Cysteine Proteinase C1A Paralog Profiles Correspond with Phylogenetic Lineages of Pathogenic Piroplasmids

Abstract

Piroplasmid parasites comprising of Babesia, Theileria, and Cytauxzoon are transmitted by ticks to farm and pet animals and have a significant impact on livestock industries and animal health in tropical and subtropical regions worldwide. In addition, diverse Babesia spp. infect humans as opportunistic hosts. Molecular phylogeny has demonstrated at least six piroplasmid lineages exemplified by B. microti, B. duncani, C. felis, T. equi, Theileria sensu stricto (T. annulata, T. parva, and T. orientalis) and Babesia sensu stricto (B. bovis, B. bigemina, and B. ovis). C1A cysteine-proteinases (C1A-Cp) are papain-like enzymes implicated in pathogenic and vital steps of the parasite life cycle such as nutrition and host cell egress. An expansion of C1A-Cp of T. annulata and T. parva with respect to B. bovis and B. ovis was previously described. In the present work, C1A-Cp paralogs were identified in available genomes of species pertaining to each piroplasmid lineage. Phylogenetic analysis revealed eight C1A-Cp groups. The profile of C1A-Cp paralogs across these groups corroborates and defines the existence of six piroplasmid lineages. C. felis, T. equi and Theileria s.s. each showed characteristic expansions into extensive families of C1A-Cp paralogs in two of the eight groups. Underlying gene duplications have occurred as independent unique evolutionary events that allow distinguishing these three piroplasmid lineages. We hypothesize that C1A-Cp paralog families may be associated with the advent of the schizont stage. Differences in the invertebrate tick host specificity and/or mode of transmission in piroplasmid lineages might also be associated with the observed C1A-Cp paralog profiles.

N-Glycosylation in Piroplasmids: Diversity within Simplicity

“…It can be observed that these three N -glycosylation enzyme sets can be assigned to the piroplasmid lineage of Babesia s.s. (Clade VI, set i), the closely related lineages of T. equi and C. felis (Clades IV and IIIa, respectively, set ii) and the distantly related B. microti and Theileria s.s. (Clades I and V, set iii) [ 8 , 9 ]. Similar to what was recently reported for piroplasmid C1A cysteine proteases and rhomboid proteinases, this observation corroborates the currently recognized phylogeny of piroplasmids [ 15 , 16 ]. On the other hand, the differences observed in the N -glycosylation pathway between B. microti and Babesia s.s., and between T. equi and Theileria s.s., underscore the need to revise the taxonomic placement of these two piroplasmids within the Babesia and the Theileria genera, respectively, as has been put forward before [ 8 , 9 , 17 ].…”

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

“…Although R. haemaphysaloides is not a typical B. microti-transmitting tick, it has been suggested as a potential vector for this parasite in China [50]. These results coincide with the inhibition exerted by R. microplus cystatins on a B. bovis C1A cysteine protease and suggest the involvement of these enzymes in tick host-pathogen interactions [51] Interestingly, the phylogenetic analysis of C1A cysteine protease paralog profiles of piroplasmids of the Babesia, Theileria and Cytauxzoon genera corroborates the assignment of analyzed species into Clades I-VI according to their 18S rRNA gene sequences [27,52].…”

Repurposing of the Malaria Box for Babesia microti in mice identifies novel active scaffolds against piroplasmosis

“…Okubo et al [ 37 ] proposed an essential role of CPs in the invasion of B. bovis to the host RBCs. Ascencio et al [ 39 ] reported that T. equi exhibited extreme expansion of C1A-CP paralogs, which might be functionally associated with the evolution of the schizont stage. However, the exact function of babesial CPs remains uncertain.…”