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Global analysis of neuropeptides in cestodes identifies Attachin, a SIFamide homolog, as a stimulant of parasite motility and attachment

ABSTRACT: Many anthelmintics target the neuromuscular system, in particular by interfering with signalling mediated by classical neurotransmitters. Although peptidergic signalling has been proposed as a target of novel anthelmintics, current knowledge of the neuropeptide complement of many helminths is still limited, especially for parasitic flatworms (cestodes, trematodes and monogeneans). In this work, we have characterised the neuropeptide complement of the model cestode Hymenolepis microstoma. Peptidomic characterization of adults of H. microstoma validated many of the neuropeptide precursor (npp) genes previously predicted in silico, and identified novel neuropeptides that are conserved in parasitic flatworms. Most neuropeptides from parasitic flatworms lack significant similarity to those from other animals, confirming the uniqueness of their peptidergic signalling. Analysis of gene expression of ten npp genes by in situ hybridization confirmed that all of them are expressed in the nervous system and identified cryptic features, including the first evidence of dorsoventral asymmetry, as well as a new population of peripheral neurosecretory cells that appears to be conserved in the trematode Schistosoma mansoni. Finally, we characterised in greater detail Attachin, an experimentally validated SIFamide homolog. Although its expression is largely restricted to the longitudinal nerve cords and cerebral commissure in H. microstoma, it shows widespread expression in the larval nervous system of Echinococcus multilocularis and Mesocestoides corti. Exogenous addition of a peptide corresponding to the highly conserved C-terminus of Attachin stimulated motility and attachment of M. corti larvae. Altogether, this work provides a robust experimental foothold for the characterization of peptidergic signalling in parasitic flatworms.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Hymenolepis Microstoma

TISSUE(S): Scolex, Whole Body

SUBMITTER: Sven Van Bael

LAB HEAD: Uriel Koziol

PROVIDER: PXD033611 | Pride | 2022-06-13

REPOSITORIES: Pride

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Project description:Infections and diseases caused by parasitic nematodes have a major adverse impact on the health and productivity of animals and humans worldwide. The control of these parasites often relies heavily on the treatment with commercially available chemical compounds (anthelmintics). However, the excessive or uncontrolled use of these compounds in livestock animals has led to major challenges linked to drug resistance in nematodes. Therefore, there is a need to develop new anthelmintics with novel mechanism(s) of action. Recently, we identified a small molecule, KM08948, with nematocidal activity against the free-living model organism Caenorhabditis elegans. Here, we evaluated KM08948’s potential as an anthelmintic in a structure-activity relationship (SAR) study in C. elegans and in the highly pathogenic, blood-feeding Haemonchus contortus (barber’s pole worm), and explored the compound-target relationship using thermal proteome profiling (TPP). First, we synthesised and tested a series of 25 KM08948 analogues for nematocidal activity in both H. contortus (larvae and adults) and C. elegans (young adults), establishing a preliminary nematocidal pharmacophore for both species. We identified several compounds with marked activity against either H. contortus or C. elegans which had greater efficacy than KM08948, and found a significant divergence in compound bioactivity between these two nematode species. We also identified a KM08948 analogue, 25, that moderately inhibited the motility of adult female H. contortus in vitro. Subsequently, we inferred three H. contortus proteins (HCON_00134350, HCON_00021470 and HCON_00099760) and five C. elegans proteins (F30A10.9, F15B9.8, B0361.6, DNC-4 and UNC-11) that interacted directly with KM08948; however, no conserved protein target was shared between the two nematode species. Future work aims to extend the SAR investigation in these and other parasitic nematode species, and validate individual proteins identified here as targets of KM08948. Overall, the present study describes an evaluation of this anthelmintic candidate and highlights some challenges associated with early anthelmintic discovery.

			Action	DRS
	Hm1.mgf	Mgf
	Hm2.mgf	Mgf
	Hm_Pool_1.raw	Raw
	Hm_Pool_1_-_peptides_1_1_0.mzid.gz	Mzid
	Hm_Pool_2.raw	Raw

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Global analysis of neuropeptides in cestodes identifies Attachin, a SIFamide homolog, as a stimulant of parasite motility and attachment

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