Microbial imprinting of the airway epithelium

The airway epithelium forms the frontline interface between the external environment and the respiratory system and is constantly exposed to microbes and their constituents. Epidemiological and preclinical evidence increasingly highlights an important role for microbial factors in shaping long-term respiratory health by maintaining immune homeostasis and modulating exacerbations in chronic inflammatory diseases. Here, we argue that these durable effects are likely due to "imprinting" events at the epithelial interface. Emerging evidence indicates that microbes can functionally imprint the airway epithelium through metabolic and epigenetic reprogramming, thereby shaping subsequent responses to microbial and inflammatory stimuli. We propose a conceptual framework of epithelial imprinting comprised of four categories: differentiation, tolerance, priming and trained immunity. This framework provides an important foundation for the mechanistic dissection of epithelial memory in the airways and highlights novel therapeutic opportunities to harness microbial factors to modulate respiratory health.