Abstract
Cholinesterase (ChE) function in schistosomes is essential for orchestration of parasite neurotransmission but has been poorly defined with respect to the molecules responsible. Interrogation of the S. mansoni genome has revealed the presence of three ChE domain-containing genes (Smche)s, which we have shown to encode two functional acetylcholinesterases (AChE)s (Smache1 –smp_154600 and Smache2 –smp_136690) and a butyrylcholinesterase (BChE) (Smbche1 –smp_125350). Antibodies to recombinant forms of each SmChE localized the proteins to the tegument of adults and schistosomula and developmental expression profiling differed among the three molecules, suggestive of functions extending beyond traditional cholinergic signaling. For the first time in schistosomes, we identified ChE enzymatic activity in fluke excretory/secretory (ES) products and, using proteomic approaches, attributed this activity to the presence of SmAChE1 and SmBChE1. Parasite survival in vitro and in vivo was significantly impaired by silencing of each smche, either individually or in combination, attesting to the essential roles of these molecules. Lastly, in the first characterization study of a BChE from helminths, evidence is provided that SmBChE1 may act as a bio-scavenger of AChE inhibitors as the addition of recombinant SmBChE1 to parasite cultures mitigated the effect of the anti-schistosome AChE inhibitor 2,2- dichlorovinyl dimethyl phosphate—dichlorvos (DDVP), whereas smbche1-silenced parasites displayed increased sensitivity to DDVP.
Highlights
The functioning of the nervous system is a tightly regulated process controlled through multiple catalytic and non-catalytic signaling proteins
Cholinesterases—aceytlcholinesterases (AChE)s and butyrylcholinesterases (BChE)s—are multi-functional enzymes that play a pivotal role in the nervous system of parasites by regulating neurotransmission through acetylcholine hydrolysis
Three putative ChE paralogs were identified from interrogation of the S. mansoni genome: smache1 (Smp_154600), smbche1 (Smp_125350) and smache2 (Smp_136690)
Summary
The functioning of the nervous system is a tightly regulated process controlled through multiple catalytic and non-catalytic signaling proteins. Cholinesterases (ChEs) play a pivotal role in regulating the signaling activity of the nervous system. AChE selectively hydrolyzes the neurotransmitter acetylcholine (ACh) to maintain neurotransmitter homeostasis [2] while the main role of BChE is widely accepted to be the detoxification of organophosphorus esters which are inhibitors of AChE [3]. The Schistosoma nervous system is important in this respect as this parasite lacks a body cavity and circulating body fluid [11, 12] and, as a result, its signaling functions are achieved via neurotransmission. The physiological concentration of ACh, must be maintained otherwise it triggers paralysis and this is achieved primarily through the action of AChE [6,7,8]
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