Exploitation of phylum-spanning omics resources reveals complexity in the nematode FLP signalling system and provides...

Parasitic nematodes significantly undermine global human and animal health and productivity. Parasite control is reliant on anthelmintic administration however over-use of a limited number of drugs has resulted in escalating parasitic nematode resistance, threatening the sustainability of parasite control and underscoring an urgent need for the development of novel therapeutics. FMRFamide-like peptides (FLPs), the largest family of nematode neuropeptides, modulate nematode behaviours including those important for parasite survival, highlighting FLP receptors (FLP-GPCRs) as appealing putative novel anthelmintic targets. Advances in omics resources have enabled the identification of FLPs and neuropeptide-GPCRs in some parasitic nematodes, but remaining gaps in FLP-ligand libraries hinder the characterisation of receptor-ligand interactions, which are required to drive the development of novel control approaches.

In this study we exploited recent expansions in nematode genome data to identify 2143 flp-genes in > 100 nematode species across free-living, entomopathogenic, plant, and animal parasitic lifestyles and representing 7 of the 12 major nematode clades. Our data reveal that: (i) the phylum-spanning flps, flp-1, -8, -14, and - 18, may be representative of the flp profile of the last common ancestor of nematodes; (ii) the majority of parasitic nematodes have a reduced flp complement relative to free-living species; (iii) FLP prepropeptide architecture is variable within and between flp-genes and across nematode species; (iv) FLP prepropeptide signatures facilitate flp-gene discrimination; (v) FLP motifs display variable length, amino acid sequence, and conservation; (vi) CLANS analysis provides insight into the evolutionary history of flp-gene sequelogues and reveals putative flp-gene paralogues and, (vii) flp expression is upregulated in the infective larval stage of several nematode parasites.

These data provide the foundation required for phylum-spanning FLP-GPCR deorphanisation screens in nematodes to seed the discovery and development of novel parasite control approaches.