Which protozoan diseases impact cattle farming in sub-Saharan Africa?

The parasites that cause the most significant protozoan diseases in cattle in sub-Saharan Africa belong to order Kinetoplastida (phylum Euglenozoa) and the phylum Apicomplexa, taxa which encompass some of the world’s most devastating disease-causing parasitic species for humans, livestock, and crops.

Apicomplexan pathogens of cattle in sub-Saharan Africa.

The Apicomplexa are a large group of intracellular pathogens. In humans, diseases resulting from apicomplexan infection include malaria, toxoplasmosis, and babesiosis. Across sub-Saharan Africa, the most important veterinary apicomplexans for cattle are 2 piroplasma species: Theileria parva, the causative agent of the East Coast fever (ECF), and Babesia bovis and Babesia bigemina, causative agents of bovine babesiosis (Table 1). Other apicomplexan species cause tropical theilerioses, cryptosporidiosis, toxoplasmosis, neosporosis, besnoitiosis, and eimeriosis in cattle.

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Table 1. Research methods used for the study of human disease–causing parasite species that could be applied to cattle disease–causing parasites [2–9].

Note that the nonhuman infective subspecies of T. brucei (T. b. brucei) is the most widely used African trypanosome in the laboratory, acting as a model system for the human-infective subspecies T. b. rhodesiense and T. b. gambiense. Example studies are not exhaustive of the available literature.

https://doi.org/10.1371/journal.ppat.1009955.t001

T. parva is transmitted by ticks (Rhipicephalus appendiculatus), which feed on the blood of cattle and other mammals. During tick feeding, T. parva sporozoites enter into the cattle bloodstream. The extracellular sporozoites attach and enter host cells, primarily lymphocytes. Once inside, the parasite rapidly dissolves the host-derived parasitophorous vacuole membrane (PVM) and proliferates as an intracellular schizont in the host cell cytoplasm. The parasite immortalises the infected host cells, resulting in a cancer-like uncontrolled proliferation [10]; the molecular basis for this remains mostly uncharacterised. The cattle suffer diarrhoea, fever, anorexia, and laboured breathing. In 1999, it was estimated that stock losses to ECF were 1 million cattle [11]. It is reasonable to assume that annual losses have increased with cattle numbers. T. parva originated in the wild African buffalo (Syncerus caffer) population, where the parasite is ubiquitous but does not typically cause disease.

Bovine babesiosis is most commonly found in tropical and subtropical countries, especially in sub-Saharan Africa and South America. Two main species cause disease in African cattle, B. bovis and B. bigemina, and are transmitted by Rhipicephalus ticks. Following tick bite, the parasites invade host red blood cells, causing anaemia and fever, and infection can also lead to cerebral babesiosis (B. bovis only) and death of cattle. A recent South African survey revealed that up to three-quarters of cattle may be infected, dependent on region [12]. Although these cattle may appear healthy, they can have decreased milk and meat production, as well as acting as carriers for transmission [12].

What preventions and treatments are available against these protozoan infections in cattle?

Efforts to control parasitic disease are hindered by the challenge of implementing vector control strategies across the vast expanses of tsetse and tick-populated land; emerging drug resistance and the prevalence of counterfeit drugs; and a lack of suitable vaccination programmes.

Tick and tsetse fly control are used to prevent against infections, as has been the case for many generations. Vector control is complex and comes with many limitations, including the following: (i) Tsetse- and tick-infected regions are vast; therefore, traps can only provide a local level of protection, which needs to be ongoing; (ii) ticks and related insects are a valuable source of nutrition to reptiles and birds and so large-scale insecticide use is not feasible; (iii) cattle plunge-dipping into toxic organophosphates or synthetic pyrethroids can cause significant illness to the farmer and the environment and is not a widely available control option; and (iv) the choice of insecticides used are key, due to selective toxicity and resistance [13].

Vaccination of cattle to prevent disease transmission is therefore considerably preferable to arthropod management. Although ECF and babesiosis are both preventable diseases through live cell vaccination, such vaccines require a cold chain from lab to cow, which is inappropriate for use in rural settings due to expense and logistics. Additionally, vaccination with T. parva is followed by antibiotic treatment in a simultaneous infection treatment immunisation model. These impracticalities mean that the vaccine is not widely used. A modern subunit, RNA or DNA vaccine, is urgently required [14].

No vaccine against AAT exists and has long been thought unlikely to be developed. This is largely due to the parasites immune evasion strategy of antigenic variation as well as the apparent lack of natural capacity for cattle to clear infection, despite the presence of antibodies to nonvariant surface proteins. However, an AAT vaccine that could prevent establishment of the infection would be hugely valuable, and recent work has identified a well-conserved T. vivax vaccine target, against which vaccination in a murine model results in long-term sterile immunity [15].

The primary drug available to treat ECF is buparvaquone; this is over 30 years old and expensive to use, yet, to our knowledge, no new drugs are under development. Buparvaquone is also used to control Theileria annulata (causative agent of tropical theileriosis), and resistance due to mutations in the cytochrome b gene has been identified. The primary treatment for babesiosis is imidocarb. Concerns have been raised regarding use of imidocarb in livestock due to its passage into milk and retention in tissues that are then used as human food [16]. Currently, AAT is primarily controlled by regular administration of prophylactic isometamidium chloride and therapeutic diminazene aceturate and homidium bromide/chloride. The latter is a mutagenic (possibly carcinogenic) DNA intercalating agent, which can be toxic at high doses. Benzoxaboroles have been identified as a potential new class of veterinary drugs against AAT (for example, see [17]), with research and development underway.

Can the developments in research on human-infective protozoa inform our understanding of cattle parasites?

Typically, human-infective parasites are subject to more experimental research than relatives that infect cattle. This research gap needs to be addressed if the effects of such pathogens on livestock are to be more effectively prevented. The cellular and infection biology of cattle-infecting parasites do vary from human-infective species and so cannot always be reliably inferred. For example, many apicomplexan parasites are motile and invade host cells using an apical complex, forming a pointed end to the cell [18]. In contrast, Theileria parasites are nonmotile and do not reorient during host cell invasion. These differences are fundamental when designing subunit vaccines against cell surface proteins. Similarly, while the mutations that lead to diminazene aceturate resistance have been characterised in T. brucei, the mode of resistance in T. congolense and T. vivax is both distinct and unknown [19,20]. However, many of the tools and techniques developed for human-infective pathogens can be adapted for use in animal pathogens.

Table 1 describes some of the important issues that require addressing. For African trypanosomes, this includes the need to establish culturing techniques for T. vivax, improved culture systems for T. congolense (especially to permit growth of additional bloodstream form strains) and established robust genetic modification protocols, progress for which has been recently made [3]. For the apicomplexans, in vitro culture and stable genetic modification of B. bovis are possible, but only one life stage of T. parva can be grown in vitro, with no ability to genetically modify to date. For all of the species discussed here, whole-cell proteomics and genome-wide knock-out studies, akin to those previously carried out in related human-infective species, would be extremely beneficial. A combination of improved experimental tractability and large datasets would provide a step change in the capacity to study these veterinary important organisms.

While conscious of biological differences, advances in human-infective parasitology research can and should be exploited wherever possible to improve research capacity and knowledge of cattle parasites. For example, related parasite species often have similar capacity for genetic modification, so experimental protocols (i.e., transfection methodology) and resources (i.e., plasmids) developed in one species can be the starting point for developing methods for others. Similarly, the advancement of experimental techniques in one species (i.e., optimisation of cell fractionation methods for subcellular proteomics) may then facilitate the use of that technique in related organisms. Where novel biology is uncovered, the assessment of similar features (i.e., conserved protein function) in related species is less resource demanding than the original discovery. Finally, the development of treatments or prevention measures against human-infective species could have real impact on cattle diseases if they were studied or developed in parallel.

There is no doubt that veterinary important species continue to be understudied compared to their human-infective counterparts and that we cannot simply extrapolate data from one species to another. However, this is progressively being recognised as an important area of research and with the ability to draw on data and methodology from human-infective parasite species, the scientific community is well placed to start to close this gap.