Fungal symbiont transmitted by free-living mice promotes type 2 immunity

Yun Liao; Iris H Gao; Takato Kusakabe; Woan-Yu Lin; Alexander Grier; Xiangyu Pan; Olga Morzhanaeva; Terrance P Shea; Hiroshi Yano; Danielle Karo-Atar; Kaitlin A Olsen; Ji Hoon Oh; Kurt J Vandegrift; Irah L King; Christina A Cuomo; David Artis; Barbara Rehermann; Neil Lipman; Iliyan D Iliev

doi:10.1038/s41586-024-08213-2

Fungal symbiont transmitted by free-living mice promotes type 2 immunity

Nature. 2024 Nov 27. doi: 10.1038/s41586-024-08213-2. Online ahead of print.

Authors

Yun Liao^#^{1

2}, Iris H Gao^#^{1

2

3}, Takato Kusakabe^{1

2}, Woan-Yu Lin^{1

2

3}, Alexander Grier^{1

2}, Xiangyu Pan^{1

2}, Olga Morzhanaeva^{1

2}, Terrance P Shea⁴, Hiroshi Yano^{1

2

5

6

7}, Danielle Karo-Atar^{8

9}, Kaitlin A Olsen^{8

9}, Ji Hoon Oh¹⁰, Kurt J Vandegrift¹¹, Irah L King^{8

9}, Christina A Cuomo^{4

12}, David Artis^{1

2

3

5

6

7}, Barbara Rehermann¹⁰, Neil Lipman¹³, Iliyan D Iliev^{14

15

16

17}

Affiliations

¹ Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA.
² The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA.
³ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA.
⁴ Infectious Disease and Microbiome Program, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁵ Friedman Center for Nutrition and Inflammation, Weill Cornell Medicine, Cornell University, New York, NY, USA.
⁶ Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA.
⁷ Allen Discovery Center for Neuroimmune Interactions, New York, NY, USA.
⁸ Department of Microbiology and Immunology, Meakins-Christie Laboratories, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.
⁹ McGill Centre for Microbiome Research, McGill University, Montreal, Quebec, Canada.
¹⁰ Immunology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, DHHS, Bethesda, MD, USA.
¹¹ Department of Biology, The Pennsylvania State University, University Park, PA, USA.
¹² Department of Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.
¹³ Center for Comparative Medicine and Pathology, Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, NY, USA.
¹⁴ Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY, USA. idi@ilievlab.org.
¹⁵ The Jill Roberts Institute for Research in Inflammatory Bowel Disease, Weill Cornell Medicine, Cornell University, New York, NY, USA. idi@ilievlab.org.
¹⁶ Immunology and Microbial Pathogenesis Program, Weill Cornell Graduate School of Medical Sciences, Weill Cornell Medicine, Cornell University, New York, NY, USA. idi@ilievlab.org.
¹⁷ Department of Microbiology and Immunology, Weill Cornell Medicine, Cornell University, New York, NY, USA. idi@ilievlab.org.

^# Contributed equally.

PMID: 39604728
DOI: 10.1038/s41586-024-08213-2

Abstract

The gut mycobiota is crucial for intestinal homeostasis and immune function¹. Yet its variability and inconsistent fungal colonization of laboratory mice hinders the study of the evolutionary and immune processes that underpin commensalism^2,3. Here, we show that Kazachstania pintolopesii is a fungal commensal in wild urban and rural mice, with an exceptional ability to colonize the mouse gastrointestinal tract and dominate the gut mycobiome. Kazachstania pintolopesii colonization occurs in a bacteria-independent manner, results in enhanced colonization resistance to other fungi and is shielded from host immune surveillance, allowing commensal presence. Following changes in the mucosal environment, K. pintolopesii colonization triggers a type 2 immune response in mice and induces gastrointestinal eosinophilia. Mechanistically, we determined that K. pintolopesii activates type 2 immunity via the induction of epithelial IL-33 and downstream IL-33-ST2 signalling during mucus fluctuations. Kazachstania pintolopesii-induced type 2 immunity enhanced resistance to helminth infections or aggravated gastrointestinal allergy in a context-dependent manner. Our findings indicate that K. pintolopesii is a mouse commensal and serves as a valuable model organism for studying gut fungal commensalism and immunity in its native host. Its unnoticed presence in mouse facilities highlights the need to evaluate its influence on experimental outcomes and phenotypes.