Hostname: page-component-cd9895bd7-lnqnp Total loading time: 0 Render date: 2024-12-27T09:36:07.202Z Has data issue: false hasContentIssue false
  • English
  • Français

Approaches for the vaccination and treatment of Neospora caninum infections in mice and ruminant models

Published online by Cambridge University Press:  02 December 2015

ANDREW HEMPHILL ,
ADRIANA AGUADO-MARTÍNEZ  and
JOACHIM MÜLLER
ANDREW HEMPHILL*
Affiliation:
Institute of Parasitology, University of Berne, Berne, Switzerland
ADRIANA AGUADO-MARTÍNEZ
Affiliation:
Institute of Parasitology, University of Berne, Berne, Switzerland
JOACHIM MÜLLER
Affiliation:
Institute of Parasitology, University of Berne, Berne, Switzerland
*
*Corresponding author: Institute of Parasitology, Vetsuisse Faculty, University of Bern, Länggass-Strasse 122, CH-3012 Bern, Switzerland. Tel. +41 31 6312384. Fax: +41 31 6312477. E-mail: andrew.hemphill@vetsuisse.unibe.ch
Get access Rights & Permissions [Opens in a new window]

Summary

Neospora caninum is a leading cause of abortion in cattle, and is thus an important veterinary health problem of high economic significance. Vaccination has been considered a viable strategy to prevent bovine neosporosis. Different approaches have been investigated, and to date the most promising results have been achieved with live-attenuated vaccines. Subunit vaccines have also been studied, and most of them represented components that are functionally involved in (i) the physical interaction between the parasite and its host cell during invasion or (ii) tachyzoite-to-bradyzoite stage conversion. Drugs have been considered as an option to limit the effects of vertical transmission of N. caninum. Promising results with a small panel of compounds in small laboratory animal models indicate the potential value of a chemotherapeutical approach for the prevention of neosporosis in ruminants. For both, vaccines and drugs, the key for success in preventing vertical transmission lies in the application of bioactive compounds that limit parasite proliferation and dissemination, without endangering the developing fetus not only during an exogenous acute infection but also during recrudescence of a chronic infection. In this review, the current status of vaccine and drug development is presented and novel strategies against neosporosis are discussed.

Keywords

ApicomplexaNeosporaanti-infective agentsvaccinechemotherapyimmunotherapy
Type
Review Article
Information
Parasitology , Volume 143 , Issue 3 , March 2016 , pp. 245 - 259
Check for updates
Copyright
Copyright © Cambridge University Press 2015 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Alaeddine, F., Keller, N., Leepin, A. and Hemphill, A. (2005). Reduced infection and protection from clinical signs of cerebral neosporosis in C57BL/6 mice vaccinated with recombinant microneme antigen NcMIC1. Journal of Parasitology 91, 657–665.Google Scholar
Ammann, P., Waldvogel, A., Breyer, I., Esposito, M., Müller, N. and Gottstein, B. (2004). The role of B- and T-cell immunity in toltrazuril-treated C57BL/6 WT, microMT and nude mice experimentally infected with Neospora caninum . Parasitology Research 93, 178–187.Google Scholar
Andrews, K. T., Fisher, G. and Skinner-Adams, T. S. (2014). Drug repurposing and human parasitic protozoan diseases. International Journal for Parasitology: Drugs and Drug Resistance 4, 95–111.Google ScholarPubMed
Arranz-Solís, D., Aguado-Martínez, A., Müller, J., Regidor-Cerrillo, J., Ortega-Mora, L. M. and Hemphill, A. (2015). Dose-dependent effects of experimental infection with the virulent Neospora caninum Nc-Spain7 isolate in a pregnant mouse model. Veterinary Parasitology 211, 133–140.Google Scholar
Arranz-Solis, D., Benavides, J., Regidor-Cerrillo, J., Fuertes, M., Ferre, I., Ferreras Mdel, C., Collantes-Fernandez, E., Hemphill, A., Perez, V. and Ortega-Mora, L. M. (2015). Influence of the gestational stage on the clinical course, lesional development and parasite distribution in experimental ovine neosporosis. Veterinary Research 46, 19.Google Scholar
Barling, K. S., Lunt, D. K., Graham, S. L. and Choromanski, L. J. (2003). Evaluation of an inactivated Neospora caninum vaccine in beef feedlot steers. Journal of the American Veterinary Medical Association 222, 624–627.Google Scholar
Barna, F., Debache, K., Vock, C. A., Küster, T. and Hemphill, A. (2013). In vitro effects of novel ruthenium complexes in Neospora caninum and Toxoplasma gondii tachyzoites. Antimicrobial Agents and Chemotherapy 57, 5747–5754.CrossRefGoogle ScholarPubMed
Basto, A. P. and Leitão, A. (2014). Targeting TLR2 for vaccine development. Journal of Immunology Research 2014, 619410.Google Scholar
Basto, A. P., Piedade, J., Ramalho, R., Alves, S., Soares, H., Cornelis, P., Martins, C. and Leitão, A. (2012). A new cloning system based on the OprI lipoprotein for the production of recombinant bacterial cell wall-derived immunogenic formulations. Journal of Biotechnology 157, 50–63.Google Scholar
Basto, A. P., Badenes, M., Almeida, S. C., Martins, C., Duarte, A., Santos, D. M. and Leitao, A. (2015). Immune response profile elicited by the model antigen ovalbumin expressed in fusion with the bacterial OprI lipoprotein. Molecular Immunology 64, 36–45.Google Scholar
Brown, C. G. (1990). Control of tropical theileriosis (Theileria annulata infection) of cattle. Parassitologia 32, 23–31.Google Scholar
Buxton, D. (1998). Protozoan infections (Toxoplasma gondii, Neospora caninum and Sarcocystis spp.) in sheep and goats: recent advances. Veterinary Research 29, 289–310.Google Scholar
Buxton, D., Maley, S. W., Thomson, K. M., Trees, A. J. and Innes, E. A. (1997). Experimental infection of non-pregnant and pregnant sheep with Neospora caninum . Journal of Comparitive Pathology 117, 1–16.Google Scholar
Buxton, D., Wright, S., Maley, S. W., Rae, A. G., Lunden, A. and Innes, E. A. (2001). Immunity to experimental neosporosis in pregnant sheep. Parasite Immunology 23, 85–91.Google Scholar
Buxton, D., McAllister, M. M. and Dubey, J. P. (2002). The comparative pathogenesis of neosporosis. Trends Parasitology 18, 546–552.Google Scholar
Cannas, A., Naguleswaran, A., Müller, N., Eperon, S., Gottstein, B. and Hemphill, A. (2003 a). Vaccination of mice against experimental Neospora caninum infection using NcSAG1- and NcSRS2-based recombinant antigens and DNA vaccines. Parasitology 126, 303–312.Google Scholar
Cannas, A., Naguleswaran, A., Muller, N., Gottstein, B. and Hemphill, A. (2003 b). Reduced cerebral infection of Neospora caninum-infected mice after vaccination with recombinant microneme protein NcMIC3 and ribi adjuvant. Journal of Parasitology 89, 44–50.Google Scholar
Casal, J. I., Langeveld, J. P., Cortes, E., Schaaper, W. W., van Dijk, E., Vela, C., Kamstrup, S. and Meloen, R. H. (1995). Peptide vaccine against canine parvovirus: identification of two neutralization subsites in the N terminus of VP2 and optimization of the amino acid sequence. Journal of Virology 69, 7274–7277.CrossRefGoogle Scholar
Casini, A., Gabbiani, C., Sorrentino, F., Rigobello, M. P., Bindoli, A., Geldbach, T. J., Marrone, A., Re, N., Hartinger, C. G., Dyson, P. J. and Messori, L. (2008). Emerging protein targets for anticancer metallodrugs: inhibition of thioredoxin reductase and cathepsin B by antitumor ruthenium(II)-arene compounds. Journal of Medicinal Chemistry 51, 6773–6781.Google Scholar
Costa, R. C., Orlando, D. R., Abreu, C. C., Nakagaki, K. Y., Mesquita, L. P., Nascimento, L. C., Silva, A. C., Maiorka, P. C., Peconick, A. P., Raymundo, D. L. and Varaschin, M. S. (2014). Histological and immunohistochemical characterization of the inflammatory and glial cells in the central nervous system of goat fetuses and adult male goats naturally infected with Neospora caninum . BMC Veterinary Research. 10, 291.Google Scholar
Das, A. K. (2015). Anticancer effect of antiMalarial Artemisinin compounds. Annals of Medical Health Sciences and Research 5, 93–102.Google Scholar
Debache, K. and Hemphill, A. (2012). Effects of miltefosine treatment in fibroblast cell cultures and in mice experimentally infected with Neospora caninum tachyzoites. Parasitology 139, 934–944.Google Scholar
Debache, K. and Hemphill, A. (2013). Differential effects of intranasal vaccination with recombinant NcPDI in different mouse models of Neospora caninum infection. Parasite Immunology 35, 11–20.Google Scholar
Debache, K., Guionaud, C., Alaeddine, F., Mevissen, M. and Hemphill, A. (2008). Vaccination of mice with recombinant NcROP2 antigen reduces mortality and cerebral infection in mice infected with Neospora caninum tachyzoites. International Journal for Parasitology 38, 1455–1463.Google Scholar
Debache, K., Alaeddine, F., Guionaud, C., Monney, T., Müller, J., Strohbusch, M., Leib, S. L., Grandgirard, D. and Hemphill, A. (2009). Vaccination with recombinant NcROP2 combined with recombinant NcMIC1 and NcMIC3 reduces cerebral infection and vertical transmission in mice experimentally infected with Neospora caninum tachyzoites. International Journal for Parasitology 39, 1373–1384.Google Scholar
Debache, K., Guionaud, C., Alaeddine, F. and Hemphill, A. (2010). Intraperitoneal and intra-nasal vaccination of mice with three distinct recombinant Neospora caninum antigens results in differential effects with regard to protection against experimental challenge with Neospora caninum tachyzoites. Parasitology 137, 229–240.CrossRefGoogle ScholarPubMed
Debache, K., Guionaud, C., Kropf, C., Boykin, D., Stephens, C. E. and Hemphill, A. (2011). Experimental treatment of Neospora caninum-infected mice with the arylimidamide DB750 and the thiazolide nitazoxanide. Experimental Parasitology 129, 95–100.Google Scholar
Donahoe, S. L., Lindsay, S. A., Krockenberger, M., Phalen, D. and Slapeta, J. (2015). A review of neosporosis and pathologic findings of Neospora caninum infection in wildlife. International Journal for Parasitology: Parasites and Wildlife 4, 216–238.Google Scholar
Dubey, J. P. (2003). Review of Neospora caninum and neosporosis in animals. Korean Journal of Parasitology 41, 1–16.Google Scholar
Dubey, J. P. and Lindsay, D. S. (1990). Neospora caninum induced abortion in sheep. Journal of Veterinary Diagnostic Investigation 2, 230–233.Google Scholar
Dubey, J. P., Schares, G. and Ortega-Mora, L. M. (2007). Epidemiology and control of neosporosis and Neospora caninum . Clinical Microbiology Reviews 20, 323–367.Google Scholar
Esposito, M., Moores, S., Naguleswaran, A., Müller, J. and Hemphill, A. (2007). Induction of tachyzoite egress from cells infected with the protozoan Neospora caninum by nitro- and bromo-thiazolides, a class of broad-spectrum anti-parasitic drugs. International Journal for Parasitology 37, 1143–1152.Google Scholar
Esposito, M., Stettler, R., Moores, S. L., Pidathala, C., Müller, N., Stachulski, A., Berry, N. G., Rossignol, J. F. and Hemphill, A. (2005). In vitro efficacies of nitazoxanide and other thiazolides against Neospora caninum tachyzoites reveal antiparasitic activity independent of the nitro group. Antimicrobial Agents and Chemotherapy 49, 3715–3723.Google Scholar
Estes, D. M. and Brown, W. C. (2002). Type 1 and type 2 responses in regulation of Ig isotype expression in cattle. Veterinary Immunology and Immunopathology 90, 1–10.Google Scholar
Gondim, L. F. (2006). Neospora caninum in wildlife. Trends in Parasitology 22, 247–252.Google Scholar
Gonzalez-Warleta, M., Castro-Hermida, J. A., Regidor-Cerrillo, J., Benavides, J., Alvarez-Garcia, G., Fuertes, M., Ortega-Mora, L. M. and Mezo, M. (2014). Neospora caninum infection as a cause of reproductive failure in a sheep flock. Veterinary Researcg 45, 88.CrossRefGoogle Scholar
Goodswen, S. J., Kennedy, P. J. and Ellis, J. T. (2014). Discovering a vaccine against neosporosis using computers: is it feasible? Trends in Parasitology 30, 401–411.Google Scholar
Gottstein, B., Eperon, S., Dai, W. J., Cannas, A., Hemphill, A. and Greif, G. (2001). Efficacy of toltrazuril and ponazuril against experimental Neospora caninum infection in mice. Parasitology Research 87, 43–48.CrossRefGoogle ScholarPubMed
Gottstein, B., Razmi, G. R., Ammann, P., Sager, H. and Muller, N. (2005). Toltrazuril treatment to control diaplacental Neospora caninum transmission in experimentally infected pregnant mice. Parasitology 130, 41–48.Google Scholar
Haerdi, C., Haessig, M., Sager, H., Greif, G., Staubli, D. and Gottstein, B. (2006). Humoral immune reaction of newborn calves congenitally infected with Neospora caninum and experimentally treated with toltrazuril. Parasitology Research 99, 534–540.Google Scholar
Haldorson, G. J., Mathison, B. A., Wenberg, K., Conrad, P. A., Dubey, J. P., Trees, A. J., Yamane, I. and Baszler, T. V. (2005). Immunization with native surface protein NcSRS2 induces a Th2 immune response and reduces congenital Neospora caninum transmission in mice. International Journal for Parasitology 35, 1407–1415.Google Scholar
Harder, A. and Haberkorn, A. (1989). Possible mode of action of toltrazuril: studies on two Eimeria species and mammalian and Ascaris suum enzymes. Parasitology Research 76, 8–12.Google Scholar
Häsler, B., Regula, G., Stark, K. D., Sager, H., Gottstein, B. and Reist, M. (2006 a). Financial analysis of various strategies for the control of Neospora caninum in dairy cattle in Switzerland. Preventive Veterinary Medicine 77, 230–253.Google Scholar
Häsler, B., Stark, K. D., Sager, H., Gottstein, B. and Reist, M. (2006 b). Simulating the impact of four control strategies on the population dynamics of Neospora caninum infection in Swiss dairy cattle. Preventive Veterinary Medicine 77, 254–283.Google Scholar
Häsler, B., Stark, K., Gottstein, B. and Reist, M. (2008). Epidemiological and financial considerations for the control of Neospora caninum on Swiss dairy farms. Schweiz Arch Tierheilkd 150, 273–280.Google Scholar
Hecker, Y. P., Moore, D. P., Quattrocchi, V., Regidor-Cerrillo, J., Verna, A., Leunda, M. R., Morrell, E., Ortega-Mora, L. M., Zamorano, P., Venturini, M. C. and Campero, C. M. (2013). Immune response and protection provided by live tachyzoites and native antigens from the NC-6 Argentina strain of Neospora caninum in pregnant heifers. Veterinary Parasitology 197, 436–446.Google Scholar
Hecker, Y. P., Coceres, V., Wilkowsky, S. E., Jaramillo Ortiz, J. M., Morrell, E. L., Verna, A. E., Ganuza, A., Cano, D. B., Lischinsky, L., Angel, S. O., Zamorano, P., Odeon, A. C., Leunda, M. R., Campero, C. M., Morein, B. and Moore, D. P. (2014). A Neospora caninum vaccine using recombinant proteins fails to prevent foetal infection in pregnant cattle after experimental intravenous challenge. Veterinary Immunology Immunopathology 162, 142–153.Google Scholar
Hemphill, A., Vonlaufen, N. and Naguleswaran, A. (2006). Cellular and immunological basis of the host-parasite relationship during infection with Neospora caninum . Parasitology 133, 261–278.CrossRefGoogle ScholarPubMed
Hemphill, A., Debache, K., Monney, T., Schorer, M., Guionaud, C., Alaeddine, F., Müller, N. and Müller, J. (2013 a). Proteins mediating the Neospora caninum-host cell interaction as targets for vaccination. Frontiers in Bioscience (Elite Ed) 5, 23–36.Google Scholar
Hemphill, A., Müller, N. and Müller, J. (2013 b). Thiazolides, a novel class of anti-infective drugs, effective against viruses, bacteria, intracellular and extracellular protozoan parasites and proliferating mammalian cells. Anti-inflammatory Agents 11, 22–30.Google Scholar
Howe, D. K. and Sibley, L. D. (1997). Development of molecular genetics for Neospora caninum: A complementary system to Toxoplasma gondii . Methods 13, 123–133.Google Scholar
Irvin, A. D. and Morrison, W. I. (1989). Vaccines against Theileria parva . In Veterinary Protozoan and Hemoparasite Vaccines (ed. Wright, I. G.), pp. 115–130. CRC Press, Inc., Boca Raton, Florida, USA.Google Scholar
Jenkins, M. C., Tuo, W. and Dubey, J. P. (2004). Evaluation of vaccination with Neospora caninum protein for prevention of fetal loss associated with experimentally induced neosporosis in sheep. American Journal of Veterinary Research 65, 1404–1408.CrossRefGoogle ScholarPubMed
Jia, L. J., Zhang, S. F., Qian, N. C., Xuan, X. N., Yu, L. Z., Zhang, X. M. and Liu, M. M. (2013). Generation and immunity testing of a recombinant adenovirus expressing NcSRS2-NcGRA7 fusion protein of bovine Neospora caninum . Korean Journal of Parasitology 51, 247–253.CrossRefGoogle ScholarPubMed
Jimenez-Ruiz, E., Alvarez-Garcia, G., Aguado-Martinez, A., Salman, H., Irache, J. M., Marugan-Hernandez, V. and Ortega-Mora, L. M. (2012). Low efficacy of NcGRA7, NcSAG4, NcBSR4 and NcSRS9 formulated in poly-epsilon-caprolactone against Neospora caninum infection in mice. Vaccine 30, 4983–4992.CrossRefGoogle ScholarPubMed
Jimenez-Ruiz, E., Alvarez-Garcia, G., Aguado-Martinez, A. and Ortega-Mora, L. M. (2013 a). Low rates of Neospora caninum infection reactivation during gestation are observed in both chronically and congenitally infected mice. Parasitology 140, 220–228.Google Scholar
Jimenez-Ruiz, E., Alvarez-Garcia, G., Aguado-Martinez, A. and Ortega-Mora, L. M. (2013 b). Mice congenitally infected with low-to-moderate virulence Neospora caninum isolates exhibited clinical reactivation during the mating period without transmission to the next generation. Experimental Parasitology 134, 244–248.Google Scholar
Kasper, L. H. and Khan, I. A. (1998). Antigen-specific CD8+ T cells protect against lethal toxoplasmosis in mice infected with Neospora caninum . Infection and Immunity 66, 1554–1560.CrossRefGoogle ScholarPubMed
Kato, T., Otsuki, T., Yoshimoto, M., Itagaki, K., Kohsaka, T., Matsumoto, Y., Ike, K. and Park, E. Y. (2014). Bombyx mori Nucleopolyhedrovirus displaying Neospora caninum antigens as a vaccine candidate against N. caninum infection in Mice. Molecular Biotechnology 57, 145–154.CrossRefGoogle Scholar
Keyloun, K. R., Reid, M. C., Choi, R., Song, Y., Fox, A. M., Hillesland, H. K., Zhang, Z., Vidadala, R., Merritt, E. A., Lau, A. O., Maly, D. J., Fan, E., Barrett, L. K., WC, V. A. N. V. and Ojo, K. K. (2014). The gatekeeper residue and beyond: homologous calcium-dependent protein kinases as drug development targets for veterinarian Apicomplexa parasites. Parasitology 141, 1499–1509.Google Scholar
Klinkert, M. Q. and Heussler, V. (2006). The use of anticancer drugs in antiparasitic chemotherapy. Mini Reviews in Medicinal Chemistry 6, 131–143.Google Scholar
Kritzner, S., Sager, H., Blum, J., Krebber, R., Greif, G. and Gottstein, B. (2002). An explorative study to assess the efficacy of toltrazuril-sulfone (ponazuril) in calves experimentally infected with Neospora caninum . Annals of Clinical Microbiology and Antimicrobials 1, 4.Google Scholar
Kropf, C., Debache, K., Rampa, C., Barna, F., Schorer, M., Stephens, C. E., Ismail, M. A., Boykin, D. W. and Hemphill, A. (2012). The adaptive potential of a survival artist: characterization of the in vitro interactions of Toxoplasma gondii tachyzoites with di-cationic compounds in human fibroblast cell cultures. Parasitology 139, 208–220.Google Scholar
Larson, R. L., Hardin, D. K. and Pierce, V. L. (2004). Economic considerations for diagnostic and control options for Neospora caninum-induced abortions in endemically infected herds of beef cattle. Journal of the American Veterinary Medical Association 224, 1597–1604.Google Scholar
Lindenthal, C., Weich, N., Chia, Y. S., Heussler, V. and Klinkert, M. Q. (2005). The proteasome inhibitor MLN-273 blocks exoerythrocytic and erythrocytic development of Plasmodium parasites. Parasitology 131, 37–44.CrossRefGoogle ScholarPubMed
Lindsay, D. S., Rippey, N. S., Cole, R. A., Parsons, L. C., Dubey, J. P., Tidwell, R. R. and Blagburn, B. L. (1994). Examination of the activities of 43 chemotherapeutic agents against Neospora caninum tachyzoites in cultured cells. American Journal of Veterinary Research 55, 976–981.Google Scholar
Lindsay, D. S., Rippey, N. S., Powe, T. A., Sartin, E. A., Dubey, J. P. and Blagburn, B. L. (1995). Abortions, fetal death, and stillbirths in pregnant pygmy goats inoculated with tachyzoites of Neospora caninum . American Journal of Veterinary Research 56, 1176–1180.Google Scholar
Lopez-Perez, I. C., Collantes-Fernandez, E., Aguado-Martinez, A., Rodriguez-Bertos, A. and Ortega-Mora, L. M. (2008). Influence of Neospora caninum infection in BALB/c mice during pregnancy in post-natal development. Veterinary Parasitology 155, 175–183.Google Scholar
Lourido, S., Shuman, J., Zhang, C., Shokat, K. M., Hui, R. and Sibley, L. D. (2010). Calcium-dependent protein kinase 1 is an essential regulator of exocytosis in Toxoplasma . Nature 465, 359–362.Google Scholar
Mansilla, F. C., Franco-Mahecha, O. L., Lavoria, M. A., Moore, D. P., Giraldez, A. N., Iglesias, M. E., Wilda, M. and Capozzo, A. V. (2012). The immune enhancement of a novel soy lecithin/beta-glucans based adjuvant on native Neospora caninum tachyzoite extract vaccine in mice. Vaccine 30, 1124–1131.CrossRefGoogle ScholarPubMed
Mansilla, F. C., Czepluch, W., Malacari, D. A., Hecker, Y. P., Bucafusco, D., Franco-Mahecha, O. L., Moore, D. P. and Capozzo, A. V. (2013). Dose-dependent immunogenicity of a soluble Neospora caninum tachyzoite-extract vaccine formulated with a soy lecithin/beta-glucan adjuvant in cattle. Veterinary Parasitology 197, 13–21.CrossRefGoogle ScholarPubMed
Marugan-Hernandez, V., Ortega-Mora, L. M., Aguado-Martinez, A., Jimenez-Ruiz, E. and Alvarez-Garcia, G. (2011). Transgenic Neospora caninum strains constitutively expressing the bradyzoite NcSAG4 protein proved to be safe and conferred significant levels of protection against vertical transmission when used as live vaccines in mice. Vaccine 29, 7867–7874.CrossRefGoogle ScholarPubMed
Mathis, G. F., Froyman, R., Irion, T. and Kennedy, T. (2003). Coccidiosis control with toltrazuril in conjunction with anticoccidial medicated or nonmedicated feed. Avian Diseases 47, 463–469.Google Scholar
Mazuz, M. L., Haynes, R., Shkap, V., Fish, L., Wollkomirsky, R., Leibovich, B., Molad, T., Savitsky, I. and Golenser, J. (2012). Neospora caninum: in vivo and in vitro treatment with artemisone. Veterinary Parasitology 187, 99–104.Google Scholar
Mazuz, M. L., Fish, L., Wolkomirsky, R., Leibovich, B., Reznikov, D., Savitsky, I., Golenser, J. and Shkap, V. (2015). The effect of a live Neospora caninum tachyzoite vaccine in naturally infected pregnant dairy cows. Preventive Veterinary Medicine 120, 232–235.Google Scholar
McAllister, M. M. (2014). Successful vaccines for naturally occurring protozoal diseases of animals should guide human vaccine research. A review of protozoal vaccines and their designs. Parasitology 141, 624–640.Google Scholar
McAllister, M. M., McGuire, A. M., Jolley, W. R., Lindsay, D. S., Trees, A. J. and Stobart, R. H. (1996). Experimental neosporosis in pregnant ewes and their offspring. Veterinary Pathology 33, 647–655.Google Scholar
Miller, C., Quinn, H., Ryce, C., Reichel, M. P. and Ellis, J. T. (2005). Reduction in transplacental transmission of Neospora caninum in outbred mice by vaccination. International Journal of Parasitology 35, 821–828.CrossRefGoogle ScholarPubMed
Monney, T. and Hemphill, A. (2014). Vaccines against neosporosis: what can we learn from the past studies? Experimental Parasitology 140, 52–70.Google Scholar
Monney, T., Rutti, D., Schorer, M., Debache, K., Grandgirard, D., Leib, S. L. and Hemphill, A. (2011). RecNcMIC3-1-R is a microneme- and rhoptry-based chimeric antigen that protects against acute neosporosis and limits cerebral parasite load in the mouse model for Neospora caninum infection. Vaccine 29, 6967–6975.Google Scholar
Monney, T., Grandgirard, D., Leib, S. L. and Hemphill, A. (2013). Use of a Th1 stimulator adjuvant for vaccination against Neospora caninum infection in the pregnant mouse model. Pathogens 2, 193–208.Google Scholar
Moore, D. P. (2005). Neosporosis in South America. Veterinary Parasitology 127, 87–97.Google Scholar
Moreno, B., Collantes-Fernandez, E., Villa, A., Navarro, A., Regidor-Cerrillo, J. and Ortega-Mora, L. M. (2012). Occurrence of Neospora caninum and Toxoplasma gondii infections in ovine and caprine abortions. Veterinary Parasitology 187, 312–318.Google Scholar
Morrison, W. I., Connelley, T., Hemmink, J. D. and MacHugh, N. D. (2015). Understanding the basis of parasite strain-restricted immunity to Theileria parva . Annual Review of Animal Biosciences. 3, 397–418.Google Scholar
Müller, J. and Hemphill, A. (2011). Drug target identification in intracellular and extracellular protozoan parasites. Current Topics in Medicinal Chemistry 11, 2029–2038.Google Scholar
Müller, J. and Hemphill, A. (2013 a). In vitro culture systems for the study of apicomplexan parasites in farm animals. International Journal for Parasitology 43, 115–124.Google Scholar
Müller, J. and Hemphill, A. (2013 b). New approaches for the identification of drug targets in protozoan parasites. International Review of Cell and Molecular Biology 301, 359–401.Google Scholar
Müller, J., Sidler, D., Nachbur, U., Wastling, J., Brunner, T. and Hemphill, A. (2008). Thiazolides inhibit growth and induce glutathione-S-transferase Pi (GSTP1)-dependent cell death in human colon cancer cells. International Journal of Cancer 123, 1797–1806.CrossRefGoogle ScholarPubMed
Müller, J., Aguado-Martinez, A., Manser, V., Balmer, V., Winzer, P., Ritler, D., Hostettler, I., Solís, D., Ortega-Mora, L. M. and Hemphill, A. (2015 a). Buparvaquone is active against Neospora caninum in vitro and in experimentally infected mice. International Journal of Parasitology: Drugs and Drug Resistance 5, 16–25.Google Scholar
Müller, J., Balmer, V., Winzer, P., Rahman, M., Manser, V., Haynes, R. K. and Hemphill, A. (2015 b). In vitro effects of new artemisinin derivatives in Neospora caninum-infected human fibroblasts. International Journal of Antimicrobial Agents 46, 88–93.Google Scholar
Mundt, H. C., Bangoura, B., Mengel, H., Keidel, J. and Daugschies, A. (2005). Control of clinical coccidiosis of calves due to Eimeria bovis and Eimeria zuernii with toltrazuril under field conditions. Parasitology Research 97 (Suppl. 1), S134–S142.Google Scholar
Mutugi, J. J., Young, A. S., Maritim, A. C., Linyonyi, A., Mbogo, S. K. and Leitch, B. L. (1988). Immunization of cattle using varying infective doses of Theileria parva lawrencei sporozoites derived from an African buffalo (Syncerus caffer) and treatment with buparvaquone. Parasitology 96(Pt 2), 391–402.Google Scholar
Nishikawa, Y., Ikeda, H., Fukumoto, S., Xuan, X., Nagasawa, H., Otsuka, H. and Mikami, T. (2000). Immunization of dogs with a canine herpesvirus vector expressing Neospora caninum surface protein, NcSRS2. International Journal for Parasitology 30, 1167–1171.Google Scholar
Nishimura, M., Kohara, J., Kuroda, Y., Hiasa, J., Tanaka, S., Muroi, Y., Kojima, N., Furuoka, H. and Nishikawa, Y. (2013). Oligomannose-coated liposome-entrapped dense granule protein 7 induces protective immune response to Neospora caninum in cattle. Vaccine 31, 3528–3535.Google Scholar
O'Handley, R. M., Morgan, S. A., Parker, C., Jenkins, M. C. and Dubey, J. P. (2003). Vaccination of ewes for prevention of vertical transmission of Neospora caninum . American Journal of Veterinary Research 64, 449–452.Google Scholar
Ojo, K. K., Reid, M. C., Kallur Siddaramaiah, L., Müller, J., Winzer, P., Zhang, Z., Keyloun, K. R., Vidadala, R. S., Merritt, E. A., Hol, W. G., Maly, D. J., Fan, E., Van Voorhis, W. C. and Hemphill, A. (2014). Neospora caninum calcium-dependent protein kinase 1 is an effective drug target for neosporosis therapy. PLoS ONE 9, e92929.Google Scholar
Pastor-Fernandez, I., Arranz-Solis, D., Regidor-Cerrillo, J., Alvarez-Garcia, G., Hemphill, A., Garcia-Culebras, A., Cuevas-Martin, C. and Ortega-Mora, L. M. (2015). A vaccine formulation combining rhoptry proteins NcROP40 and NcROP2 improves pup survival in a pregnant mouse model of neosporosis. Veterinary Parasitology 207, 203–215.Google Scholar
Ramamoorthy, S., Lindsay, D. S., Schurig, G. G., Boyle, S. M., Duncan, R. B., Vemulapalli, R. and Sriranganathan, N. (2006). Vaccination with gamma-irradiated Neospora caninum tachyzoites protects mice against acute challenge with N. caninum . Journal of Eukaryotic Microbiology 53, 151–156.CrossRefGoogle ScholarPubMed
Ramamoorthy, S., Duncan, R., Lindsay, D. S. and Sriranganathan, N. (2007 a). Optimization of the use of C57BL/6 mice as a laboratory animal model for Neospora caninum vaccine studies. Veterinary Parasitology 145, 253–259.Google Scholar
Ramamoorthy, S., Sanakkayala, N., Vemulapalli, R., Duncan, R. B., Lindsay, D. S., Schurig, G. S., Boyle, S. M., Kasimanickam, R. and Sriranganathan, N. (2007 b). Prevention of lethal experimental infection of C57BL/6 mice by vaccination with Brucella abortus strain RB51 expressing Neospora caninum antigens. International Journal for Parasitology 37, 1521–1529.Google Scholar
Ramamoorthy, S., Sanakkayala, N., Vemulapalli, R., Jain, N., Lindsay, D. S., Schurig, G. S., Boyle, S. M. and Sriranganathan, N. (2007 c). Prevention of vertical transmission of Neospora caninum in C57BL/6 mice vaccinated with Brucella abortus strain RB51 expressing N. caninum protective antigens. International Journal for Parasitology 37, 1531–1538.Google Scholar
Ravera, M., Baracco, S., Cassino, C., Zanello, P. and Osella, D. (2004). Appraisal of the redox behaviour of the antimetastatic ruthenium(III) complex [ImH][RuCl(4)(DMSO)(Im)], NAMI-A. Dalton Transactions 15, 2347–2351.Google Scholar
Reichel, M. P. and Ellis, J. T. (2006). If control of Neospora caninum infection is technically feasible does it make economic sense? Veterinary Parasitology 142, 23–34.Google Scholar
Reichel, M. P. and Ellis, J. T. (2009). Neospora caninum–how close are we to development of an efficacious vaccine that prevents abortion in cattle? International Journal for Parasitology 39, 1173–1187.Google Scholar
Reichel, M. P., Alejandra Ayanegui-Alcerreca, M., Gondim, L. F. and Ellis, J. T. (2013). What is the global economic impact of Neospora caninum in cattle - the billion dollar question. International Journal for Parasitology 43, 133–142.CrossRefGoogle ScholarPubMed
Reichel, M. P., McAllister, M. M., Pomroy, W. E., Campero, C., Ortega-Mora, L. M. and Ellis, J. T. (2014). Control options for Neospora caninum–is there anything new or are we going backwards? Parasitology 141, 1455–1470.Google Scholar
Reichel, M. P., Moore, D. P., Hemphill, A., Ortega-Mora, L. M., Dubey, J. P. and Ellis, J. T. (2015). A live vaccine against Neospora caninum abortions in cattle. Vaccine 33, 1299–1301.Google Scholar
Rojo-Montejo, S., Collantes-Fernandez, E., Lopez-Perez, I., Risco-Castillo, V., Prenafeta, A. and Ortega-Mora, L. M. (2012). Evaluation of the protection conferred by a naturally attenuated Neospora caninum isolate against congenital and cerebral neosporosis in mice. Veterinary Research 43, 62.Google Scholar
Rojo-Montejo, S., Collantes-Fernandez, E., Perez-Zaballos, F., Rodriguez-Marcos, S., Blanco-Murcia, J., Rodriguez-Bertos, A., Prenafeta, A. and Ortega-Mora, L. M. (2013). Effect of vaccination of cattle with the low virulence Nc-Spain 1H isolate of Neospora caninum against a heterologous challenge in early and mid-gestation. Veterinary Research 44, 106.Google Scholar
Romero, J. J., Perez, E. and Frankena, K. (2004). Effect of a killed whole Neospora caninum tachyzoite vaccine on the crude abortion rate of Costa Rican dairy cows under field conditions. Veterinary Parasitology 123, 149–159.Google Scholar
Rosypal, A. C. and Lindsay, D. S. (2005). The sylvatic cycle of Neospora caninum: where do we go from here? Trends in Parasitology 21, 439–440.Google Scholar
Rottmann, M., McNamara, C., Yeung, B. K., Lee, M. C., Zou, B., Russell, B., Seitz, P., Plouffe, D. M., Dharia, N. V., Tan, J., Cohen, S. B., Spencer, K. R., Gonzalez-Paez, G. E., Lakshminarayana, S. B., Goh, A., Suwanarusk, R., Jegla, T., Schmitt, E. K., Beck, H. P., Brun, R., Nosten, F., Renia, L., Dartois, V., Keller, T. H., Fidock, D. A., Winzeler, E. A. and Diagana, T. T. (2010). Spiroindolones, a potent compound class for the treatment of malaria. Science 329, 1175–1180.Google Scholar
Saadatnia, G. and Golkar, M. (2012). A review on human toxoplasmosis. Scandinavian Journal of Infectious Diseases 44, 805–814.Google Scholar
Sateriale, A., Bessoff, K., Sarkar, I. N. and Huston, C. D. (2014). Drug repurposing: mining protozoan proteomes for targets of known bioactive compounds. Journal of the American Medical Informatics Association 21, 238–244.Google Scholar
Schetters, T. P., Moubri, K. and Cooke, B. M. (2009). Comparison of Babesia rossi and Babesia canis isolates with emphasis on effects of vaccination with soluble parasite antigens: a review. Journal of the South African Veterinary Association 80, 75–78.Google Scholar
Schorer, M., Debache, K., Barna, F., Monney, T., Müller, J., Boykin, D. W., Stephens, C. E. and Hemphill, A. (2012). Di-cationic arylimidamides act against Neospora caninum tachyzoites by interference in membrane structure and nucleolar integrity and are active against challenge infection in mice. International Journal for Parasitology: Drugs and Drug Resistance 2, 109–120.Google Scholar
Scolaro, C., Chaplin, A. B., Hartinger, C. G., Bergamo, A., Cocchietto, M., Keppler, B. K., Sava, G. and Dyson, P. J. (2007). Tuning the hydrophobicity of ruthenium(II)-arene (RAPTA) drugs to modify uptake, biomolecular interactions and efficacy. Dalton Transactions 43, 5065–5072.Google Scholar
Sharman, P. A., Smith, N. C., Wallach, M. G. and Katrib, M. (2010). Chasing the golden egg: vaccination against poultry coccidiosis. Parasite Immunology 32, 590–598.Google Scholar
Soeiro, M. N., Werbovetz, K., Boykin, D. W., Wilson, W. D., Wang, M. Z. and Hemphill, A. (2013). Novel amidines and analogues as promising agents against intracellular parasites: a systematic review. Parasitology 140, 929–951.Google Scholar
Spillman, N. J., Allen, R. J., McNamara, C. W., Yeung, B. K., Winzeler, E. A., Diagana, T. T. and Kirk, K. (2013). Na(+) regulation in the malaria parasite Plasmodium falciparum involves the cation ATPase PfATP4 and is a target of the spiroindolone antimalarials. Cell Host & Microbe 13, 227–237.Google Scholar
Srinivasan, S., Müller, J., Suana, A. and Hemphill, A. (2007). Vaccination with microneme protein NcMIC4 increases mortality in mice inoculated with Neospora caninum . Journal of Parasitology 93, 1046–1055.Google Scholar
Staska, L. M., Davies, C. J., Brown, W. C., McGuire, T. C., Suarez, C. E., Park, J. Y., Mathison, B. A., Abbott, J. R. and Baszler, T. V. (2005). Identification of vaccine candidate peptides in the NcSRS2 surface protein of Neospora caninum by using CD4+ cytotoxic T lymphocytes and gamma interferon-secreting T lymphocytes of infected holstein cattle. Infection and Immunity 73, 1321–1329.Google Scholar
Steinfelder, S., Lucius, R., Greif, G. and Pogonka, T. (2005). Treatment of mice with the anticoccidial drug Toltrazuril does not interfere with the development of a specific cellular intestinal immune response to Eimeria falciformis . Parasitology Research 97, 458–465.CrossRefGoogle Scholar
Strohbusch, M., Müller, N., Hemphill, A., Greif, G. and Gottstein, B. (2008). NcGRA2 as a molecular target to assess the parasiticidal activity of toltrazuril against Neospora caninum . Parasitology 135, 1065–1073.Google Scholar
Strohbusch, M., Müller, N., Hemphill, A., Krebber, R., Greif, G. and Gottstein, B. (2009). Toltrazuril treatment of congenitally acquired Neospora caninum infection in newborn mice. Parasitology Research 104, 1335–1343.Google Scholar
Telfer, J. C. and Baldwin, C. L. (2015). Bovine gamma delta T cells and the function of gamma delta T cell specific WC1 co-receptors. Cellular Immunology 296, 76–86.Google Scholar
Tuo, W., Zhao, Y., Zhu, D. and Jenkins, M. C. (2011). Immunization of female BALB/c mice with Neospora cyclophilin and/or NcSRS2 elicits specific antibody response and prevents against challenge infection by Neospora caninum . Vaccine 29, 2392–2399.Google Scholar
Uchida, M., Nagashima, K., Akatsuka, Y., Murakami, T., Ito, A., Imai, S. and Ike, K. (2013). Comparative study of protective activities of Neospora caninum bradyzoite antigens, NcBAG1, NcBSR4, NcMAG1, and NcSAG4, in a mouse model of acute parasitic infection. Parasitology Research 112, 655–663.Google Scholar
Weber, F. H., Jackson, J. A., Sobecki, B., Choromanski, L., Olsen, M., Meinert, T., Frank, R., Reichel, M. P. and Ellis, J. T. (2013). On the efficacy and safety of vaccination with live tachyzoites of Neospora caninum for prevention of neospora-associated fetal loss in cattle. Clinical Vaccine Immunology 20, 99–105.Google Scholar
Weston, J. F., Howe, L., Collett, M. G., Pattison, R. S., Williamson, N. B., West, D. M., Pomroy, W. E., Syed-Hussain, S. S., Morris, S. T. and Kenyon, P. R. (2009). Dose-titration challenge of young pregnant sheep with Neospora caninum tachyzoites. Veterinary Parasitology 164, 183–191.Google Scholar
Weston, J. F., Heuer, C. and Williamson, N. B. (2012). Efficacy of a Neospora caninum killed tachyzoite vaccine in preventing abortion and vertical transmission in dairy cattle. Preventive Veterinary Medicine 103, 136–144.Google Scholar
Williams, D. J. and Trees, A. J. (2006). Protecting babies: vaccine strategies to prevent foetopathy in Neospora caninum-infected cattle. Parasite Immunology 28, 61–67.Google Scholar
Williams, D. J., Guy, C. S., Smith, R. F., Guy, F., McGarry, J. W., McKay, J. S. and Trees, A. J. (2003). First demonstration of protective immunity against foetopathy in cattle with latent Neospora caninum infection. International Journal for Parasitology 33, 1059–1065.Google Scholar
Williams, D. J., Guy, C. S., Smith, R. F., Ellis, J., Bjorkman, C., Reichel, M. P. and Trees, A. J. (2007). Immunization of cattle with live tachyzoites of Neospora caninum confers protection against fetal death. Infection and Immunity 75, 1343–1348.Google Scholar
Williams, D. J., Hartley, C. S., Bjorkman, C. and Trees, A. J. (2009). Endogenous and exogenous transplacental transmission of Neospora caninum - how the route of transmission impacts on epidemiology and control of disease. Parasitology 136, 1895–1900.Google Scholar
Winzer, P., Müller, J., Aguado-Martínez, A., Rahman, M., Balmer, V., Ortega-Mora, L., Ojo, K. K., Fan, E., Maly, D., Van Voorhis, W. C. and Hemphill, A. (2015). In vitro and in vivo effects of the bumped kinase inhibitor 1294 in the related cyst-forming apicomplexans Toxoplasma gondii and Neospora caninum . . Antimicrobial Agents and Chemotherapy 59, 6361–6374.Google Scholar
Xin, H., Cartmell, J., Bailey, J. J., Dziadek, S., Bundle, D. R. and Cutler, J. E. (2012). Self-adjuvanting glycopeptide conjugate vaccine against disseminated candidiasis. PLoS ONE 7, e35106.Google Scholar
Zhang, G., Huang, X., Boldbaatar, D., Battur, B., Battsetseg, B., Zhang, H., Yu, L., Li, Y., Luo, Y., Cao, S., Goo, Y. K., Yamagishi, J., Zhou, J., Zhang, S., Suzuki, H., Igarashi, I., Mikami, T., Nishikawa, Y. and Xuan, X. (2010). Construction of Neospora caninum stably expressing TgSAG1 and evaluation of its protective effects against Toxoplasma gondii infection in mice. Vaccine 28, 7243–7247.Google Scholar
Zhang, N. Z., Chen, J., Wang, M., Petersen, E. and Zhu, X. Q. (2013). Vaccines against Toxoplasma gondii: new developments and perspectives. Expert Review of Vaccines 12, 1287–1299.Google Scholar
Zhang, Z., Ojo, K. K., Vidadala, R., Huang, W., Geiger, J. A., Scheele, S., Choi, R., Reid, M. C., Keyloun, K. R., Rivas, K., Siddaramaiah, L. K., Comess, K. M., Robinson, K. P., Merta, P. J., Kifle, L., Hol, W. G., Parsons, M., Merritt, E. A., Maly, D. J., Verlinde, C. L., Van Voorhis, W. C. and Fan, E. (2014). Potent and selective inhibitors of CDPK1 from and based on a 5-aminopyrazole-4-carboxamide scaffold. ACS Medicinal Chemistry Letters 5, 40–44.Google Scholar