Novel cholinesterase paralogs of Schistosoma mansoni have perceived roles in cholinergic signaling and drug detoxification and are essential for parasite survival


Autoři: Bemnet A. Tedla aff001;  Javier Sotillo aff001;  Darren Pickering aff001;  Ramon M. Eichenberger aff001;  Stephanie Ryan aff001;  Luke Becker aff001;  Alex Loukas aff001;  Mark S. Pearson aff001
Působiště autorů: Centre for Molecular Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, Cairns, Queensland, Australia aff001;  Centro Nacional de Microbiología, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain aff002;  Institute of Parasitology, University of Zurich, Zurich, Switzerland aff003
Vyšlo v časopise: Novel cholinesterase paralogs of Schistosoma mansoni have perceived roles in cholinergic signaling and drug detoxification and are essential for parasite survival. PLoS Pathog 15(12): e32767. doi:10.1371/journal.ppat.1008213
Kategorie: Research Article
doi: 10.1371/journal.ppat.1008213

Souhrn

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.

Klíčová slova:

Glucose – Cholinergics – Parasitic diseases – Sequence alignment – Schistosoma – Schistosoma mansoni – Small interfering RNAs – Schistosoma haematobium


Zdroje

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