Bacterial-fungal interactions in the neonatal gut influence asthma outcomes later in life
- University of British Columbia, Canada
- University of Manitoba, Canada
- University of Alberta, Canada
- The Hospital for Sick Children, Canada
- McMaster University, Canada
Abstract
Bacterial members of the infant gut microbiota and bacterial-derived short-chain fatty acids (SCFAs) have been shown to be protective against childhood asthma, but a role for the fungal microbiota in asthma etiology remains poorly defined. We recently reported an association between overgrowth of the yeast Pichia kudriavzevii in the gut microbiota of Ecuadorian infants and increased asthma risk. In the present study, we replicated these findings in Canadian infants and investigated a causal association between early life gut fungal dysbiosis and later allergic airway disease (AAD). In a mouse model, we demonstrate that overgrowth of P. kudriavzevii within the neonatal gut exacerbates features of type-2 and -17 inflammation during AAD later in life. We further show that P. kudriavzevii growth and adherence to gut epithelial cells are altered by SCFAs. Collectively, our results underscore the potential for leveraging inter-kingdom interactions when designing putative microbiota-based asthma therapeutics.
Data availability
Data Availability: All data generated or analyzed during this study are included in the manuscript and supporting files. Sequencing data have been deposited in the NCBI SRA under accession code SUB7276684 (https://www.ncbi.nlm.nih.gov/sra/PRJNA624902).
Article and author information
Author details
Funding
Canadian Institutes of Health Research (Project Grant PJT-148484)
- Brett Finlay
Canadian Institutes of Health Research (Foundation Grant FDN-159935)
- Brett Finlay
AllerGen (12CHILD)
- Meghan B Azad
- Allan B Becker
- Piush J Mandhane
- Theo J Moraes
- Malcolm R Sears
- Padmaja Subbarao
- Stuart E Turvey
- Brett Finlay
Canadian Institutes of Health Research (Doctoral: Vanier Canada Graduate Scholarships)
- Rozlyn CT Boutin
Vancouver Coastal Health-Canadian Institutes of Health Research (UBC MD/PhD Studentship Award)
- Rozlyn CT Boutin
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All animal experiments were in accordance with the University of British Columbia Animal Care Committee guidelines and approved by the UBC Animal Care Committee (protocols A17-0322 and A13-0344).
Human subjects: The CHILD Cohort Study protocols were approved by the human clinical research ethics boards at all universities and institutions directly involved with the CHILD cohort (McMaster University, University of British Columbia, the Hospital for Sick Children, University of Manitoba, and University of Alberta). Work in the Finlay/Turvey labs is conducted under the ethics certificate number H07-03120.
Reviewing Editor
- Antonis Rokas, Vanderbilt University, United States
Publication history
- Received: February 21, 2021
- Accepted: April 7, 2021
- Accepted Manuscript published: April 20, 2021 (version 1)
- Version of Record published: April 26, 2021 (version 2)
- Version of Record updated: April 27, 2021 (version 3)
Copyright
© 2021, Boutin et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,270
- Page views
-
- 285
- Downloads
-
- 4
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Further reading
-
- Immunology and Inflammation
The oxidative state of a critical cysteine residue determines the enzymatic activity of a phosphatase involved in T-cell immune responses.
-
- Immunology and Inflammation
- Structural Biology and Molecular Biophysics
Dimorphic amino acids at positions 77 and 80 delineate HLA-C allotypes into two groups, C1 and C2, which associate with disease through interactions with C1 and C2-specific natural killer cell receptors. How the C1/C2 dimorphism affects T cell recognition is unknown. Using HLA-C allotypes that differ only by the C1/C2-defining residues, we found that KRAS-G12D neoantigen-specific T cell receptors (TCR) discriminated between C1 and C2 presenting the same KRAS-G12D peptides. Structural and functional experiments, and immunopeptidomics analysis revealed that Ser77 in C1 and Asn77 in C2 influence amino acid preference near the peptide C-terminus (pW), including the pW-1 position, in which C1 favors small and C2 prefers large residues. This resulted in weaker TCR affinity for KRAS-G12D-bound C2-HLA-C despite conserved TCR contacts. Thus, the C1/C2 dimorphism on its own impacts peptide presentation and HLA-C restricted T cell responses, with implications in disease, including adoptive T cell therapy targeting KRAS-G12D-induced cancers.
