Although Babesia represents an important worldwide veterinary threat and an emerging risk to humans, this parasite has been poorly studied as compared to Plasmodium, its malaria-causing relative. In fact, Babesia employs highly specific survival strategies during its intraerythrocytic development and its intricate journey through the tick vector. This review introduces a substantially extended molecular phylogeny of the order Piroplasmida, challenging previous taxonomic classifications. The intriguing developmental proficiencies of Babesia are highlighted and compared with those of other haemoparasitic Apicomplexa. Molecular mechanisms associated with distinctive events in the Babesia life cycle are emphasized as potential targets for the development of Babesia-specific treatments.
- MeSH
- Babesia klasifikace genetika růst a vývoj MeSH
- babezióza parazitologie MeSH
- fylogeneze * MeSH
- lidé MeSH
- Piroplasmida klasifikace genetika růst a vývoj MeSH
- protozoální geny genetika MeSH
- stadia vývoje genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Babesiosis is a tick-transmitted zoonosis caused by apicomplexan parasites of the genus Babesia. Treatment of this emerging malaria-related disease has relied on antimalarial drugs and antibiotics. The proteasome of Plasmodium, the causative agent of malaria, has recently been validated as a target for anti-malarial drug development and therefore, in this study, we investigated the effect of epoxyketone (carfilzomib, ONX-0914 and epoxomicin) and boronic acid (bortezomib and ixazomib) proteasome inhibitors on the growth and survival of Babesia. Testing the compounds against Babesia divergens ex vivo revealed suppressive effects on parasite growth with activity that was higher than the cytotoxic effects on a non-transformed mouse macrophage cell line. Furthermore, we showed that the most-effective compound, carfilzomib, significantly reduces parasite multiplication in a Babesia microti infected mouse model without noticeable adverse effects. In addition, treatment with carfilzomib lead to an ex vivo and in vivo decrease in proteasome activity and accumulation of polyubiquitinated proteins compared to untreated control. Overall, our results demonstrate that the Babesia proteasome is a valid target for drug development and warrants the design of potent and selective B. divergens proteasome inhibitors for the treatment of babesiosis.
- MeSH
- Babesia microti účinky léků genetika růst a vývoj MeSH
- Babesia účinky léků genetika růst a vývoj MeSH
- babezióza farmakoterapie MeSH
- buněčné linie MeSH
- inhibitory proteasomu aplikace a dávkování škodlivé účinky farmakologie terapeutické užití MeSH
- kyseliny boronové farmakologie MeSH
- makrofágy účinky léků parazitologie MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- oligopeptidy farmakologie MeSH
- proteasomový endopeptidasový komplex účinky léků MeSH
- proteom účinky léků genetika MeSH
- systémy cílené aplikace léků * MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- validační studie MeSH
BACKGROUND: Babesia divergens is the most common blood parasite in Europe causing babesiosis, a tick-borne malaria-like disease. Despite an increasing focus on B. divergens, especially regarding veterinary and human medicine, the sexual development of Babesia is poorly understood. Development of Babesia sexual stages in the host blood (gametocytes) plays a decisive role in parasite acquisition by the tick vector. However, the exact mechanism of gametocytogenesis is still unexplained. METHODS: Babesia divergens gametocytes are characterized by expression of bdccp1, bdccp2 and bdccp3 genes. Using previously described sequences of bdccp1, bdccp2 and bdccp3, we have established a quantitative real-time PCR (qRT-PCR) assay for detection and assessment of the efficiency of B. divergens gametocytes production in bovine blood. We analysed fluctuations in expression of bdccp genes during cultivation in vitro, as well as in cultures treated with different drugs and stimuli. RESULTS: We demonstrated that all B. divergens clonal lines tested, originally derived from naturally infected cows, exhibited sexual stages. Furthermore, sexual commitment was stimulated during continuous growth of the cultures, by addition of specific stress-inducing drugs or by alternating cultivation conditions. Expression of bdccp genes was greatly reduced or even lost after long-term cultivation, suggesting possible problems in the artificial infections of ticks in feeding assays in vitro. CONCLUSIONS: Our research provides insight into sexual development of B. divergens and may facilitate the development of transmission models in vitro, enabling a more detailed understanding of Babesia-tick interactions.
- MeSH
- arachnida jako vektory parazitologie MeSH
- Babesia genetika růst a vývoj fyziologie MeSH
- babezióza parazitologie MeSH
- gametogeneze * MeSH
- klíšťata parazitologie MeSH
- nemoci skotu parazitologie MeSH
- protozoální proteiny genetika metabolismus MeSH
- skot MeSH
- zárodečné buňky cytologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- skot MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
