This groundbreaking discovery opens up new opportunities to study the role of host-fungus interactions in intestinal immunity
SOURCE: MUHC
December 20, 2024
The intestine is a shelter for trillions of commensal microbes, called the microbiome, that coexist with their host. While the microbiome is critical for strengthening our immune system and protecting the body against infection, it can also contribute to autoimmune and inflammatory diseases, highlighting the complexity of the interactions at play. A groundbreaking collaborative discovery recently published in Nature, involving researchers at the Research Institute of the McGill University Health Centre (The Institute), is shedding new light on host-microbe relationships.
While most microbiome studies have examined how commensal bacteria shape our health, scientists in Irah King’s lab at The Institute have contributed to the identification of the first true commensal fungus in laboratory mice: a species of yeast called Kazachstania pintolopesii (Kp). This fungus stably colonizes and dominates the mouse intestinal tract, can be passed on to offspring and triggers an immune response that significantly increases resistance to intestinal helminth infections — parasitic worms that affect millions of people worldwide.
Led by Iliyan Iliev, PhD, at Weill Cornell Medical College in New York City, the study reveals how commensal and pathogenic fungi shape intestinal immunity and opens up new opportunities to study host-fungus interactions. Most significantly, it shows that Kp enhances type 2 immune responses, most commonly associated with allergy and parasitic worm infection.
“The experiments we performed in our lab have shown that when the intestinal barrier is disrupted, Kp colonization significantly enhances resistance to intestinal helminth infection,” says Irah King, PhD, Senior Scientist in the Translational Research in Respiratory Diseases Program at The Institute and co-author of the study. “This is a very atypical response as fungi usually induce a type 3 immune response, which is associated with fungal killing, but is also implicated in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.”
“Prior to this work, researchers lacked a reliable model for studying fungal commensalism because most fungi only transiently colonize the mouse gut. Our collaborative discovery provides an indispensable new model organism for understanding host-fungal interactions and their impact on the immune response to infection. This is particularly valuable because fungi are an often overlooked but crucial component of the intestinal ecosystem across all life forms," adds Prof. King, also Professor in the Department of Microbiology and Immunology at McGill University.
A discovery with multiple implications
This discovery opens up a number of new research opportunities. For example, understanding how Kp enhances anti-helminth immunity could inform the development of novel therapeutic strategies. Moreover, characterizing Kazachstania colonization in the human microbiome may help predict and understand human immune activation in other disease contexts such as asthma.
Further studies could also:
- Uncover the complex relationships between fungi, bacteria, parasites and the host, deepening scientists' understanding of how the microbiota influences health;
- Demonstrate the important role of fungi in shaping gut immune responses, a role that has been overlooked in previous microbiome studies;
- Reveal unrecognized ways in which the immunomodulatory properties of fungi may influence experimental and clinical outcomes in various studies of health and disease.
A serendipitous discovery
The King Lab at The Institute is deeply interested in how the microbiome shapes immunity to infectious diseases. Specifically, the lab uses parasitic worms (helminths) to study intestinal immune responses. At one point, the team made a series of intriguing observations, such as unexpectedly low worm counts during infection in mice and yeast contamination in cultures grown from mouse intestines.
“Rather than dismissing these observations as technical obstacles, we wondered if the aberrant infections might be due to actions of the microbiota. We decided to reach out to a colleague and leading expert in host-fungal interactions, Prof. Iliyan Iliev at Weill Cornell Medical College in New York City, to sequence the yeast in our mice. He identified a single species, Kazachstania pintolopesii. Coincidentally, he had also discovered Kp in his lab mice and was investigating its role in intestinal immunity!” says Prof King.
The researchers then decided to deliberately colonize mice with Kp and observed the same reduction in worm burden, demonstrating that Kp colonization directly enhances the anti-helminth response.
“While previous work has examined either host-fungal or host-helminth interactions separately, this study reveals how these kingdoms interact in a three-way relationship that influences host immunity,” says Kaitlin Olsen, a graduate student at The Institute who performed some of the study experiments.
“Our compelling discovery of Kp colonization shaping the host anti-parasite response highlights the importance of paying attention to unexpected findings in research and seeking scientific collaboration,” adds Prof. King. “What initially seemed like technical issues revealed a fundamental framework to study the exciting axis of fungal-helminth-host interactions.”
The King Lab team is now investigating how early-life Kp colonization may influence long-term immune development and disease susceptibility. It is also seeking potential connections between Kp colonization and human health outcomes, in collaboration with scientists and clinicians from the McGill Centre for Microbiome Research – studies that could inform therapeutic approaches for both helminth infections and immune-mediated disorders.
About the study
Liao, Y., Gao, I.H., Kusakabe, T. et al. Fungal symbiont transmitted by free-living mice promotes type 2 immunity. Nature 636, 697–704 (2024). https://doi.org/10.1038/s41586-024-08213-2