Editorial: Exploring new technologies, investigating new targets, and shedding new light on Babesia

Editorial on the Research Topic
Exploring new technologies, investigating new targets, and shedding new light on Babesia

Babesia is a tick-borne zoonotic pathogen, found worldwide, that causes significant economic losses in animal husbandry. In order to explore the mechanism involved in tick-Babesia-host interactions, as well as potential drug targets or vaccines, we opened the Research Topic “Babesia: Biology, Interactions, and Mechanisms of Pathogenesis in Ticks and Its Hosts.” Ultimately, eight articles were accepted for publication.

Wang et al. established a transient and stable genetic manipulation system for B. duncani and successfully isolated a single transfected clone. Their work thus provides a genetic modification method suitable for this species, which will greatly facilitate gene function research on this parasite. Meanwhile, Alzan et al. evaluated the impact of an in vitro culture system for B. bovis and found that long-term in vitro culture (> 12 years) led to the loss of the sexual stage–specific 6cysA and 6cysB proteins, resulting in the failure of these parasites to develop sexual forms. Moreover, the adapted Babesia in the culture system was smaller in size, less virulent, and unable to be transmitted to cattle via ticks. These two articles illustrate that there are two sides to every coin: In vitro culture systems can be beneficial for gene functional analysis or drug selection. However, the use of long-term cultured parasites (LTCP) as surrogates of the parental strain to define virulence or vaccine candidates can be disadvantageous, as their genetic composition and phenotype differ from the parental strain. This needs to be properly taken into consideration in upcoming research.

Recently, the essential metabolic pathways that supply adenosine triphosphate (ATP) to Babesia via anaerobic glycolysis have begun to attract researchers’ attention as possible drug targets. Lactate dehydrogenase (LDH) is a critical glycolytic enzyme in the anaerobic glycolysis pathway, and has already been suggested as a potential drug target in Plasmodium, Toxoplasma, Cryptosporidium, and piroplasma (Yu et al.). In this Research Topic, the structure of LDH in B. orientalis (BoLDH) was solved at a resolution of 2.67-Å, and a comparison to LDH in B. microti (BmLDH) was performed (Yu et al.). The results showed that the overall structure of BoLDH and BmLDH is highly conserved, but the catalytic pocket of BoLDH is larger than that of BmLDH. The binding of the active pocket of BoLDH with gossypol was predicted by Discovery Studio software. Further experiments indicated a significant inhibitory effect of gossypol on the in vitro growth of B. bigemina, suggesting that gossypol may be a potentially effective drug (He et al.).

Merozoite proteins have been described as playing important roles in B. microti, yet detailed information on them is still lacking. In the present topic, a thioredoxin (Trx)-like protein was isolated and shown to significantly protect mice from B. microti infection (Piao et al.), indicating this protein may be a possible target for Babesia control.

To investigate the immune dynamics during Babesia co-infection, Zafar et al. infected mice with two species, B. microti and B. rodhaini. Their results demonstrated a down-regulation of the splenic immune response in acute Babesia co-infection, including a significant reduction in splenic B and T cells, and antibody levels, along with a decline in humoral immunity. Infection with B. microti affected B. rodhaini parasitemia and increased the survival of the co-infected mice. Insights such as these could be useful for developing anti-Babesia vaccines in the future.

We also obtained two in-depth reviews on this topic. Paoletta et al. discusses the thrombospondin-related anonymous protein (TRAP) superfamily, which contains either one or two types of adhesive domains (thrombospondin type 1 repeat and von Willebrand factor type A) and is secreted from apical organelles with a micronemal localization. TRAPs have been well studied in Plasmodium, and have been proven to be associated with the motility, invasion, and egress of the parasite. With regard to Babesia, TRAP-2 from B. gibsoni has been shown to bind to erythrocytes. These adhesins from the TRAP- and TRP- families are thus considered attractive targets for developing specific drugs or vaccines.

Allred, meanwhile, has shed new light on Babesia’s survival mechanisms. He describes several methods that Babesia has evolved to overcome the oxidative environment in the red blood cell. In detail, the ves large multigene families in Babesia spp. that mediate cytoadhesion have massive sequence variability. Cytoadhesion is thought to prevent infected erythrocytes from passing through the spleen, thus avoiding splenic clearance. Many—perhaps most—VESA1 variants are non-functional in cytoadhesion. However, the extreme environment has stimulated a process of segmental gene conversion that has generated rapid antigenic variation and the selection of VESA1 isoforms capable of binding to one or more endothelial receptors (i.e., cytoadhesion), and thus increased in vivo survival of cytoadhesive parasites and immunologic elimination of non-cytoadhesive parasites in the spleen. With repeated rounds of positive selection and amplification, this mechanism could enhance Babesia’s chances of survival.

In summary, this Research Topic has presented us with a new genetic manipulation technique, new information on potential vaccine or drug targets, and a unique insight into Babesia’s survival mechanism, all of which merit further exploration for the benefit of human and animal health.

Author contributions

HG organized and wrote the editorial. LH and HA revised it. All authors contributed to the article and approved the submitted version.

Funding

This work was supported by Shanghai Agriculture applied Technology Development Program China (2020-02-08-00-03-F01485) and the National Key Research and Development Program of China (2017YFC1200202).

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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