Using Cell-specific Late-phase Asthma mRNA Biomarkers to Repurpose Drugs that Concurrently Reverse Disease Signatures Across Multiple Immune Cell-types
Mingming Zhang, Young Woong Kim, Chen Xi Yang, Gail M. Gauvreau, John Marcus FitzGerald, Louis-Philippe Boulet, Paul M. O’Byrne, Scott J. Tebbutt, Amrit Singh
Abstract
The allergen-induced late-phase asthmatic response (LAR) is used to study the mechanisms and treatment of asthma. We hypothesized that gene-expression (mRNA) biomarkers of the LAR may predict asthma exacerbations and severity.
Introduction
Allergen inhalation challenge has long been used as a controlled human model to induce airway responses and associated inflammatory processes in individuals with mild allergic asthma. Following exposure to a sensitizing allergen, most allergic individuals develop an acute bronchoconstrictive response known as the early-phase asthmatic response (EAR), which typically resolves within 1–3 hours. A substantial subset of individuals subsequently develops a late-phase asthmatic response (LAR), emerging 3–4 hours after allergen exposure and characterized by sustained bronchoconstriction, immune-cell infiltration of the airways, and transient airway hyperresponsiveness.
Materials and Methods:
The Institutional Review Boards of the participating institutions, the University of British Columbia (UBC), McMaster University, and Université Laval, approved this study (NCT01113697) and participants provided written informed consent.
Discussion:
In this study we identified a gene-expression biomarker panel to predict a subject’s response to allergen challenge and identify participants who experience the late-phase asthmatic response. Combined with existing gene-expression biomarkers of the LAR, we were able to show the utility of these biomarkers in discriminating exacerbation from non-exacerbation and severe from moderate asthma. Further we demonstrated that most LAR-mRNA biomarkers are up-regulated in various immune cell subtypes and that existing drugs may be used to suppress this inflammatory response.
Acknowledgments
We thank the research participants for taking part in these studies, as well as Johane Lepage, Philippe Prince, Joanne Milot, Mylène Bertrand, Richard Watson, George Obminski, Heather Campbell, Abbey Torek, Tara Strinich, Karen Howie, Linda Hui and Joyce Kum for their expertise and assistance with participant recruitment, allergen challenge and sample collection, as part of the AllerGen NCE Clinical Investigator Collaborative. We used ChatGPT v5.2 to assist in drafting parts of the text, and refactoring code. We reviewed and revised all AI-generated content and verified the accuracy and integrity of the final manuscript.
Citation: Zhang M, Kim YW, Yang CX, Gauvreau GM, FitzGerald JM, Boulet L-P, et al. (2026) Using cell-specific late-phase asthma mRNA biomarkers to repurpose drugs that concurrently reverse disease signatures across multiple immune cell-types. PLoS Comput Biol 22(4): e1014081. https://doi.org/10.1371/journal.pcbi.1014081
Editor: Hao Hu, University of Macau, MACAO
Received: August 8, 2025; Accepted: March 2, 2026; Published: April 3, 2026.
Copyright: © 2026 Zhang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All data files used for this paper can be found here: https://zenodo.org/records/18034997. Code used to reproduce all analyses can be found here: https://github.com/CompBio-Lab/asthma_LAR-mRNA_biomarkers.
Funding: This work was supported by funding from AllerGen NCE Inc. (16B&B_MSI-C7 to S.J.T.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
