Infection, Genetics and Evolution journal homepage: www.slsevier.com/locate/meegia Review Babesia: A world emerging Leonhard Schnittger*®*, Anabel E. Rodriguez*”, Monica Florin-Christensen*», David A. Morrison‘ ‘insta of ates Cente of Research m Yeerinry and Agronomic Scenes INTA-Cstetar. Argentina "Nasoal Resear Counc of Argentine (CONEY) Av Radava 1017, CTOSIAN, CARA Argentina “Section for Pauselegy, Deparment of chemical Sciences ond Veterinary Pac Hell, Seok Unive of Agra Sciences Uppal Seden ARTICLE INFO ABSTRACT Aric ony [obevia ae ticketransmitted hemoprotozooans that infect mammals and birds, and which are acknowl Received 12 March 2012 ‘edged (or ther major impact on (tm and pet animal health and associated economic costs worldwide Received in revised for 6 uty 2012 ‘Aaitionally,Babesiainfeetions of wife can be atl asociated with sressfol management practices Decepee# fly 2012 seemt GRY land human babesisis, als tansmited by blood transfusion, san increasing publichealth concern, Due {arthe huge diversity of species reported to serve as Babesia hosts, al vertebrates might be potential c= hits as longa they ate adequate hosts for Babesavector ticks. We hete provide a comprehensive over= me View of Ue most relevant Babesa species, anda discussion ofthe elassea taxonomic etletia. Babes Thelere {teunzeen and Thee parasites are closely related and collectively refered to as piroplasmids pos raion sible scenario fr the history of piroplasmds is presented in the context of recent ndings and its impli Molec phylogeny ‘ations for Fuute research avenues ate outlined, Phylogenetic wees ofall avaliable 185 RNA and hsp70 Molecular txoneny _Eenes were generated, based on which we presenta shoroughly revised mnolecularcassifiation, compris pulaton gets Ing fve monophyletic Babesa lineages, one Cyrouezoen clade, and one Theeia clade. Updated 165 RNA and beta-iubulin gene tres ofthe 5. micro isolates agree with those previously reported. To reconcile ‘estimates of the origin of piroplasmids and ticks (~300 Ma, respectively), and mammalian radiation (G0 Ma}, we hypothesize chat the dixenaus picoplasiid lifecycle evlved with the arigin of ticks. Thus, ‘the observed time gap detveen tek origin and mammalian cadation indicates the existence of hitherto “unknown piroplasmid lineages andjor species in extant vertebrate taxa, induding reptiles and possibly Amphibians. The development snd current status of the molecular taxonomy of Babesia, with emphasi ‘on human-infecting species, discussed. Finally, recent results from population genetic studies of Babe- sa parasites, and their implications forthe development of pathogenicity, érug resistance and vaccines fre summarize, (© 2012 Elsevier BY. Alright reserved Contents 1. teoduetion 1789 2 Disttbution and pathological eitects of seme relevant Babeia spp 1789 5. The acura history of Babesa ae 4 Chasial taxonomy. 1795, 5. Molecular phylogeny 1795, 5.1. Tracing the ancestots: the 185 RNA gene, 1795, 52. Tracing the ancestors other genes. 1799) 5.3. A piroplasmid re: the way ahead 1800 6 Molecular taxonomy 1801 7 Population genetis 1802 ‘Bireviions: AFL. amplified fagment-ength polymorphism: BC, bloga species concept: Cconheenc interval: HPO, highes posterior density: TS, neem spacer region: LD. linkage disequilibrium: Ma lin years ago: MT. malleus genotype: MOL mulpiety of infin: MRA most recent commen anestr PC Diblogencti species concept RAPD, rnd apsiaon of plymarive DNA * Corespneing autor a insite ge Faabaloga,CICWA INTACCastlt, Los Resros y Niclas Repel, 1686 Hurngham Prev. unos Aes, retina TL: 154 iasarto¥entas 1567-1585 se nt matter © 2012 Esler Al ight eeserved Inept rao oleh meena 201207008Stier infection Gentes and Evtton 12 (2012) 1788-1808 789 8. Conelding remarks ‘Acknowledgments Appencix A. Supplementary data References 1804 1804 1804 1804 1. Introduction Babesia are tick-transmitted protozoan hemoparasites, of great economic, veterinary and medical impact worldwide, They are considered to be the second most commonly found parasites in the blood of mammals after trypanosomes, and they have also been described infecting birds. n thei vertebrate hosts they repro- duce asexually inside erythrocytes, and together with Theleria sp. they are referred to as piroplasms or piroplasmids. The sexual phase of the Babesia life cycle typically takes place in Lxodid ticks, Which acquire and transmit the parasites during their blood meals (Fig. 1) (Kakoma and Mehlhorn, 1994; Telford et al, 1993: Gray and Weiss, 2008) Vietor Babes (1888) was the frst to discover microorganisms inside bovine erythrocytes of Romanian cattle that presented hemoglobinuria; and he later observed a similar organism in sheep blood (Babes, 1892) Five years later in the USA, Smith and Kilbour described that the presence of an intraerythrocytic parasite was the cause of tick-transmitted Texas Cattle Fever, a disease chat had long stricken cattle ranchers inthe Southern US states (Smit and Kilbourne, 1893), This turned out to be the frst description of, an arthropod-transmitted pathogen of vertebrates. The parasites described by Babes, and Smith and Kilbour were later named Bobesia bovis. B. ovis and 8. bigemina, respectively (Starcovici, 1893; Mihalea, 2010), Soon afterwards, babesias parasitizing the Tick Host - >— i ery blood of other domestic animals were observed, such as those that eventually became known as 8. canis and B, caball, described by Piana and Calli-Valerio (1895) and by Koch (1804), in dog. and horse erythrocytes, respectively. Since these early findings, more than 100 different Babesia species have been discovered, and ‘thanks to the advances in microscopy, cll biology and molecular biology techniques our knowledge of the Rabesia world is rapidly expanding (Levine, 1988; Roncalli Amici, 2001; Criado-Fornelio eval, 2004; de Waal and Van Heerden, 2004; Vilenberg, 2006; Lack eval, 2012) 2. Distribution and pathological effects of some relevant Babesia spp. The remarkable impact of babesia infections in three host groups: domestic animals, humans ané, most recently acknow!- edged, some wildlife species, has inspired a great amount of re- search efforts in recent decades. ‘In general, babesia infections course with varying degrees of, severity that can often be associated to the host's age, immunolog- ical status, concurrent infections with other pathogens, andjor ‘genetic factors. Common manifestations of acute babesia infections in different hosts can include fever, anemia, hemoglobinuria, jain- dice, malaise, lethargy and anorexia, while the chronic status is _generally asymptomatic. Among domestic animals, babesia infec Vertebrate Host ’ / =@~ @- eo ‘Krrtt= Fig 1. Gener e-ycle Babes spp Sabeso sporozoites (2) ar injected int the Bonita of vercebrate ht wth minute zmauns esa, uring he boed meal f'n infected tik: ter invacing erthocyes they eiferentate ice aphoroes(T).which die avexaly merogey) into two ot sarees our merozoites (M) Meozaes ext the eythracyes and invade new ene, continuing the replative cei the hs. A few meroclies step evisan and transform ilo gamans ot {netcyes(G),Caiogony and spocozay tae place ate tick When gaan ae aken up bya Uc eed oa acted hast. they fereabate theft gues, so knoe 35a bose Stahlenkorper (SK) chat fase forming ile zygote (2. gamogory). Zygotes undergo mess giving sete mote Rape ketes whieh Itinly by spregony ane seers the Remalymph inating an ensnsng thet repletion in reveal ek etgene eon the slvary sans (5) ere fil ee 9f Tanae nymph or nyanpht aul ranetaial tranemiesin Ts in some Babi sp, (abe sensu sit knees lvade the ck ovcies a es, An ec ‘pororote te oree inte salivaty glands of the nee genrstin le (ranvavatal anrmisan To} Menihern and Schein, 198Seige a /Ifecton Gents and Eston 12 (2012) 1788-1608 able nds sp. pastes of éomesti animals. Hess) Specie Diaition Referee Gale 1 bor ‘aca, America, Ava, Rana Farope Babes (V868),sarcvil (1805 Cra Fora a (2000) S.bigemina ‘lnc, Aerica, AS, Atala EufopeSareowe (1693), ender (2006) mer ts Europe Uenbere (2005 ciado-Frneo ea (2008 Atay et (2008 Becmitow Aten Gray and De Vos (1961) 2 owte fie Lender (2000), Kadverzens Europe Zin ea (2003) Bipkasn) Chine ee (2005), Waterbutle ovens asta Luu et a (19978) bows onesie, Asia tet (19873 Ferre (208) Horse Teg urpe. Ameria Mehbrn and Schein (199) Petrobeli ta. (2007, (aesForei eta (20035) Hats, dkey, mule 5. cabal ea, Amerie, Asa, Europe ad Fone eta (2002), Nagore ea (2004 Leader 2006) shee. z0zt 1 casa sia Hasnemi-Fesharld and Ueber 1961), ehntgere (2003) Bone ‘inc, via, rope fsbey (1888) Stren (1890, Bale (2000) Senger al (2003) sheep Hsp Xinjiang chine vet (2007) De 1B voget Asis, Aree, Aaa Aus, Etope Care (2009 Relcenow (1937), Uenberge a (2989), cate eal (1999 {Cad-Forei et a (2005), Selane-lleg (2008) Mata ea (200 2 ebsont ‘Asa (Atria, America, Europe} Burkenbeues et al (1999), riade-Forneli et al (2003), Lee etal. (2008) Macnee a (2002) Meinkoth et. (2002) wat Ares (Brn Desa et a (201 Bros South Africa ‘Carete€ a. (1999), acobson (2006), Keller et al. (2004), Lesewitz etal (2001) Tomae Spain Poros {Gmache et 208) (2oosa}, solan-caege et a (2608) oe 8 pe South cs Conrad eta. (2006), acbson et a. (2000) 2 (ans) preent Asal) tions are of concern to both productive and companion species (Table). Bovine babesiosis,or red water fever, as itis commonly called, is economically the most important arthropod-transmitted patho- gen of cattle. The costs of bovine babesiosis are connected with ‘mortalities, abortions, decreased meat and milk production, con- ‘ol measures, as well a losses of potential production, and cattle trade restrictions ‘The economic burden imposed by this disease can be illustrated. by the radical tick-control campaign that was mounted in the Southern USA in 1906, lasing for four decades, and demanding an investment of millions of dollars. This campaign ended with the eradication of the cattle tick and, hence, its transmitted para- sites, thus making bovine babesiosis the frst disease eradicated from continental USA. Since the country was declared free of bo- vine babesiosis, the estimated savings for the livestock industry are at least 3 billion dollars per year. Yet, most of the 1-2 billion cattle around the world are still exposed to babesiosis and, even in the USA, outbreaks accasionally accur and epidemiological sur- veillance is a permanent concern (Uilenberg, 1995; Bock et al 2004; Guerrero et al, 2007; Perez de Leon et al, 2010; Ramos eal, 2010; Holman et al, 2011). ‘Tie most economically relevant bovine babesias ae B. bovis, B Digertina and B. divergens. The first wo are found in tropical and ‘subtropical regions of the globe, where their vector ticks - belong ing to the gente Rhipicephalus and Boophilus - can survive &,diver- ‘gens, on the other hand, mainly affects cattle in Europe ~ from ‘Scandinavia to the Mediterranean ~ and Northern Aftica Its dstri- ‘bution is connected to the ample range of temperatutes tolerated by its tick vector, Ixodes ricinus. Clinical cases of bovine babesiosis, ‘occur when naive adult catle acquire the parasite through a tick bite, while calves can get infected, but do not get sick. The etiology ofthe disease varies according tothe infecting species. B. bovis clin ‘cal cases are characterized by hypotension, respiratory stress syn drome and neurological symptoms, due to the accumulation of infected erythrocytes in lung and brain capillaries. Consequently, B.bovis infections normally show low parasitemia levels. Infections by B,bigemina and B. divergens, on the other hand, result in high pparasitemias, and in these cases pathogenicity is mainly associated, with massive erythrocyte destruction. leading to severe anemia, (Bock etal, 2004; Zin! et ab, 2003) ‘Water buffalo (Bubalus Bubalis) are mainly exploited as catle in ‘sia, but have also been introduced into the Americas, Austtalia and Europe. amounting to over 160 million head worldwide. Their tobustness, ability to thtive in poor pastures and floodable lands, and resilience to most infections make them particularly suitable as cattle in tick-endemic tropical and subtropical regions. Water bbullalos have been reported to bear subclinical infections of B.bo- vis and B,bigemina; however B. orientalis, whichis transmitted by Rhipicephalus haemaphysaloides in China, is highly pathogenic to ‘these animals and produces great economic losses (Lit et al, 1997ab; Ullenberg, 2006: Ferreri et al, 2008 Terkawi et al. 2011; He et al, 2011, 2012) There is currently only one recognized Babesia species that ‘causes equine piroplasmosis, B. cabal, which is transmitted by Hyaloma, Dermacentor and Rhipicephalus tick species. It has been estimated that only 10% of horses around the world are raised in piroplasmosis-free regions, while the disease is endemic in vast ‘tropical and subtropical regions. After a weakening acute infection, ‘the chronic state is characterized by decreased performance de t0