null Parasitic worms reprogram intestinal stem cells to evade the immune system
A new collaboration between immunoparasitologists and stem cell biologists at the RI‑MUHC describes how parasitic worms, or helminths, directly inhibit an anti-parasitic immune response by the intestinal epithelium
Recently published in the Journal of Experimental Medicine, new work by researchers from the Research Institute of the McGill University Health Centre (RI-MUHC) may lead to the development of novel treatments for parasitic worm infections and inflammatory bowel disease.
Parasitic worms, known as helminths, cause a significant health and economic burden in many areas around the world, infecting approximately a quarter of the world’s population. Chronic infection is common because helminths can often evade the defensive immune response of their host.
“We wanted to know more about how helminths can regulate immunity in order to evade host defense. In this study, we specifically focused on the impact of helminths on the function of epithelial cells, which are a sentinel of host defense at the intestinal barrier,” says Irah King, PhD, a scientist in the Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program at the RI-MUHC and senior author of the study.
“To address this question, we extracted stem cells from mouse intestinal tissue to culture a mini-gut model. The mini-gut is an intestinal organoid that forms an elaborate 3D structure in culture, closely mimicking the structure of the in vivo intestine,” explains first author Danielle Karo-Atar, PhD, a postdoctoral fellow in Irah King’s laboratory. “We were able to use the mini-gut model to assess the response of the intestinal stem cell compartment to infection.”
When the researchers cultured the mini-guts with an intestinal worm, they found that the mini-guts assumed a distinct physical structure and expressed a specific genetic signature.
“This discovery allowed us to demonstrate how helminths directly target an area of the gut epithelium where intestinal stem cells reside,” adds Danielle Karo-Atar. “We learned that the worms can cause the epithelium to revert into a highly regenerative, yet immature, fetal-like state and inhibit the anti-worm immune response of the epithelium.”
The team also discovered that while the worms were suppressing the host’s epithelial immune response, at the same time, the infected host’s immune system was also working to suppress this fetal reversion of the epithelium.
“Our study suggests that helminths and the host immune response are in a tug-of-war for control of the intestinal stem cell compartment”
— Alex Gregorieff, PhD
“Our study suggests that helminths and the host immune response are in a tug-of-war for control of the intestinal stem cell compartment,” says Alex Gregorieff, PhD, a stem cell expert in the Cancer Research Program at the RI-MUHC and additional senior author in the study.
The research suggests that regulation of the host intestinal epithelium by parasitic worms may promote the process of mucosal healing. Mucosal healing is a restorative response that involves the activation of cellular regenerative programs and abrogation of destructive tissue inflammation. To date, an imperfect understanding of mucosal healing has been a major obstacle in the treatment of inflammatory bowel diseases.
“Our findings provide a foundation for the discovery of specific helminth-derived molecules and pathways that can be targeted for the development of novel anti-helminthic drugs,” concludes Irah King. “Additionally, our work provides a new conceptual framework for helminth-based therapies designed to rejuvenate the intestinal barrier following acute injury.”
About the study:
Read the publication in the Journal of Experimental Medicine
The authors thank the Histopathology Platform of the RI-MUHC.
August 11, 2022