Theileria spp. are hemoparasites belonging to the Phylum Apicomplexa [11,12]. The species of this intracellular protozoa that infects bovines include T. annulata, T. parva, T. mutans, T. orientalis complex, T. tarurotragi, T. velifera, T. sinensis, and Theileria spp. Yokoyama [13,14]. Theileria spp. are transmitted by ixodid ticks of the genera Amblyomma, Haemaphysalis, Hyalomma, and Rhipicephalus, and the species is determined by their geographical location [14,15]. Although there are many Theileria species, only a few, particularly Theileria parva and Theileria annulata, are associated with severe clinical disease in cattle. Theileria parva occurs in eastern and southern Africa and is transmitted by Rhipicephalus appendiculatus ticks. Theileria annulata is widespread across the Mediterranean basin, northeast Africa, the Middle East, India, and Southern Asia, and is transmitted by several species of Hyalomma ticks [12].

In Table 1, we can see that the prevalence of Theileria annulata, responsible for Tropical Theileriosis, varies from less than 10% (Greece, Turkey, Pakistan, Ethiopia, and South Sudan) to values greater than or equal to 50% (Bangladesh, Sudan, Egypt, and Tunisia). The existence of high prevalence values and wide distribution may be associated with the use of the Holstein cattle breed for its excellence in milk production, increased animal movement, and climate change [16].

Tick-borne diseases are the cause of serious economic losses to livestock farming. There are recent studies that indicate an increase in the spread of ticks and tick-borne diseases, due to climate and environmental changes, which affect domestic ruminants and humans, leading to annual losses of USD 13.9 to 18.7 billion [34]. One of the critical tick-borne diseases of domestic cattle is theileriosis, which is caused by several Theileria species in tropical and subtropical countries. Some of these species causes disease outbreaks, high rates of mortality and morbidity, decreased production, and, consequently, serious economic losses [13,15,35,36]. According to Perera et al. (2014), dairy cows suffering from severe oriental theileriosis (resulting from infection by Theileria orientalis) produce 624 L less per capita at 305 days of lactation, leading to an estimated annual economic loss of AUD 202 (Australian dollars) (the equivalent of USD 179). In addition to the losses associated with production, there are also losses from mortality. In 2003 in the state of Victoria, Australia, the mortality rate from eastern theileriosis was 11%. The annual per capita cost (approximately AUD 227) associated with eastern theileriosis is significant and appears to be comparable to that of T. parva infection in Tanzania. Notably, the Tanzanian study included not only the costs associated with reduced milk production but also the costs of weight loss, acaricide treatments, and immunization [37]. It is estimated that worldwide there are around 250 million cattle at risk of tropical theileriosis (resulting from infection by Theileria annulata) [38]. In a study carried out in Pakistan, losses of 13.83% of farm income were estimated to be due to tropical theileriosis [23]. Considering the economic impact of theileriosis on livestock production, investment in research into sustainable control strategies for the disease is imperative to reduce losses in livestock production and ensure food and nutritional security worldwide.

In susceptible animals, pathogenic Theileria species cause acute lymphoproliferative diseases, with high levels of morbidity and mortality. This parasite infects nucleated cells such as monocytes, macrophages, T cells (CD4+ e CD8+), and B cells (B1 and B2), but also erythrocytes. The type of nucleated blood cells targeted by the parasite differ according to the species of Theileria. Nonetheless, pathogenicity is attributable to the life cycle stage in nucleated cells [12,39,40,41]. The aim of the parasite is to ensure its survival and increase its population, while increasing the probability of its transmission [40].

The life cycle of Theileria spp. occurs among its invertebrate and vertebrate hosts. In vertebrate hosts, Theileria spp. infects ruminants and equids; in invertebrate hosts Theileria spp. infects ticks [40]. Initially, the host infection occurs with the invasion of sporozoites, transmitted through saliva secretion when an infected tick takes a meal. The sporozoite invasion occurs rapidly after entry, and the sporozoite nuclei divide to form a schizont. The schizont presents 30 nuclei in approximately 20 h as it approaches the nucleus of the host cell [40,42]. When leukocyte division occurs, the schizont is also divided because it is tightly bound to mitotic spindles [40,43]. Host cell transformation and proliferation is induced by the parasite. Depending on the Theileria species there may be multiple divisions in the lymphocyte stage and few or no divisions at the erythrocyte stage (e.g., Theileria parva), but in other species, there is little or no intralymphocytic multiplication, and Theileria multiplies essentially in the erythrocyte stage (e.g., Theileria mutans) [42].

A proportion of schizonts differentiates into merozoites that invade erythrocytes. When the multiplication is in the lymphocyte stage, at the end of multiplication, the schizont initiates transition into the next development stage, i.e., merozoites, which then infect erythrocytes. Merozoites are also known as piroplasms due to the fever they provoke [40]. Infected erythrocytes infect ticks when they take a meal, and gametogenesis and fertilization take place in the gut lumen of ticks. Thus, merozoites develop into male and female gametes that fuse, and sexual reproduction occurs, producing a zygote. The zygote or ookinete invades a gut epithelial cell where it remains during the tick molt cycle and develops into a single motile kinete that migrates to tick salivary glands [40,42]. In specific acini cells of the salivary gland, the parasite undergoes multiple divisions and generates thousands of sporozoites. The life cycle is completed only when mature sporozoites are transmitted from a tick to a new ruminant host in the later stages of feeding [40,41]. Transmission in the tick is transstadial whereby larvae or nymphs can become infected [42].

The first clinical sign of theileriosis in cattle typically appears 7 to 15 days after attachment of the infected tick [45]. The most common sign is an increase in body temperature, which can reach 41.1 °C. In addition, the animal may have anorexia, pale mucous membranes (hemolytic anemia), jaundice, hemoglobinuria, swollen lymph lumps, loss of body condition, presence of petechiae on the conjunctiva, and the presence of ticks on the animal’s body [45,46,47]. Other clinical signs include lethargy, depression, corneal opacity, tachycardia, tachypnea, dyspnea, nasal discharge, diarrhea, reduced production, stillbirths, and miscarriages. In the final phase of clinical evolution, in serious cases, before death, the animal is typically in lateral recumbency, with hypothermia and severe dyspnea due to pulmonary edema [45,47]. The presence of these clinical signs, as well as their intensity, may differ according to the species and genotype of Theileria spp. that infected the animal [45,46,47].

The diagnosis of theileriosis may be based on the use of traditional or molecular diagnostic methods. Traditional diagnostic methods include the identification of the aforementioned clinical signs present in infected animals, detection of findings in postmortem evaluations, and microscopic and serological evaluation. In the postmortem evaluation, pathological changes such as jaundice, pallor and enlargement of the liver, kidney, and spleen, hemorrhagic duodenitis, ulcers in the abomasal mucosa, pulmonary edema, and enteritis may be detected [47]. The microscopic evaluation includes identification of the parasite in red blood cells in blood smears stained with Giemsa. This method can be also used to estimate the degree of parasitemia, but it is only possible when the number of infected erythrocytes is high. Finally, the Immunofluorescence Antibody Test (IFAT: Sensitivity (Se)—71%; Specificity (Sp)—93% [48]), enzyme immunoassay (ELISA: Se—93.5%; Sp—93.5% [49]), and latex agglutination test can be performed [13,47]. These are serological methods which have a higher sensitivity compared to traditional methods. The specificity is relatively good, but generally lower than that of molecular methods. Molecular methods can overcome this limitation, in particular polymerase chain reaction (PCR: Se—83%; Sp—93% [48]), reverse line transfer hybridization assay (RLB), loop-mediated isothermal amplification (LAMP), real-time/quantitative PCR (qPCR: Se—97.1%; Sp—97.4% [50]) using hydrolysis probes, and multiplexed tandem PCR (MT-PCR: Se—98%; Sp—98.9% [50]) assays. Thus, molecular methods have greater specificity and sensitivity than traditional and serological methods, allowing the detection, characterization, differentiation, and quantification of different species of Theileria spp. [47].

Theileriosis control strategies includes measures the pathogen (acaricides), cattle (e.g., vaccination, culling diseased animals and selection of resistant animals), or environmental control (e.g., biosecurity, sanitation, etc.) [51]. At present, there are no effective vaccines or drugs to control bovine theileriosis. The use of acaricides to eliminate the vector and reduction of cattle movement from nonendemic to endemic areas are the main methods of disease control [52]. As a preventive measure, cattle are routinely treated with synthetic pyrethroids prior to being put out to graze in pastures [53]. However, the widespread use of acaricides has resulted in an increased tick resistance to these chemical compounds. Acaricide resistance results from the selection of specific hereditary traits in a tick population due to exposure of the population to an acaricide, which results in an increase in the number of ticks that will survive after administration of the recommended dose of the acaricide in question. The main mechanisms that prevent the action of chemicals in ticks and that are responsible for this resistance are increased metabolic detoxification and point mutations at target sites. This resistance has a strong negative impact on tick and tick-borne disease control in cattle [54]. Cumulatively, the continued use of acaricides becomes economically unsustainable [51,55].

Buparvaquone, a known antiprotozoal, is used in the treatment of theileriosis, although it is not approved for the treatment of livestock in many countries, including European countries since it is not approved by the EMA (European Medicines Agency) [52,53,56,57,58,59]. Other substances are commonly used to treat theileriosis, such as oxytetracycline, imidocarb, halofunginone, or erythromycin, but to little effect [52,53,56]. According to the variation in clinical manifestations, additional drugs are used [57,58]. For example, in animals with a high temperature, Meloxicam or Paracetamol are indicated. In animals with lameness and difficulty in getting up, sodium acid phosphate is useful [57]. A symptomatic treatment option for extremely anemic animals is blood transfusion. In these animals, a solution with hydroxy ethyl starch in isotonic sodium chloride intravenous infusion is administered [52,57].

In recent times, there has been investment in the development of vaccines, although their realized ability to protect against certain Theileria species, when animals are naturally infected, is not yet fully known [52]. Some of these vaccines are produced via the culture of cells infected with the attenuated T. annulata schizont [55,56,58]. On the other hand, development of subunit vaccines is generally regarded as problematic for apicomplexan parasites due their genetic diversity. While there are promising initial results, further investment in research and the development of effective and affordable vaccines will be needed [52,53].

Currently, alternative strategies to control Theileriosis are being sought, such as the selection of animals with greater resistance to Theileria sp. infection and disease development. Disease resistance results from genetic variation found in comparing animals of different breeds [9]. Several studies have reported greater resistance in cattle of indigenous breeds compared to exotic breeds. The analyzed characteristics that prove the different resistance between breeds are associated with the severity of the clinical signs manifested by the animals, the exuberance of the immune response to the infection, and the differential expression of genes identified as candidate genes differentially expressed between breeds [10].