A history of Neospora caninum research
The December paper of the month from Parasitology is ‘Approaches for the vaccination and treatment of Neospora caninum infections in mice and ruminant models’ by Andrew Hemphill et al. In this blog Professor Hemphill chronicles the study of this deadly parasite.
“Neospora caninum was first described in 1984, named as a unique genus and species in 1988, and was identified as a causative agent of bovine abortion, stillbirth and birth of weak calves, and also of neuromuscular disease in dogs. In the mid-nineties, the study of N. caninum and its interactions with its host was largely, but not exclusively, regarded upon as a rather esoteric subject, justified by an inherent need to investigate the biology of parasitism rather than by the necessity to provide measures to limit the disease and economic impact of neosporosis. In addition, during the first years after the description of N. caninum, and mostly because of its close morphological similarities with Toxoplasma gondii, there was a widespread believe that the considerable knowledge that had accumulated by research on Toxoplasma and toxoplasmosis over many years could be directly applied for the development of countermeasures against N. caninum infection and neosporosis.
Twenty years down the road, things have changed: latest after the genome and transcriptome data of N. caninum has been generated, it became clear that there are some distince differences in the infection biology of these two species. In addition, it has become clear that neosporosis represents a significant veterinary public health problem with a high economic impact, affecting not only cattle, but also goats and sheep, and many wildlife species. The economic impact of neosporosis has led to considerable investments to develop vaccines that would prevent infection and abortion in ruminants. Many efforts have been undertaken to generate recombinant subunit vaccines based on antigens involved in adhesion/invasion or other parasite-host-cell interaction processes. A major factor that has hampered the development of such subunit vaccines is the immunomodulation that occurs during pregnancy. Thus, several promising vaccine candidates have been shown to elicit protective immunity in non-pregnant infection models, but once pregnancy is initiated, this protective immunity is overridden by the inherent, pregnancy-related immunomodulation. Basically, what is really needed is a more robust and thorough knowledge on how this immunomodulation is achieved, and how it could be circumvented without negative impact on pregnancy. In contrast to most subunit vaccines, live-attenuated vaccines have been shown to confer some limited protection against N. caninum infection in experimentally infected mice and cattle, but more recently the application of a live vaccine in a large study on naturally infected cattle carried out in Israel did not really provide very promising efficacy. In addition, live vaccines may cause problems due to regulatory issues, stability, production and other drawbacks.
Drug-based intervention could be an option, but has for the longest time been ruled out, since no effective and safe drugs have been available, and depending on the compounds the milk or meat from drug-treated animals would remain unacceptable for consumption for some time. However, in recent years, the boost of public-private partnerships for the search of novel treatment options for infectious diseases, especially in the field of neglected diseases, has lead to the development of a vast number of drugs and compound classes potentially applicable for N. caninum as well. The most interesting ones, however, have been derived from screenings carried out in the framework of Plasmodium research. Their application against other apicomplexans, including Neospora, is thus a good example of drug repurposing, and instead of developing a drug that would specifically limit N. caninum infection, it will make more sense to use piggy-back approach based on already known compounds. One of these novel compound classes that were originally developed for the treatment of malaria are targeted against calcium-dependent protein kinases (CDPKs), which are enzymes that are encoded in the DNA of an apicomplexa-specific organelle, the apicoplast. CDPKs are found in plants, funghi and in apicomplexan parasites, but not in mammalian cells, and thus represent highly interesting drug targets.
Ive been working in the Neospora field for 20 years now, a time characterized by small successes and considerable failures. When I tell this to friends and colleagues, I often get comments such as: “What?! You have worked on this for such a long time and still no vaccine or drug!? What have you been doing all these years!?” I`ve been asking myself the same question, and the only answers I can give: “Pregnancy can make life complicated. And maybe these guys are a lot cleverer than we think they are…” Without any doubt, the development of countermeasures against Neospora infection and associated disease will remain a challenge for some years to come.”