Transcriptional and genomic analyses reveal an analogous mechanism for a Piperidinyl-Benzimidazolone analog in Babesia divergens compared to other apicomplexans

Abstract

Human babesiosis is a rapidly emerging, zoonotic, infectious disease causing potentially lifethreatening malaria-like symptoms in humans. Disease prevalence has escalated over the past 50 years from a few isolated cases to endemic areas now being recognized. Early disease detection, diagnosis and treatment with effective anti-babesiacidal compounds are vital for both human and animal health. In humans, Babesia parasites can be cleared by anti-malarials including atovaquone (with azithromycin) or quinine (plus clindamycin) but highly immunecompromised individuals respond poorly to these treatments. In the past few years, reports of resistance against these combinations have emerged, stressing the need for alternative treatments. Ideally one would prefer one drug compound to be effective against numerous pathogens based on a single, commonly shared target feature within the cells. In the postgenomic era, bioinformatics along with several computational strategies have become invaluable for drug discovery to aid in drug target identification followed by in vitro and in vivo validation. The precise progression and duration of the intra-erythrocytic, asexual developmental cycle (IDC) of Babesia has not been clarified to date and current understanding is fraught with uncertainties. This study focuses on the application of sensitive cell- biological -and molecular functional genomics tools to describe the IDC of B. divergens parasites from immature, mononucleated ring forms to bi-nucleated paired piriforms and ultimately multi-nucleated tetrads which was further correlated for the first time to nuclear content increases during intraerythrocytic development progression. This provides insight into the life cycle that occurs during human infection. This study provides the first temporal evaluation of the functional transcriptome of B. divergens parasites. This study contributes to anti-babesiacidal control strategies by evaluating a promising anti- Plasmodium, apicoplast specific piperidinyl-benzimidazolone analogue (A51B1C1_1) as potential therapeutic with low toxicity, against one of the causative agents of human babesiosis, B. divergens. This study set out to describe the global transcriptome of B. divergens parasites (under treated conditions) through its IDC as an indicator of the physiological processes involved. By unravelling the Babesia transcriptome, key gene expression transcripts were defined and conserved gene expression networks between P. falciparum and B. divergens parasites treated with the same compound (A51B1C1_1) identified. This study ultimately contributed to the identification of an apicomplexan parasitic response to treatment. Additionally, it established the investigated compounds’ mode-of-action.