Age-Dependent Reduction in Asthmatic Pathology through Reprogramming of Postviral Inflammatory Responses

Guy Hazan, Anna Eubanks, Carrie Gierasch, Jeffrey Atkinson, Carolyn Fox, Ariel Hernandez-Leyva, Anne L. Rosen, Andrew L. Kau, Eugene Agapov, Jennifer Alexander-Brett, Deborah Steinberg, Diane Kelley, Michael White, Derek Byers, Kangyun Wu, Shamus P. Keeler, Yong Zhang, Jeffrey R. Koenitzer, Elise Eiden, Neil AndersonMichael J. Holtzman, Jeffrey Haspel

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Asthma is a chronic disease of childhood, but for unknown reasons, disease activity sometimes subsides as children mature. In this study, we present clinical and animal model evidence suggesting that the age dependency of childhood asthma stems from an evolving host response to respiratory viral infection. Using clinical data, we show that societal suppression of respiratory virus transmission during coronavirus disease 2019 lockdown disrupted the traditional age gradient in pediatric asthma exacerbations, connecting the phenomenon of asthma remission to virus exposure. In mice, we show that asthmatic lung pathology triggered by Sendai virus (SeV) or influenza A virus is highly age-sensitive: robust in juvenile mice (4-6 wk old) but attenuated in mature mice (>3 mo old). Interestingly, allergen induction of the same asthmatic traits was less dependent on chronological age than viruses. Age-specific responses to SeV included a juvenile bias toward type 2 airway inflammation that emerged early in infection, whereas mature mice exhibited a more restricted bronchiolar distribution of infection that produced a distinct type 2 low inflammatory cytokine profile. In the basal state, aging produced changes to lung leukocyte burden, including the number and transcriptional landscape of alveolar macrophages (AMs). Importantly, depleting AMs in mature mice restored post-SeV pathology to juvenile levels. Thus, aging influences chronic outcomes of respiratory viral infection through regulation of the AM compartment and type 2 inflammatory responses to viruses. Our data provide insight into how asthma remission might develop in children.

Original languageEnglish
Pages (from-to)1467-1482
Number of pages16
JournalJournal of immunology (Baltimore, Md. : 1950)
Volume208
Issue number6
DOIs
StatePublished - Mar 15 2022

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