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.
