Review
Babesia: A world emerging

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Abstract

Babesia are tick-transmitted hemoprotozooans that infect mammals and birds, and which are acknowledged for their major impact on farm and pet animal health and associated economic costs worldwide. Additionally, Babesia infections of wildlife can be fatal if associated with stressful management practices; and human babesiosis, also transmitted by blood transfusion, is an increasing public-health concern. Due to the huge diversity of species reported to serve as Babesia hosts, all vertebrates might be potential carriers, as long as they are adequate hosts for Babesia-vector ticks. We here provide a comprehensive overview of the most relevant Babesia species, and a discussion of the classical taxonomic criteria. Babesia, Cytauxzoon and Theileria parasites are closely related and collectively referred to as piroplasmids. A possible scenario for the history of piroplasmids is presented in the context of recent findings, and its implications for future research avenues are outlined. Phylogenetic trees of all available 18S rRNA and hsp70 genes were generated, based on which we present a thoroughly revised molecular classification, comprising five monophyletic Babesia lineages, one Cytauxzoon clade, and one Theileria clade. Updated 18S rRNA and beta-tubulin gene trees of the B. microti isolates agree with those previously reported. To reconcile estimates of the origin of piroplasmids and ticks (∼300 Ma, respectively), and mammalian radiation (60 Ma), we hypothesize that the dixenous piroplasmid life cycle evolved with the origin of ticks. Thus, the observed time gap between tick origin and mammalian radiation indicates the existence of hitherto unknown piroplasmid lineages and/or species in extant vertebrate taxa, including reptiles and possibly amphibians. The development and current status of the molecular taxonomy of Babesia, with emphasis on human-infecting species, is discussed. Finally, recent results from population genetic studies of Babesia parasites, and their implications for the development of pathogenicity, drug resistance and vaccines, are summarized.

Highlights

► Relevant Babesia parasites of man, and domestic and wildlife animals are introduced. ► Evolution scenarios of piroplasmids in relation to vertebrates and ticks are offered. ► An improved phylogenetic classification of major piroplasmid lineages is presented. ► The classical and molecular taxonomy of Babesia species is reviewed. ► The significance of recent population genetic findings is summarized.

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. In their vertebrate hosts they reproduce asexually inside erythrocytes, and together with Theileria spp. they are referred to as piroplasms or piroplasmids. The sexual phase of the Babesia life cycle typically takes place in Ixodid 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).

Victor Babeş (1888) was the first to discover microorganisms inside bovine erythrocytes of Romanian cattle that presented hemoglobinuria; and he later observed a similar organism in sheep blood (Babeş, 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 that had long stricken cattle ranchers in the Southern US states (Smith and Kilbourne, 1893). This turned out to be the first description of an arthropod-transmitted pathogen of vertebrates. The parasites described by Babeş, and Smith and Kilbour were later named Babesia bovis, B. ovis and B. bigemina, respectively (Starcovici, 1893, Mihalca, 2010). Soon afterwards, babesias parasitizing the blood of other domestic animals were observed, such as those that eventually became known as B. canis and B. caballi, described by Piana and Galli-Valerio (1895) and by Koch (1904), 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, cell biology and molecular biology techniques our knowledge of the Babesia world is rapidly expanding (Levine, 1988, Roncalli Amici, 2001, Criado-Fornelio et al., 2004, De Waal and Van Heerden, 2004, Uilenberg, 2006, Lack et al., 2012).

Section snippets

Distribution and pathological effects of some relevant Babesia spp.

The remarkable impact of babesia infections in three host groups: domestic animals, humans and, most recently acknowledged, some wildlife species, has inspired a great amount of research efforts in recent decades.

In general, babesia infections course with varying degrees of severity that can often be associated to the host’s age, immunological status, concurrent infections with other pathogens, and/or genetic factors. Common manifestations of acute babesia infections in different hosts can

The natural history of Babesia

To gain some insight into the nature of co-evolution and interaction between apicomplexan piroplasmids and their invertebrate and vertebrate hosts, an inevitably tentative view of their evolutionary history is outlined here based on recent research findings. Comparative morphology suggests that the most recent common ancestor (MRCA) of apicomplexans (which include gregarines, piroplasmids, Plasmodium, coccidians, cryptosporidia, etc.) possessed a prevailing presence in marine environments, with

Classical taxonomy

The group comprising Babesia and Theileria has been baptized “piroplasmids” due to the pear-shaped morphology of the multiplying parasite stage in the blood of the vertebrate host. As non-pigment forming hemoparasites, piroplasmids can be further distinguished from other erythrocyte-infecting genera, such as Plasmodium and Haemoproteus, which in contrast form pigment (hemozoin) in the parasitized cell (Uilenberg, 2006).

Before the application of molecular methodologies, no less than 111 valid

Tracing the ancestors: the 18S rRNA gene

In contrast to phenotypic characters, those derived from molecular sequences have the advantage of differentiating morphologically similar species and quantifying these differences. Recently, molecular phylogeny has made and will continue to make major contributions towards revealing evolutionary lineages and relations, and suggesting classification of piroplasmids. Importantly, these contributions have largely confirmed previous taxonomic classifications, based on a limited number of

Molecular taxonomy

As has been outlined above, the identification and definition of an increasing number of piroplasmid lineages and species cannot be achieved by the relatively few available phenotypic characters. As a steadily increasing number of piroplasmid species are described, molecular taxonomic approaches to define and outline species and higher taxon boundaries will become increasingly important (Blaxter, 2004; Blaxter et al., 2005, DeSalle et al., 2005, Hajibabaei et al., 2007). It is essential to

Population genetics

Population genetics provides important insights into the genetic diversity, population dynamics, and structure of parasite populations. As these parameters describe the adaptation of the parasite population for survival in response to environmental challenges, they have a major impact on vaccination strategies, as well as on the understanding of drug resistance, epidemiology, and pathogenicity (Beck et al., 2009a). The advent of molecular genetics and genomics, specifically PCR-based

Concluding remarks

We have presented a comprehensive summary of recent research findings that outline and integrate the important historic events of piroplasmid evolution in relation to their tick and vertebrate hosts. A novel improved classification of major piroplasmid lineages has been proposed based on an extensive molecular phylogenetic analysis of the 18S rRNA gene. The classic taxonomy of Babesia parasites, as well as Theileria and Cytauxzoon, was discussed, and recent developments of molecular taxonomy,

Acknowledgments

Financial support from the National Research Council of Argentina (CONICET), the National Institute of Technological Agriculture (INTA, AESA 203961 and AERG 232152), and the European Commission (INCO 245145, PIROVAC), as well as the assistance of Daniela Flores, are gratefully acknowledged.

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