineus. J. Vet. Med. Sci. 61, 697–699. 10.1292/jvms.61.697 PubMed DOI

Higuchi S., Oya H., Hoshi F., Kawamura S., Yasuda Y. (1992). Observations of Babesia gibsoni in midgut epithelial cells of the tick, Haemaphysalis longicornis. Kitasato. Arch. Exp. Med. 65, 143–147. PubMed

Higuchi S., Oya H., Hoshi F., Kawamura S., Yasuda Y. (1994). Development of Babesia ovata in the salivary glands of the nymphal tick, Haemaphysalis longicornis. J. Vet. Med. Sci. 56, 207–209. 10.1292/jvms.56.207 PubMed DOI

Higuchi S., Simomura S., Yoshida H., Hoshi F., Kawamura S., Yasuda Y. (1991a). Development of Babesia gibsoni in the gut epithelium of the tick, Haemaphysalis longicornis. J. Vet. Med. Sci. 53, 129–131. 10.1292/jvms.53.129 PubMed DOI

Higuchi S., Simomura S., Yoshida H., Hoshi F., Kawamura S., Yasuda Y. (1991b). Development of Babesia gibsoni in the hemolymph of the vector tick, Haemaphysalis longicornis. J. Vet. Med. Sci. 53, 491–493. 10.1292/jvms.53.491 PubMed DOI

Holbrook A. A., Anthony D. W., Johnson A. J. (1968). Observations on the development of Babesia caballi(Nuttall) in the tropical horse tick Dermacentor nitens Neumann. J. Protozool. 15, 391–396. 10.1111/j.1550-7408.1968.tb02143.x PubMed DOI

Homer M. J., Aguilar-Delfin I., Telford S. R., Krause P. J., Persing D. H. (2000). Babesiosis. Clin. Microbiol. Rev. 13, 451–469. 10.1128/CMR.13.3.451-469.2000 PubMed DOI PMC

Hunfeld K. P., Hildebrandt A., Gray J. S. (2008). Babesiosis: recent insights into an ancient disease. Int. J. Parasitol. 38, 1219–1237. 10.1016/j.ijpara.2008.03.001 PubMed DOI

Jalovecka M., Bonsergent C., Hajdusek O., Kopacek P., Malandrin L. (2016). Stimulation and quantification of Babesia divergens gametocytogenesis. Parasit. Vectors 9:439. 10.1186/s13071-016-1731-y PubMed DOI PMC

Janouskovec J., Horák A., Oborník M., Lukes J., Keeling P. J. (2010). A common red algal origin of the apicomplexan, dinoflagellate, and heterokont plastids. Proc. Natl. Acad. Sci. U.S.A. 107, 10949–10954. 10.1073/pnas.1003335107 PubMed DOI PMC

Joyner L. P., Davies S. F., Kendall S. B. (1963). The experimental transmission of Babesia divergens by Ixodes ricinus. Exp. Parasitol. 14, 367–373. 10.1016/0014-4894(63)90044-4 PubMed DOI

Kappmeyer L. S., Thiagarajan M., Herndon D. R., Ramsay J. D., Caler E., Djikeng A., et al. . (2012). Comparative genomic analysis and phylogenetic position of Theileria equi. BMC Genomics. 13:603. 10.1186/1471-2164-13-603 PubMed DOI PMC

Karakashian S. J., Rudzinska M. A., Spielman A., Lewengrub S., Campbell J. (1986). Primary and secondary ookinetes of Babesia microti in the larval and nymphal stages of the tick Ixodes dammini. Can. J. Zool. 64, 328–339. 10.1139/z86-053 DOI

Karakashian S. J., Rudzinska M. A., Spielman A., Lewengrub S., Piesman J., Shoukrey N. (1983). Ultrastructural studies on sporogony of Babesia microti in salivary gland cells of the tick Ixodes dammini. Cell Tissue Res. 231, 275–287. 10.1007/BF00222180 PubMed DOI

Kawai S., Igarashi I., Abgaandorjiin A., Ikadai H., Omata Y., Saito A., et al. . (1999a). Tubular structures associated with Babesia caballi in equine erythrocytes in vitro. Parasitol. Res. 85, 171–175. 10.1007/s004360050530 PubMed DOI

Kawai S., Igarashi I., Abgaandorjiin A., Miyazawa K., Ikadai H., Nagasawa, et al. . (1999b). Ultrastructural characteristics of Babesia caballi in equine erythrocytes in vitro. Parasitol. Res. 85, 794–799. 10.1007/s004360050635 PubMed DOI

Kawai S., Takahashi K., Kawamoto S., Nagahara A., Sonoda M., Kurosawa T., et al. . (1989). Bar-structure in bovine erythrocytes infected with Theileria sergenti. Nippon Juigaku Zasshi 51, 1219–1225. 10.1292/jvms1939.51.1219 PubMed DOI

Kawai S., Takahashi K., Sonoda M., Kurosawa T. (1986). Ultrastructure of intra-erythrocytic stages of Babesia ovata. Nippon Juigaku Zasshi 48, 943–949. 10.1292/jvms1939.48.943 PubMed DOI

Kjemtrup A. M., Conrad P. A. (2000). Human babesiosis: an emerging tick-borne disease. Int. J. Parasitol. 30, 1323–1337. 10.1016/S0020-7519(00)00137-5 PubMed DOI

Kjemtrup A. M., Wainwright K., Miller M., Penzhorn B. L., Carreno R. A. (2006). Babesia conradae, sp. Nov., a small canine Babesia identified in California. Vet. Parasitol. 138, 103–111. 10.1016/j.vetpar.2006.01.044 PubMed DOI

Leiby D. A. (2011). Transfusion-transmitted Babesia spp.: bull's-eye on Babesia microti. Clin. Microbiol. Rev. 24, 14–28. 10.1128/CMR.00022-10 PubMed DOI PMC

Lempereur L., Larcombe S. D., Durrani Z., Karagenc T., Bilgic H. B., Bakirci S., et al. . (2017). Identification of candidate transmission-blocking antigen genes in Theileria annulata and related vector-borne apicomplexan parasites. BMC Genomics 18:438. 10.1186/s12864-017-3788-1 PubMed DOI PMC

Lewis D., Purnell R. E., Shaw S. R. (1980). The isolation and characterization of human and bovine strains of Babesia divergens from Drumnadrochit, Scotland. Parasitology 81, 145–155. 10.1017/S0031182000055116 PubMed DOI

Lewis D., Young E. R. (1980). The transmission of a human strain of Babesia divergens by Ixodes ricinus ticks. J. Parasitol. 66, 359–360. 10.2307/3280841 PubMed DOI

Lobo C. A., Rodriguez M., Cursino-Santos J. R. (2012). Babesia and red cell invasion. Curr. Opin. Hematol. 19, 170–175. 10.1097/MOH.0b013e328352245a PubMed DOI

MacKenstedt U., Gauer M., Fuchs P., Zapf F., Schein E., Mehlhorn H. (1995). DNA measurements reveal differences in the life cycles of Babesia bigemina and B. canis, two typical members of the genus Babesia. Parasitol. Res. 81, 595–604. 10.1007/BF00932027 PubMed DOI

Mackenstedt U., Gauer M., Mehlhorn H., Schein E., Hauschild S. (1990). Sexual cycle of Babesia divergens confirmed by DNA measurements. Parasitol. Res. 76, 199–206. 10.1007/BF00930815 PubMed DOI

Malandrin L., Jouglin M., Sun Y., Brisseau N., Chauvin A. (2010). Redescription of Babesia capreoli (Enigk and Friedhoff, 1962) from roe deer (Capreolus capreolus): isolation, cultivation, host specificity, molecular characterisation and differentiation from Babesia divergens. Int. J. Parasitol. 40, 277–284. 10.1016/j.ijpara.2009.08.008 PubMed DOI

Mehlhorn H., Moltmann U., Schein E., Voigt W. P. (1981). Fine structure of supposed gametes and syngamy of Babesia canis (Piroplasmea) after in-vitro development. Zentralbl. Bakteriol. Mikrobiol. Hyg. A. 250, 248–255. PubMed

Mehlhorn H., Schein E. (1993). The piroplasms: “A long story in short” or “Robert Koch has seen it”. Eur. J. Protistol. 29, 279–293. 10.1016/S0932-4739(11)80371-8 PubMed DOI

Mehlhorn H., Schein E. (1998). Redescription of Babesia equi Laveran, 1901 as Theileria equi Mehlhorn, Schein 1998. Parasitol. Res. 84, 467–475. 10.1007/s004360050431 PubMed DOI

Mehlhorn H., Schein E., Voigt W. P. (1980). Light and electron microscopic study on developmental stages of Babesia canis within the gut of the tick Dermacentor reticulatus. J. Parasitol. 66, 220–228. 10.2307/3280808 PubMed DOI

Mehlhorn H., Schein E., Warnecke M. (1978). Electron microscopic studies on the development of kinetes of Theileria parva Theiler, 1904 in the gut of the vector ticks Rhipicephalus appendiculatus Neumann, 1901. Acta Trop. 35, 123–136. PubMed

Mehlhorn H., Schein E., Warnecke M. (1979). Electron-microscopic studies on Theileria ovis Rodhain, 1916: development of kinetics in the gut of the vector tick, Rhipicephalus evertsi evertsi Neumann, 1897, and their transformation within cells of the salivary glands. J. Protozool. 26, 377–385. 10.1111/j.1550-7408.1979.tb04640.x PubMed DOI

Mehlhorn H., Shein E. (1984). The piroplasms: life cycle and sexual stages. Adv. Parasitol. 23, 37–103. 10.1016/S0065-308X(08)60285-7 PubMed DOI

Moltmann U. G., Mehlhorn H., Friedhoff K. T. (1982a). Electron microscopic study on the development of Babesia ovis (Piroplasmia) in the salivary glands of the vector tick Rhipicephalus bursa. Acta Trop. 39, 29–40. PubMed

Moltmann U. G., Mehlhorn H., Friedhoff K. T. (1982b). Ultrastructural study of the development of Babesia ovis (Piroplasmia) in the ovary of the vector tick Rhipicephalus bursa. J. Protozool. 29, 30–38. 10.1111/j.1550-7408.1982.tb02877.x PubMed DOI

Moltmann U. G., Mehlhorn H., Schein E., Rehbein G., Voigt W. P., Zweygarth E. (1983a). Fine structure of Babesia equi Laveran, 1901 within lymphocytes and erythrocytes of horses: an in vivo and in vitro study. J. Parasitol. 69, 111–120. 10.2307/3281285 PubMed DOI

Moltmann U. G., Mehlhorn H., Schein E., Voigt W. P., Friedhoff K. T. (1983b). Ultrastructural study on the development of Babesia equi (Coccidia: Piroplasmia) in the salivary glands of its vector ticks. J. Protozool. 30, 218–225. 10.1111/j.1550-7408.1983.tb02907.x PubMed DOI

Montero E., Rodriguez M., Oksov Y., Lobo C. A. (2009). Babesia divergens apical membrane antigen 1 and its interaction with the human red blood cell. Infect. Immun. 77, 4783–4793. 10.1128/IAI.00969-08 PubMed DOI PMC

Mosqueda J., Ramos J. A., Falcon A., Alvarez J. A., Aragon V., Figueroa J. V. (2004). Babesia bigemina: sporozoite isolation from Boophilus microplus nymphs and initial immunomolecular characterization. Ann. N.Y. Acad. Sci. 1026, 222–231. 10.1196/annals.1307.034 PubMed DOI

Nene V., Kiara H., Lacasta A., Pelle R., Svitek N., Steinaa L. (2016). The biology of Theileria parva and control of East Coast fever - Current status and future trends. Ticks Tick Borne Dis. 7, 549–564. 10.1016/j.ttbdis.2016.02.001 PubMed DOI

Nene V., Morrison W. I. (2016). Approaches to vaccination against Theileria parva and Theileria annulata. Parasite Immunol. 38, 724–734. 10.1111/pim.12388 PubMed DOI PMC

Piesman J., Karakashian S. J., Lewengrub S., Rudzinska M. A., Spielmank A. (1986). Development of Babesia microti sporozoites in adult Ixodes dammini. Int. J. Parasitol. 16, 381–385. 10.1016/0020-7519(86)90118-9 PubMed DOI

Pieszko M., Weir W., Goodhead I., Kinnaird J., Shiels B. (2015). ApiAP2 Factors as Candidate regulators of stochastic commitment to merozoite production in Theileria annulata. PLoS Negl. Trop. Dis. 9:e0003933. 10.1371/journal.pntd.0003933 PubMed DOI PMC

Potgieter F. T., Els H. J. (1976). Light and electron microscopic observations on the development of small merozoites of Babesia bovis in Boophilus microplus larvae. Onderstepoort. J. Vet. Res. 43, 123–128. PubMed

Potgieter F. T., Els H. J. (1977a). Light and electron microscopic observations on the development of Babesia bigemina in larvae, nymphae and non-replete females of Boophilus decoloratus. Onderstepoort. J. Vet. Res. 44, 213–231. PubMed

Potgieter F. T., Els H. J. (1977b). The fine structure of intra-erythrocytic stages of Babesia bigemina. Onderstepoort. J. Vet. Res. 44, 157–168. PubMed

Potgieter F. T., Els H. J., Vuuren A. S. (1976). The fine structure of merozoites of Babesia bovis in the gut epithelium of Boophilus microplus. Onderstepoort. J. Vet. Res. 43, 1–9. PubMed

Purnell R. E., Joyner L. P. (1968). The development of Theileria parva in the salivary glands of the tick, Rhipicephalus appendiculatus. Parasitology. 58, 725–732. 10.1017/S0031182000029036 PubMed DOI

Ramsay J. D., Ueti M. W., Johnson W. C., Scoles G. A., Knowles D. P., Mealey R. H. (2013). Lymphocytes and macrophages are infected by Theileria equi, but T cells and B cells are not required to establish infection in vivo. PLoS ONE 8:e76996. 10.1371/journal.pone.0076996 PubMed DOI PMC

Rudzinska M. A. (1976). Ultrastructure of intraerythrocytic Babesia microti with emphasis on the feeding mechanism. J. Protozool. 23, 224–233. 10.1111/j.1550-7408.1976.tb03759.x PubMed DOI

Rudzinska M. A., Lewengrub S., Spielman A., Piesman J. (1983a). Invasion of Babesia microti into epithelial cells of the tick gut. J. Protozool. 30, 338–346. 10.1111/j.1550-7408.1983.tb02927.x PubMed DOI

Rudzinska M. A., Spielman A., Lewengrub S., Piesman J., Karakashian S. (1982). Penetration of the peritrophic membrane of the tick by Babesia microti. Cell Tissue Res. 221, 471–481. 10.1007/BF00215696 PubMed DOI

Rudzinska M. A., Spielman A., Lewengrub S., Piesman J., Karakashian S. (1984). The sequence of developmental events of Babesia microti in the gut of Ixodes dammini. Protistologica 4, 649–663.

Rudzinska M. A., Spielman A., Lewengrub S., Trager W., Piesman J. (1983b). Sexuality in piroplasms as revealed by electron microscopy in Babesia microti. Proc. Natl. Acad. Sci. U.S.A. 80, 2966–2970. 10.1073/pnas.80.10.2966 PubMed DOI PMC

Rudzinska M. A., Spielman A., Riek R. F., Lewengrub S. J., Piesman J. (1979). Intraerythrocytic ’gametocytes’ of Babesia microti and their maturation in ticks. Can. J. Zool. 57, 424–434. 10.1139/z79-050 PubMed DOI

Rudzinska M. A., Trager W. (1962). Intracellular phagotrophy in Babesia rodhaini as revealed by electron microscopy. J. Protozool. 9, 279–288. 10.1111/j.1550-7408.1962.tb02621.x PubMed DOI

Rudzinska M. A., Trager W. (1977). Formation of merozoites in intraerythrocytic Babesia microti: an ultrastructural study. Can. J. Zool. 55, 928–938. 10.1139/z77-121 PubMed DOI

Rudzinska M. A., Trager W., Lewengrub S. J., Gubert E. (1976). An electron microscopic study of Babesia microti invading erythrocytes. Cell Tissue Res. 169, 323–334. 10.1007/BF00219605 PubMed DOI

Sato M., Kamio T., Tanaka S., Taniguchi T., Fujisaki K. (1994). Development of Theileria sergenti schizonts in the lymph node of experimentally infected cattle. J. Vet. Med. Sci. 56, 715–722. 10.1292/jvms.56.715 PubMed DOI

Schein E., Friedhoff K. T. (1978). Light microscopic studies on the development of Theileria annulata (Dschunkowsky and Luhs, 1904) in Hyalomma anatolicum excavatum (Koch, 1844): the development in haemolymph and salivary glands. Z. Parasitenkd. 56, 287–303. 10.1007/BF00931721 PubMed DOI

Schein E., Mehlhorn H., Voigt W. P. (1979). Electron microscopical studies on the development of Babesia canis (Sporozoa) in the salivary glands of the vector tick Dermacentor reticulatus. Acta Trop. 36, 229–241. PubMed

Schein E., Rehbein G., Voigt W. P., Zweygarth E. (1981). Babesia equi (Laveran 1901) development in horses and in lymphocyte culture. Tropenmed. Parasitology 32, 223–227. PubMed

Schein E., Warnecke M., Kirmse P. (1977). Development of Theileria parva (Theiler, 1904) in the gut of Rhipicephalus appendiculatus (Neumann, 1901). Parasitology 75, 309–316. 10.1017/S0031182000051854 PubMed DOI

Schnittger L., Rodriguez A. E., Florin-Christensen M., Morrison D. A. (2012). Babesia: a world emerging. Infect. Genet. Evol. 12, 1788–1809. 10.1016/j.meegid.2012.07.004 PubMed DOI

Schreeg M. E., Marr H. S., Tarigo J. L., Cohn L. A., Bird D. M., Scholl E. H., et al. . (2016). Mitochondrial genome sequences and structures aid in the resolution of piroplasmida phylogeny. PLoS ONE 11:e0165702. 10.1371/journal.pone.0165702 PubMed DOI PMC

Shaw M. K. (1995). Mobilization of intrasporozoite Ca2+ is essential for Theileria parva sporozoite invasion of bovine lymphocytes. Eur. J. Cell Biol. 68, 78–87. PubMed

Shaw M. K. (1996a). Characterization of the parasite-host cell interactions involved in Theileria parva sporozoite invasion of bovine lymphocytes. Parasitology 113, 267–277. PubMed

Shaw M. K. (1996b). Theileria parva sporozoite entry into bovine lymphocytes involves both parasite and host cell signal transduction processes. Exp. Parasitol. 84, 344–354. 10.1006/expr.1996.0123 PubMed DOI

Shaw M. K. (1997). The same but different: the biology of Theileria sporozoite entry into bovine cells. Int. J. Parasitol. 27, 457–474. 10.1016/S0020-7519(97)00015-5 PubMed DOI

Shaw M. K. (1999). Theileria parva: sporozoite entry into bovine lymphocytes is not dependent on the parasite cytoskeleton. Exp. Parasitol. 92, 24–31. 10.1006/expr.1998.4393 PubMed DOI

Shaw M. K. (2003). Cell invasion by Theileria sporozoites. Trends Parasitol. 19, 2–6. 10.1016/S1471-4922(02)00015-6 PubMed DOI

Shaw M. K., Tilney L. G. (1992). How individual cells develop from a syncytium: merogony in Theileria parva (Apicomplexa). J. Cell. Sci. 101, 109–123. PubMed

Shaw M. K., Tilney L. G. (1995). The entry of Theileria parva merozoites into bovine erythrocytes occurs by a process similar to sporozoite invasion of lymphocytes. Parasitology 11, 455–461. 10.1017/S0031182000065951 PubMed DOI

Shaw M. K., Tilney L. G., McKeever D. J. (1993). Tick salivary gland extract and interleukin-2 stimulation enhance susceptibility of lymphocytes to infection by Theileria parva sporozoites. Infect. Immun. 61, 1486–1495. PubMed PMC

Shaw M. K., Tilney L. G., Musoke A. J. (1991). The entry of Theileria parva sporozoites into bovine lymphocytes: evidence for MHC class I involvement. J. Cell Biol. 113, 87–101. 10.1083/jcb.113.1.87 PubMed DOI PMC

Simpson C. F., Bild C. E., Stolkier H. E. (1963). Electron microscopy of canine and equine Babesia. Am. J. Vet. Res. 24, 408–414. PubMed

Simpson C. F., Neal F. C. (1980). Ultrastructure of Babesia equi in ponies treated with imidocarb. Am. J. Vet. Res. 41, 267–271. PubMed

Sivakumar T., Hayashida K., Sugimoto C., Yokoyama N. (2014). Evolution and genetic diversity of Theileria. Infect. Genet. Evol. 27, 250–263. 10.1016/j.meegid.2014.07.013 PubMed DOI

Soldati D., Foth B. J., Cowman A. F. (2004). Molecular and functional aspects of parasite invasion. Trends Parasitol. 20, 567–574. 10.1016/j.pt.2004.09.009 PubMed DOI

Sonenshine D. E. (1991). Biology of Ticks. New York, NT: Oxford University Press.

Sun Y., Moreau E., Chauvin A., Malandrin L. (2011). The invasion process of bovine erythrocyte by Babesia divergens: knowledge from an in vitro assay. Vet. Res. 42:62. 10.1186/1297-9716-42-62 PubMed DOI PMC

Susta L., Torres-Velez F., Zhang J., Brown C. (2009). An in situ hybridization and immunohistochemical study of cytauxzoonosis in domestic cats. Vet. Pathol. 46, 1197–1204. 10.1354/vp.08-VP-0132-B-FL PubMed DOI

Takahashi K., Kawai S., Yaehata K., Kawamoto S., Hagiwara K., Kurosawa T., et al. . (1993). Sporogony of Theileria sergenti in the salivary glands of the tick vector Haemaphysalis longicornis. Parasitol. Res. 79, 1–7. 10.1007/BF00931210 PubMed DOI

Uilenberg G. (2006). Babesia–a historical overview. Vet. Parasitol. 138, 3–10. 10.1016/j.vetpar.2006.01.035 PubMed DOI

Vannier E. G., Diuk-Wasser M. A., Ben Mamoun C., Krause P. J. (2015). Babesiosis. Infect. Dis. Clin. North Am. 29, 357–370. 10.1016/j.idc.2015.02.008 PubMed DOI PMC

Votypka J., Modry D., Obornik M., Slapeta J., Lukes J. (2017). Apicomplexa, in Handbook of the Protists, eds Archibald J. M., Simpson A. G. B., Slamovits C. H. (Cham: Springer International Publishing AG; ), 1–58. 10.1007/978-3-319-32669-6_20-1 DOI

Ward P. A., Jack R. M. (1981). The entry process of Babesia merozoites into red cells. Am. J. Pathol. 102, 109–113. PubMed PMC

Warnecke M., Schein E., Voigt W. P., Uilenberg G., Young A. S. (1980). Development of Theileria mutans (Theiler, 1906) in the gut and the haemolymph of the tick Amblyomma variegatum (Fabricius, 1794). Z. Parasitenkd. 62, 119–125. 10.1007/BF00927858 PubMed DOI

Weber G., Friedhoff K. (1979). Electron microscopic detection of initial and some subsequent developmental stages of Babesia bigemina in salivary glands of ticks. Z. Parasitenkd. 58, 191–194. 10.1007/BF01951346 PubMed DOI

Weber G., Friedhoff K. T. (1977). Preliminary observations on the ultrastructure of suppossed sexual stages of Babesia bigemina (Piroplasmea). Z. Parasitenkd. 53, 83–92. 10.1007/BF00383118 PubMed DOI

Weber G., Walter G. (1980). Babesia microti (Apicomplexa, Piroplasmida) - electron-microscope detection in salivary glands of the tick vector Ixodes ricinus (Ixodoidea, Ixodidae). Z. Parasitenkd. 64, 113–115. 10.1007/BF00927061 PubMed DOI

Webster P., Dobbelaere D. A., Fawcett D. W. (1985). The entry of sporozoites of Theileria parva into bovine lymphocytes in vitro. Immunoelectron microscopic observations. Eur. J. Cell Biol. 36, 157–162. PubMed

Wise L. N., Kappmeyer L. S., Mealey R. H., Knowles D. P. (2013). Review of equine piroplasmosis. J. Vet. Intern. Med. 27, 1334–1346. 10.1111/jvim.12168 PubMed DOI

Yabsley M. J., Shock B. C. (2013). Natural history of Zoonotic Babesia: role of wildlife reservoirs. Int. J. Parasitol. Parasites Wildl. 2, 18–31. 10.1016/j.ijppaw.2012.11.003 PubMed DOI PMC

Yano Y., Saito-Ito A., Anchalee D., Takada N. (2005). Japanese Babesia microti cytologically detected in salivary glands of naturally infected tick Ixodes ovatus. Microbiol. Immunol. 49, 891–897. 10.1111/j.1348-0421.2005.tb03680.x PubMed DOI

Zapf F., Schein E. (1994a). New findings in the development of Babesia (Theileria) equi (Laveran, 1901) in the salivary glands of the vector ticks, Hyalomma species. Parasitol. Res. 80, 543–548. 10.1007/BF00933000 PubMed DOI

Zapf F., Schein E. (1994b). The development of Babesia (Theileria) equi (Laveran, 1901) in the gut and the haemolymph of the vector ticks, Hyalomma species. Parasitol. Res. 80, 297–302. 10.1007/BF02351869 PubMed DOI

Zintl A., Mulcahy G., Skerrett H. E., Taylor S. M., Gray J. S. (2003). Babesia divergens, a bovine blood parasite of veterinary and zoonotic importance. Clin. Microbiol. Rev. 16, 622–636. 10.1128/CMR.16.4.622-636.2003 PubMed DOI PMC

Zweygarth E., Koekemoer O., Josemans A. I., Rambritch N., Pienaar R., Putterill J., et al. . (2009). Theileria-infected cell line from an African buffalo (Syncerus caffer). Parasitol. Res. 105, 579–581. 10.1007/s00436-009-1467-0 PubMed DOI

Babesia, Theileria, Plasmodium and Hemoglobin

Plasmepsin-like Aspartyl Proteases in Babesia