Transient efficacy of buparvaquone against the US isolate of Theileria orientalis Ikeda genotype in sub-clinically infected cattle

Authors: Bastos, Reginaldo; HASSAN, AMANY - Washington State University; ONZERE, CYNTHIA - Washington State University; Herndon, David; VILLARINO, NICOLAS - Washington State University; LAUGHERY, JACOB - Washington State University; FRY, LINDSAY - Former ARS Employee

Submitted to: Frontiers in Veterinary Science
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/18/2024
Publication Date: 7/26/2024
Citation: Bastos, R.G., Hassan, A., Onzere, C.K., Herndon, D.R., Villarino, N.F., Laughery, J.M., Fry, L.M. 2024. Transient efficacy of buparvaquone against the US isolate of Theileria orientalis Ikeda genotype in sub-clinically infected cattle. Frontiers in Veterinary Science. https://doi.org/10.3389/fvets.2024.1421710.
DOI: https://doi.org/10.3389/fvets.2024.1421710

Interpretive Summary: Theileria orientalis Ikeda, transmitted by the Asian longhorned ticks Haemaphysalis longicornis, is a significant tick-borne parasite with global implications for cattle health and productivity. While infection often leads to severe outcomes such as anemia, abortions, and mortality, a notable proportion of cases present as asymptomatic subclinical infections. However, effective drugs targeting T. orientalis in subclinical cases are currently lacking. In addressing this critical gap, we investigated the potential of buparvaquone, originally developed as an anti-malarial agent, to clear the T. orientalis Ikeda US isolate in subclinical infections of cattle. Our findings revealed that buparvaquone swiftly reduced parasite levels to undetectable levels in the peripheral blood post-treatment. Nonetheless, the drug failed to eradicate the parasite completely in subclinical cases, with all treated animals experiencing parasite relapse. These results underscore the urgent need for novel therapeutic interventions to combat and eliminate this parasite. Integration of such therapeutics with vaccines and diagnostic tools is imperative for devising effective strategies to control T. orientalis Ikeda infections.

Technical Abstract: Theileria orientalis, an economically significant tick-borne hemoparasite, widely infects cattle globally. The T. orientalis Ikeda genotype, transmitted by Haemaphysalis longicornis ticks, is associated with clinical manifestations typified by anemia, abortions, and mortality, although subclinical infections prevail. Despite the common occurrence of subclinical infections, therapeutic interventions targeting T. orientalis Ikeda in such cases are currently lacking, impeding effective parasite control measures. To address this critical knowledge gap, we assessed the efficacy of buparvaquone (BPQ) in eliminating the T. orientalis Ikeda, US isolate, in subclinically infected cattle. Twelve subclinically infected calves, identified by the presence of T. orientalis in peripheral blood alongside the absence of fever and anemia, were enrolled in the study. Six calves received two treatments of the BPQ label dose (2.5 mg/kg) at a 48-hour interval, while an additional three calves received the drug at a dosage of 6 mg/kg following the same regimen. Three untreated calves served as controls. Endpoint and quantitative PCR analyses revealed that BPQ exerted a transient effect on T. orientalis parasitemia. Parasites remained undetectable in peripheral blood until weeks 4 and 11 post-treatment in animals administered 2.5 mg/kg and 6 mg/kg of BPQ, respectively. Intriguingly, following recrudescence, administering 6 mg/kg to animals previously treated with 2.5 mg/kg did not result in a reduction in parasite load. Pharmacokinetic analysis data suggested that escalating the dosage led to a less than proportional increase in serum concentrations of BPQ. Moreover, a significant yet reversible decrease (P<0.05) in blood urea nitrogen was observed in animals treated with the drug, irrespective of the dosage. Despite parasitemia relapse, animals treated with 6 mg/kg BPQ exhibited a noteworthy decrease (P<0.05) in IgG levels specific to the T. orientalis major piroplasm surface protein compared to controls and animals treated with 2.5 mg/kg of the drug. In conclusion, BPQ did not demonstrate efficacy in clearing subclinical T. orientalis Ikeda infection. Future investigations are warranted to explore innovative therapeutic modalities that, in synergy with vaccines and diagnostic assays, can facilitate the development of comprehensive programs aimed at controlling and eradicating this parasite.