ILC2s as drivers of lung dysfunction in response to early-life inflammation

Childhood asthma is a leading cause of chronic disease and hospitalization in children. Viral infections within the first year or two of life are strongly associated with childhood asthma risk, but the immune mechanisms mediating this association are poorly understood. The long-term goal of this proposal is to define how early-life inflammation determines asthma susceptibility by reprogramming the fate and function of type 2 innate lymphoid cells from hematopoietic progenitors during early life. This proposal builds on preliminary data linking Type I interferon-mediated inflammation induced by maternal immune activation with poly(I:C) and associated with common viral infections with a hyperactivated Type 2 innate lymphoid cell (ILC2) response in the postnatal lung that drives asthma susceptibility in mice. ILC2s are strongly implicated in asthma pathogenesis in mouse models and have also been identified in human asthma, but their role as mediators of asthma susceptibility is undefined. The overall objectives of this proposal are to define the cellular and molecular mechanisms by which viral-induced inflammation initiates a hyperactivated ILC2 phenotype at the progenitor level and determine the requirement and sufficiency for hyperactivated ILC2s in remodeling lung immunity and susceptibility to asthma during early life. We will also examine hyperactivated ILC2s in human development in response to infection as a putative biomarker for asthma susceptibility. The central hypothesis of this proposal is that early-life infections promote lung dysfunction and asthma susceptibility by programming hematopoietic progenitors to produce hyperactive tissue-resident ILC2s that shape lung immunity. We will test this hypothesis in three specific aims. In Aim 1, we will define the cellular and molecular mechanisms underlying the persistent hyperactivated function of ILC2s in response to early-life inflammation by performing progenitor fate-mapping and orthogonal transcriptomic and epigenomic analyses, In Aim 2, we will test whether hyperactivated ILC2s in the postnatal lung are necessary and sufficient to induce lung immune remodeling and lung dysfunction using a combination of specific gene deletion models and transplantation approaches. In Aim 3, we will perform phenotypic and functional investigation of human umbilical cord blood ILC2s from normal pregnancies and pregnancies affected by chorioamnionitis to gage the response of human ILC2s to early-life infection. We will also leverage comparisons to our own single-cell transcriptomic datasets in mice to define transcriptional regulators of the human ILC2 response. The concept of this proposal is innovative in defining perturbation of “layered immune development” of ILC2s as a novel pathogenic driver of asthma susceptibility, and innovative in approach by using overlapping inducible fate-mapping and genetic deletion models in parallel with single-cell transcriptomics, ATAC-seq, and adoptive transfer assays. The proposed research is significant because it will address gaps in understanding asthma pathogenesis and will pave the way for the identification of new therapeutic targets for asthma treatment and prevention. Project Number: 1R01HL174024-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Anna E Beaudin | Institution: UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH, SALT LAKE CITY, UT | Award Amount: $740,709 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 RCCS-M (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17402401A1