Genome-wide reconstruction of the intrinsic apoptosis pathway in Haemonchus contortus

Programmed cell death (or apoptosis) is a fundamental process in metazoans, extensively characterised in mammals and other vertebrates but much less so in invertebrates beyond the free-living nematode Caenorhabditis elegans and the vinegar fly - Drosophila melanogaster. Here, we present the first reconstruction of the complete intrinsic apoptosis pathway in the parasitic nematode Haemonchus contortus, a blood-feeding pathogen of ruminants and a major cause of global production losses.

Using C. elegans proteins as references, we combined genome-wide homology searches, structural modelling, and developmental transcriptomic and proteomic analysis to identify and characterise apoptosis regulators in H. contortus. Homologues of all canonical C. elegans components were found, including CEP-1, EGL-1, CED-9, CED-4 and CED-3, together with modulators such as DRE-1 and PUF-8. Structural models revealed conservation of the CED-9:CED-4 and CED-4:CED-3 complexes, while EGL-1 and CEP-1 retained key structural domains despite significant sequence divergence. Transcriptomic data showed that the genes Hc-ced-9 and Hc-ced-3 are constitutively expressed across developmental stages, whereas Hc-cep-1 and Hc-egl-1 display stage-specific transcription. Proteomic data confirmed the presence of Hc-CED-9, Hc-CED-4 and Hc-CED-3 in at least one developmental stage, while Hc-EGL-1 and Hc-DRE-1 were not detected. Discordances between RNA and protein profiles, particularly for Hc-EGL-1, suggest tight post-transcriptional control. These findings demonstrate that, while the core architecture of apoptosis is conserved in H. contortus, regulatory divergence has occurred, reflecting lineage-specific adaptations.

This molecular framework highlights conserved structural features and developmental regulation of apoptosis in a parasitic nematode and provides a basis for functional studies to evaluate apoptotic regulators as potential targets for anthelmintic development.