Pan-Nematoda Transcriptomic Elucidation of Essential Intestinal Functions and Therapeutic Targets With Broad Potential

Abstract

The nematode intestine is continuous with the outside environment, making it easily accessible to anthelmintics for parasite control, but the development of new therapeutics is impeded by limited knowledge of nematode intestinal cell biology. We established the most comprehensive nematode intestinal functional database to date by generating transcriptional data from the dissected intestines of three parasitic nematodes spanning the phylum, and integrating the results with the whole proteomes of 10 nematodes (including 9 pathogens of humans or animals) and 3 host species and 2 outgroup species. We resolved 10,772 predicted nematode intestinal protein families (IntFams), and studied their presence and absence within the different lineages (births and deaths) among nematodes. Conserved intestinal cell functions representing ancestral functions of evolutionary importance were delineated, and molecular features useful for selective therapeutic targeting were identified. Molecular patterns conserved among IntFam proteins demonstrated large potential as therapeutic targets to inhibit intestinal cell functions with broad applications towards treatment and control of parasitic nematodes.

Keywords: Intestinal protein families; Molecular functions; Nematode intestine; Therapeutic targets.

Fig. 1

Characteristics of core species: phylogeny, host location and trophic ecology. *Phylogeny based on Blaxter et al., 1998. ** GI tract, gastro-intestinal tract.

Fig. 2

Derivation of the intestinal protein families (IntFams) in this study.

Fig. 3

Protein family birth/death and gene duplication/loss events observed in this study. (a) Protein family birth and death events within the intestinal protein families. (b) Protein family change index (PFCI) within the protein families (proteome) and intestinal protein families (transcriptome). (c) Gene duplication and loss events for the universal families. The number or species name at each lineage corresponds to the label used in Table S5.

Fig. 4

Conservation and expression level of the ELT-2 gene. (a) ELT-2 like protein domain architecture and its overall sequence conservation from the 10 nematode species. (b) Expression profile of the ELT-2 like gene in A. suum (GS_05212).

Fig. 5

A 7 amino acid deletion in retinoid X receptor α (RXR-α) of A. suum creates a unique ligand binding site. (a) IPR domain annotations for the orthologs within the IntFam. (b) Sequence alignment of the deleted region in RXR-α from A. suum with all the other members of the intestinal protein family. The deleted region is in red box. Another deletion specific to clade I is in blue box. (c) Side-by-side view of the crystal structure for H. sapiens (PDB ID: 3E00) with the homology model of A. suum. Crystal structure is colored in blue; model is colored in green. The natural ligand 9-cis retinoic acid is shown in yellow stick model in both panels. The cavity created by the deletion is pointed out by a red arrow in the model.