Helminths battle type 2 immunity for control of the intestinal stem cell niche
Danielle Karo-Atar1, Shaida Ouladan2, Tanvi Javkar2, Ghislaine Fontes1, Alex Gregorieff2, Irah L. King1
1 Department of Microbiology and Immunology, Meakins-Christie Laboratories, McGill University Health Center, Montreal, Quebec, Canada
2 Department of Pathology, McGill University and Cancer Research Program, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
Intestinal helminths remain pervasive throughout the animal kingdom by manipulating host defense pathways to prioritize tissue adaptation and repair over parasite expulsion (1). This host defense strategy begins at the gut epithelium: a monolayer of cells continually replenished by intestinal stem cells (ISCs) residing at the crypt base. As frontline effectors of barrier integrity, a key attribute of the ISC compartment is its ability to undergo extensive transcriptional reprogramming in response to injury (2, 3). Whether infectious organisms exploit ISC plasticity to persist in their hosts remains unknown. By interrogating Heligmosomoides polygyrus bakeri (Hpb) infection in mice, we demonstrate that these parasites directly reprogram ISCs, independent of host-derived factors. This reprogramming event coincides with adult parasite adherence to intestinal villi and is characterized by activation of a fetal-like, regenerative Hippo pathway signature and the emergence of Clusterin-expressing ‘revival’ stem cells (revSC). Morphological and single cell transcriptomic analyses of intestinal organoids exposed to Hpb excretory-secretory products (HES) revealed direct targeting of the ISC niche. HES also suppressed IL-13-induced secretory cell differentiation while deletion of type 2 cytokine signaling in vivo led to an epithelial-intrinsic expansion of revSCs and improved parasite fitness. Collectively, our study reveals how a helminth parasite co-opts a tissue development program to counter type 2 immune-mediated expulsion and maintain chronic infection.
1.  I. L. King, Y. Li, Host–Parasite Interactions Promote Disease Tolerance to Intestinal Helminth Infection. Front. Immunol. 9, 1–10 (2018).
2.  A. J. M. Santos, Y. H. Lo, A. T. Mah, C. J. Kuo, The Intestinal Stem Cell Niche: Homeostasis and Adaptations. Trends Cell Biol. 28 (2018), , doi:10.1016/j.tcb.2018.08.001.
3.  F. de Sousa e Melo, F. J. de Sauvage, Cellular Plasticity in Intestinal Homeostasis and Disease. Cell Stem Cell. 24 (2019), , doi:10.1016/j.stem.2018.11.019.

**Helminths battle type 2 immunity for control of the intestinal stem cell niche**
Danielle Karo-Atar1, Shaida Ouladan2, Tanvi Javkar2, Ghislaine Fontes1, Alex Gregorieff2, Irah L. King1
1 Department of Microbiology and Immunology, Meakins-Christie Laboratories, McGill University Health Center, Montreal, Quebec, Canada
2 Department of Pathology, McGill University and Cancer Research Program, Research Institute of McGill University Health Centre, Montreal, Quebec, Canada
Intestinal helminths remain pervasive throughout the animal kingdom by manipulating host defense pathways to prioritize tissue adaptation and repair over parasite expulsion (_1_). This host defense strategy begins at the gut epithelium: a monolayer of cells continually replenished by intestinal stem cells (ISCs) residing at the crypt base. As frontline effectors of barrier integrity, a key attribute of the ISC compartment is its ability to undergo extensive transcriptional reprogramming in response to injury (_2_, _3_). Whether infectious organisms exploit ISC plasticity to persist in their hosts remains unknown. By interrogating _Heligmosomoides polygyrus bakeri_ (_Hpb_) infection in mice, we demonstrate that these parasites directly reprogram ISCs, independent of host-derived factors. This reprogramming event coincides with adult parasite adherence to intestinal villi and is characterized by activation of a fetal-like, regenerative Hippo pathway signature and the emergence of _Clusterin_-expressing ‘revival’ stem cells (revSC). Morphological and single cell transcriptomic analyses of intestinal organoids exposed to _Hpb_ excretory-secretory products (HES) revealed direct targeting of the ISC niche. HES also suppressed IL-13-induced secretory cell differentiation while deletion of type 2 cytokine signaling _in vivo_ led to an epithelial-intrinsic expansion of revSCs and improved parasite fitness. Collectively, our study reveals how a helminth parasite co-opts a tissue development program to counter type 2 immune-mediated expulsion and maintain chronic infection.
1.  I. L. King, Y. Li, Host–Parasite Interactions Promote Disease Tolerance to Intestinal Helminth Infection. _Front. Immunol._ **9**, 1–10 (2018).
2.  A. J. M. Santos, Y. H. Lo, A. T. Mah, C. J. Kuo, The Intestinal Stem Cell Niche: Homeostasis and Adaptations. _Trends Cell Biol._ **28** (2018), , doi:10.1016/j.tcb.2018.08.001.
3.  F. de Sousa e Melo, F. J. de Sauvage, Cellular Plasticity in Intestinal Homeostasis and Disease. _Cell Stem Cell_. **24** (2019), , doi:10.1016/j.stem.2018.11.019.

Helminths battle type 2 immunity for control of the intestinal stem cell niche

Exploring the intricacies of host-pathogen communication is vital in order to understand why
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Host-Pathogen Communication (HPC) 2021

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