Lactate dehydrogenase as a potential therapeutic drug target to control Babesia bigemina

Authors: HE, LAN - Huazhong University Of Science And Technology; BASTOS, REGINALDO - Washington State University; YU, LONG - Huazhong University Of Science And Technology; LAUGHERY, JACOB - Washington State University; Suarez, Carlos

Submitted to: Frontiers in Cellular and Infection Microbiology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 3/15/2022
Publication Date: 4/19/2022
Citation: He, L., Bastos, R.G., Yu, L., Laughery, J.M., Suarez, C.E. 2022. Lactate dehydrogenase as a potential therapeutic drug target to control Babesia bigemina. Frontiers in Cellular and Infection Microbiology. 12. Article 870852. https://doi.org/10.3389/fcimb.2022.870852.
DOI: https://doi.org/10.3389/fcimb.2022.870852

Interpretive Summary: Babesiosis is an emerging tick-borne disease with global impact caused by parasites of the phylum apicomplexan, genus Babesia. Bovine babesiosis is an acute disease characterized by fever, anemia, hemoglobinuria and death due to severe lysis of erythrocytes, which can be caused by Babesia bigemina, and B. bovis. Gossypol is a natural compound that already proved to be effective against in vitro cultured B. bovis. In this study, we explored the potential of gossypol as a therapeutic drug against in vitro cultured B. bigemina and calculated the doses of the drug that effectively inhibit the growth of the parasite. Gossypol efficiently controls the growth of parasite in vitro; however, viability of the host cells might be compromised by the drug. Altogether, the results suggest that gossypol is an effective drug against B. bigemina, but its toxic effects for the bovine host should be further evaluated in in vivo trials.

Technical Abstract: Babesia bigemina is a tick-borne apicomplexan haemoprotozoan responsible for bovine babesiosis. Current drugs used for bovine babesiosis treatment have several drawbacks, including toxicity, lack of effectiveness to clear the parasite, and the potential to develop resistance. Identifying compounds that target essential and unique parasite metabolic pathways is a rational approach toward finding alternative drug treatments. Based on genome sequence and transcriptomics analysis, it can be inferred that anaerobic glycolysis is the dominant ATP Supply for Babesia, and Lactate dehydrogenase (LDH) is one of the essential enzymes in this pathway. Considering that the Babesia LDH sequence is distinct from its bovine homologue, it is reasonable to assume that therapeutic drugs could block specifically the activity of the parasite LDH. This would result in decreasing the ATP supply to the parasite, without affecting the host. Gossypol is a known efficient specific inhibitor of LDH in the sensu stricto Babesia bovis and the sensu lato Babesia microti, among other related parasites, but no report is available in the sensu strict Babesia bigemina parasites. Hereby we show that the LDH amino acid sequence is highly conserved among sensu stricto, but not in sensu lato Babesia spp. Results shown that gossypol has a significant (P < 0.0001) inhibitory effect on the in vitro growth of B. bigemina, with IC50 of 43.97 mM after 72 h of treatment. The maximum IC (IC98) was observed at 60 mM gossypol. Significant effect on the viability of cattle PBMC was observed when the cells were cultured with 60 mM gossypol compared with DMSO-exposed control cells, suggesting that the drug might be toxic for the bovine cells exposed to IC98 concentration. Altogether, the results suggest the potential of gossypol as an effective drug against B. bigemina infection, whether host toxicity occurs at therapeutic doses should be further addressed