Why is Babesia not killed by artemisinin like Plasmodium?

Abstract

AbstractBabesia spp. are intraerythrocytic apicomplexan organisms digesting hemoglobin similar to intraerythrocytic Plasmodium spp. However, unlike Plasmodium spp., Babesia spp. are not sensitive to artemisinin, The difference between Babesia genomes and Plasmodium genomes revealed that smaller Babesia genomes lack numerous genes, especially haem synthesis-related genes. Single-cell sequencing analysis showed that different groups of B. microti with expressed pentose phosphate pathway (PPP)-related, DNA replication-related, antioxidation-related, glycolysis-related, and glutathione-related genes were not as sensitive to artemether as P. yoelii 17XNL. Especially, PPP-related, DNA replication-related, and glutathione-related genes were inactively expressed compared with P. yoelii 17XNL. Adding iron supply in vivo can promote the reproduction of B. microti. These results suggest that Babesia spp. lack a similar mechanism to that in malaria parasites, by which haem or iron in hemoglobin is utilized, but it likely leads to their insensitivity to artemisinin in turn.Author summaryBabesia and Plasmodium are similar in many ways, from morphology to life history. In particular, both ingest and break down hemoglobin. However, compared with Plasmodium, Babesia cannot form hemozoin with less pathogenicity and insensitivity to artemisinin. Recent studies suggest that artemisinin can kill malaria parasites through free-radical and iron-capture effects, indicating that iron and haem play a key role in the sensitivity of malaria parasites to artemisinin. The Babesia genome is smaller and does not contain haem synthesis-related genes, indicating low requirements and utilization of haem and iron (HI). Moreover, we found that the expression of PPP-related and DNA replication-related genes is not active, distinctly different from malaria parasites. However, adding iron supply in vivo can increase the infection rate of B. microti. Therefore, we hypothesized that Babesia lacks mechanisms for the efficient utilization of HI, resulting in low requirements for HI, and therefore insensitivity to artemisinin.