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Unravelling the Cellular and Molecular Pathogenesis of Bovine Babesiosis: Is the Sky the Limit? ⇑ Carlos E

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Unravelling the Cellular and Molecular Pathogenesis of Bovine Babesiosis: Is the Sky the Limit? ⇑ Carlos E International Journal for Parasitology 49 (2019) 183–197 Contents lists available at ScienceDirect International Journal for Parasitology journal homepage: www.elsevier.com/locate/ijpara Invited Review Unravelling the cellular and molecular pathogenesis of bovine babesiosis: is the sky the limit? ⇑ Carlos E. Suarez a,b, , Heba F. Alzan a,c, Marta G. Silva a,b, Vignesh Rathinasamy d, William A. Poole d, ⇑ Brian M. Cooke d, a Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, United States b Animal Disease Research Unit, Agricultural Research Service, USDA, WSU, Pullman, WA, United States c Parasitology and Animal Diseases Department, National Research Center, Dokki, Giza, Egypt d Department of Microbiology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia article info abstract Article history: The global impact of bovine babesiosis caused by the tick-borne apicomplexan parasites Babesia bovis, Received 23 October 2018 Babesia bigemina and Babesia divergens is vastly underappreciated. These parasites invade and multiply Received in revised form 21 November 2018 asexually in bovine red blood cells (RBCs), undergo sexual reproduction in their tick vectors Accepted 21 November 2018 (Rhipicephalus spp. for B. bovis and B. bigemina, and Ixodes ricinus for B. divergens) and have a trans- Available online 26 January 2019 ovarial mode of transmission. Babesia parasites can cause acute and persistent infections to adult naïve cat- tle that can occur without evident clinical signs, but infections caused by B. bovis are associated with more Keywords: severe disease and increased mortality, and are considered to be the most virulent agent of bovine babesio- Babesia sis. In addition, babesiosis caused by B. divergens has an important zoonotic potential. The disease caused Babesiosis Tick fever by B. bovis and B. bigemina can be controlled, at least in part, using therapeutic agents or vaccines compris- Parasite vaccines ing live-attenuated parasites, but these methods are limited in terms of their safety, ease of deployability Pathogenesis and long-term efficacy, and improved control measures are urgently needed. In addition, expansion of tick habitats due to climate change and other rapidly changing environmental factors complicate efficient con- trol of these parasites. While the ability to cause persistent infections facilitates transmission and persis- tence of the parasite in endemic regions, it also highlights their capacity to evade the host immune responses. Currently, the mechanisms of immune responses used by infected bovines to survive acute and chronic infections remain poorly understood, warranting further research. Similarly, molecular details on the processes leading to sexual reproduction and the development of tick-stage parasites are lacking, and such tick-specific molecules can be targets for control using alternative transmission blocking vac- cines. In this review, we identify and examine key phases in the life-cycle of Babesia parasites, including dependence on a tick vector for transmission, sexual reproduction of the parasite in the midgut of the tick, parasite-dependent invasion and egression of bovine RBCs, the role of the spleen in the clearance of infected RBCs (IRBCs), and age-related disease resistance in cattle, as opportunities for developing improved control measures. The availability of integrated novel research approaches including ‘‘omics” (such as genomics, transcriptomics, and proteomics), gene modification, cytoadhesion assays, RBC inva- sion assays and methods for in vitro induction of sexual-stage parasites will accelerate our understanding of parasite vulnerabilities. Further, producing new knowledge on these vulnerabilities, as well as taking full advantage of existing knowledge, by filling important research gaps should result in the development of next-generation vaccines to control acute disease and parasite transmission. Creative and effective use of current and future technical and computational resources are needed, in the face of the numerous chal- lenges imposed by these highly evolved parasites, for improving the control of this disease. Overall, bovine babesiosis is recognised as a global disease that imposes a serious burden on livestock production and human livelihood, but it largely remains a poorly controlled disease in many areas of the world. Recently, important progress has been made in our understanding of the basic biology and host-parasite interactions of Babesia parasites, yet a good deal of basic and translational research is still needed to achieve effective control of this important disease and to improve animal and human health. Ó 2020 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). ⇑ Corresponding authors at: Animal Disease Research Unit, ARS-USDA and Department of Veterinary Microbiology and Pathology, Washington State University, Pullman, WA, United States (C.E. Suarez) and Department of Microbiology, Biomedicine Discovery Institute, Monash University, Victoria 3800, Australia (B.M. Cooke). E-mail addresses: [email protected] (C.E. Suarez), [email protected] (B.M. Cooke). https://doi.org/10.1016/j.ijpara.2018.11.002 0020-7519/Ó 2020 The Authors. Published by Elsevier Ltd on behalf of Australian Society for Parasitology. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). 184 C.E. Suarez et al. / International Journal for Parasitology 49 (2019) 183–197 1. Introduction measures. However, as our research toolbox expands due to emer- gence of novel technologies, our knowledge of the complexities in Apicomplexans are obligate intracellular parasites defined by parasite biology and host-parasite interactions also increases at a the presence of a cell invasion apparatus consisting of rhoptries, faster rate. micronemes, and conoid organelles, known as the apical complex, Improved control of babesiosis relies on practical, sensitive and which facilitates invasion of these parasites into their host red specific methods for serological and molecular diagnosis of the dis- blood cells (RBCs). Members of Babesia, of which more than 100 ease. Diagnostic and genotyping methods are useful not only to species have been described (Chauvin et al., 2009), reside within demonstrate the presence and impact of the disease in the field, the order of Piroplasmida and can infect domestic and wild verte- but also to inform on the complexity of the strain variation among brates as well as becoming an emerging pathogen of humans, of and between Babesia populations, their relative virulence and the particular importance in transfusion medicine (Lobo et al., 2013). presence of co-infections. In addition, the variable results usually These tick-borne apicomplexan parasites are trans-ovarially trans- derived from the application of serological diagnostic methods mitted by Ixodidae ticks and similar to other related Alveolata, based on apparently widely conserved antigens can provide impor- including dinoflagellates, they contain a remnant membrane- tant clues on the antigenicity of key molecules that can be required bound, DNA-containing plastid organelle, derived from a vestigial to elicit protective immunity. Serological diagnosis can also inform endosymbiotic photosynthetic organism, most likely a red alga on the evolution of the immune responses in endemic areas, since (Arisue and Hashimoto, 2015). Babesia parasites contain most api- diagnostic data can provide valuable evidence that may suggest complexan invading organelles, except conoids. The evolutionary hypotheses on the mechanisms involved in the variations of the origin of Babesia parasites, similar to other apicomplexans, is most antigens involved. Therefore, diagnostic tools are also highly rele- probably related to a photosynthetic colpodellid-like organism vant for vaccine development, and for controlling the disease. Con- (Kuvardina et al., 2002; Leander et al., 2003; Mathur et al., 2018). trol of babesiosis can also be achieved by the elimination of the How apicomplexans switched from an autotrophic to a parasitic parasites’ tick vectors using acaricides. So far, none of the strategies life-style is currently an active field of research that may provide applied to control babesiosis have succeeded in complete elimina- clues towards our understanding of the mechanisms involved in tion of the disease in endemic areas, with the sole exception of a the evolution of virulence in these organisms of both veterinary long-term campaign (the Cattle Fever Tick Eradication Program) and medical importance. that was developed in the United States (USA) from 1906–1943 Babesiosis is a globally important tick-borne disease caused by and beyond, based on the eradication of Rhipicephalus ticks apicomplexan parasites of the genus Babesia. Babesia spp. are (https://www.aphis.usda.gov/animal_health/animal_diseases/tick/ highly successful intracellular parasites, which acquired highly downloads/draft_eis_document.pdf). This campaign succeeded sophisticated mechanisms for survival during long term co- under very special circumstances (Bowman, 2006) and could not evolution with their hosts. As a result, these parasites have devel- be reproduced elsewhere, despite important efforts using a similar oped a complex life-cycle involving hard ticks as definitive hosts approach developed in several countries
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