Tales from the crypt: on helminth regulation of the stem cell compartment
Abstract:
Intestinal helminths remain pervasive throughout the animal kingdom by manipulating host defense pathways to prioritize tissue adaptation and repair over parasite expulsion. These parasites 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. By interrogating Heligmosomoides polygyrus bakeri (Hpb) infection in mice, we demonstrate that these parasites directly reprogram the ISC compartment, independent of host-derived factors. This reprogramming event coincides with adult parasite colonization of the intestinal lumen and is characterized by activation of a regenerative fetal-like, signature and the emergence of Clusterin-expressing ‘revival’ stem cells (revSC). 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 co-opt a tissue development program to counter type 2 immune-mediated expulsion and maintain chronic infection.
