In Silico Survey and Characterization of Babesia microti Functional and Non-Functional Proteases

Abstract

Human babesiosis caused by the intraerythrocytic apicomplexan Babesia microti is an expanding tick-borne zoonotic disease that may cause severe symptoms and death in elderly or immunocompromised individuals. In light of an increasing resistance of B. microti to drugs, there is a lack of therapeutic alternatives. Species-specific proteases are essential for parasite survival and possible chemotherapeutic targets. However, the repertoire of proteases in B. microti remains poorly investigated. Herein, we employed several combined bioinformatics tools and strategies to organize and identify genes encoding for the full repertoire of proteases in the B. microti genome. We identified 64 active proteases and 25 nonactive protease homologs. These proteases can be classified into cysteine (n = 28), serine (n = 21), threonine (n = 14), asparagine (n = 7), and metallopeptidases (n = 19), which, in turn, are assigned to a total of 38 peptidase families. Comparative studies between the repertoire of B. bovis and B. microti proteases revealed differences among sensu stricto and sensu lato Babesia parasites that reflect their distinct evolutionary history. Overall, this data may help direct future research towards our understanding of the biology and pathogenicity of Babesia parasites and to explore proteases as targets for developing novel therapeutic interventions.

Comparative Degradome Analysis of the Bovine Piroplasmid Pathogens Babesia bovis and Theileria annulata

“…Supporting this notion, an ortholog of subtilisin is not encoded in the genome of B. microti , a representative of Babesia s.l. [ 56 ]. However, an ortholog was also found in a single parasite of Theileria s.s., T. orientalis (XP_009690597).…”

“…Notably, a proteinase annotated as signal peptide peptidase belonging to the aspartic proteinase family A22 has been identified in B. microti but found to be absent in both, B. bovis and T. annulata [ 56 ]. Proteinases of the family A22 have been reported to process intramembrane proteins and are present in the protozoans P. falciparum and T. gondii [ 57 ].…”

“…Previously, we identified 66 and 64 proteinases predicted as active in the proteomes of B. bovis and B. microti [ 55 , 56 ]. Comparison of both arrays of proteinases showed that a representative of family S8 is present in B. bovis , but not in B. microti , whereas a representative of family A22 is not present in B. bovis , but in B. microti [ 56 ]. These differences may be related to the different evolutionary history of Babesia s.s and Babesia sensu lato (s.l.).…”

The Digestive Vacuole of the Malaria Parasite: A Specialized Lysosome

“…It is presumed that extracellular digestion of host cytoplasm takes place through this organelle, and thus, feeding relies heavily on osmotrophy. In this regard, it is speculated that Babesia may secrete proteases into host erythrocyte cytoplasm [ 110 ]. Other than falcipain-2, Babesia does not have orthologs of the hemoglobin degrading proteases of Plasmodium [ 104 ].…”

Babesia and Human Babesiosis

“…The identification of chemotherapeutic targets in these parasites thus becomes an important research priority. Florin-Christensen et al [26] focus on species-specific proteases and have used bioinformatics to identify genes in the B. microti genome that code for these enzymes. They classify 89 proteases into five groups and report that comparisons between B. microti and B. bovis reveal differences between sensu lato and sensu stricto parasites, reflecting their distinct evolutionary histories, which is probably relevant to their susceptibilities to antibabesials [25].…”