Treatment of Human Babesiosis: Then and Now

Abstract

Babesiosis is an emerging tick-borne disease caused by apicomplexan parasites of the genus Babesia. With its increasing incidence worldwide and the risk of human-to-human transmission through blood transfusion, babesiosis is becoming a rising public health concern. The current arsenal for the treatment of human babesiosis is limited and consists of combinations of atovaquone and azithromycin or clindamycin and quinine. These combination therapies were not designed based on biological criteria unique to Babesia parasites, but were rather repurposed based on their well-established efficacy against other apicomplexan parasites. However, these compounds are associated with mild or severe adverse events and a rapid emergence of drug resistance, thus highlighting the need for new therapeutic strategies that are specifically tailored to Babesia parasites. Herein, we review ongoing babesiosis therapeutic and management strategies and their limitations, and further review current efforts to develop new, effective, and safer therapies for the treatment of this disease.

Keywords: Babesia duncani; Babesia microti; atovaquone; babesiosis; endochin-like quinolones (ELQs); parasite; therapy.

Figure 1

Cycle of transmission of the most common Babesia species, B. microti. During a blood meal, an infected tick introduces merozoites into the host (mouse or deer, for example). Free merozoites enter red blood cells and undergo asexual replication. While in the blood, some parasites differentiate into male and female gametocytes (not morphologically recognizable by light microscopy). These gametocytes are then taken up by a tick during a blood meal and differentiate into gametes. While in the gut, gametes fuse to form a zygote, that will subsequently undergo meiotic and several mitotic divisions to form sporozoites that are then transmitted to a mammalian host. Humans are typically accidental hosts and become infected through the bite of an infected tick. Human to human transmission is also possible via blood transfusion.

Figure 2

Schematic representation of a Babesia-infected red blood cell and sites of action of some approved and experimental drugs. Azithromycin and clindamycin target the apicoplast; atovaquone and ELQs target the mitochondrion. A: apicoplast, C: conoid + polar rings, DG: dense granule, ER: endoplasmic reticulum, G: Golgi apparatus, M: mitochondrion, MN: microneme, PPM: parasite plasma membrane and R: rhoptry.

Figure 3

Proposed mechanism of action of atovaquone and endochin-like quinolones in Babesia mitochondrion. (a) Schematic representation the mitochondrial electron transfer chain. (b) Schematic representation of the parasite bc₁ complex with proposed mode of action of atovaquone and ELQs.