Tales from the crypt: On helminth regulation of the stem cell compartment

Enteric helminths form intimate physical connections with the intestinal epithelium, yet little is known about the ability of helminths to directly shape the fate of this barrier tissue. Here we demonstrate that infection of mice with the parasite Heligmosomoides polygyrus bakeri (Hpb), reprograms the intestinal stem cells compartment into a regenerative fetal-like state marked by the emergence of Clusterin-expressing revival stem cells (revSCs). Using lineage-tracing, transcriptomics and advanced imaging techniques both in vitro in organoids cultures and in vivo, we show that Hpb-mediated revSC generation is critically regulated by oxidative stress, occurs independent of host-derived immune signals and inhibits type 2 cytokine-driven differentiation of secretory epithelial lineages that promote worm expulsion. Reciprocally, type 2 cytokine signals limit revSC differentiation and, consequently, Hpb fitness indicating that helminths compete with their host for control of the intestinal stem cell compartment to promote continuation of their life cycle.