## 4 USPs in Schistosomiasis  
Schistosomiasis is an ancient tropical disease that typically plagues the poorest and most destitute of developing countries, particularly in sub-Saharan Africa, imposing serious economic and social threats on the affected regions [61]. Outcomes of infection include severe cases of morbidity and mortality. In the absence of a vaccine, the discovery of target proteins has been on the agenda for alternative drug discovery to Praziquantel, which is the only chemotherapeutic drug of treatment against the causative agent but is slowly losing credibility because of various side effects and recent evidence of drug resistance. The genome sequence of _S. mansoni_, investigated using whole genome shotgun sequencing, revealed the presence of 11,809 putative genes encoding 13,197 transcripts [62]. This project opened an avenue for the discovery of drug development and vaccine targets, as many of these genes encoded for ligand and voltage-gated ion channels, proteases, lipid metabolism receptors, kinases and neuropeptides. Subsequent researchers realized that eight of these genes, still within the _S. mansoni_ strain, are _usp_ genes that encode USP domain-containing proteins [8; 35]. Six of the genes (Smp_001000, Smp_001010, Smp_031300, Smp_043120, Smp_076400 and Smp_097930) include ATP binding motif residues (thus indicating ATP regulation), a phosphorylation site and ligand-binding residues, while the other two (Smp_136870 and Smp_136890) do not. All the genes are present in at least one of the worm's life stages, while six of them are more pronounced in the miracidium, which is a crucial stage for transmission of the parasite into the snail intermediate host. It has been proposed that the up-regulation of USPs during the intra-snail stages is triggered by stressors to perform various functions such as protection against oxidative stress induced by hydrogen peroxide within snail hematocytes [35]. Reactive oxygen species are generated by phagocytic cells such as sporocysts and hematocytes in the intermediate host to eliminate pathogens. In the human host, killing of _S. mansoni_ schistosomulae coincides with the production of H\({}_{2}\)O\({}_{2}\) from neutrophils [63]. SAGE profiling showed transcription of Smp_136870 during the miracidium and sporocyst stages, which are both exposed to oxidative stress. This observation suggests that the USP observed may serve as a prime candidate in the defense of these intra-molluscan stages against oxidative stress, which is in turn crucial to the parasite's survival [35]. Apart from this, Smp_001010 and Smp_043120 displayed the highest transcription in both the intra-molluscan and intra-mammalian stages, highlighting the need for additional studies to be carried out on discovering the specific functions or mechanisms involved in their response to environmental stress. [PERSON] and co-workers went a step further and discovered, using bioinformatics-based predictions that there are in fact 13 _Schistosoma_ USP sequences, all possessing conserved sites for aspartate, leucine, glycine, histidine and proline at positions 57, 101, 127, 166 and 176 respectively, proposing that these could actually be common regulatory sites for _Schistosoma_ USPs [39]. Prioritizing two of the proteins, Q86 DW2 from _S. japonicum_ and G4 LZI3 from _S. mansoni_, three metal ion ligands, namely Ca\({}^{2+}\), Zn\({}^{2+}\) and Mg\({}^{2+}\), were predicted. It was proposed that Mg\({}^{2+}\) binds to the Mg-ATP binding groove either during phosphorylation or stress responses driven by ATP-dependent mechanisms, thus preventing interaction of the Mg\({}^{2+}\) ion with ATP at the groove, in turn compromising ATP binding and phosphorylation. In the absence of Mg\({}^{2+}\), Ca\({}^{2+}\) simulates ATPase activity, which is crucial, as Ca\({}^{2+}\) holds important functions in motor and musculature-related activities, egg hatching processes, regulating miracidia to sporocyst transformation and modulating musculature activity, especially during exposure to PZQ.