A tissue-scale strategy for sensing threats in barrier organs

Barrier organs rely on a limited set of pattern recognition receptors (PRRs) to detect diverse immunogenic challenges. How organs assess threats and adjust immune responses to balance host protection with collateral tissue damage remains unclear. Here, by analyzing influenza infection in the lung using single-molecule imaging and spatial transcriptomics, we discovered a tiered threat-sensing strategy at the tissue scale, where the probability of detecting and responding to infection is lowest in the outermost epithelia and highest in the inner stroma. This strategy emerges from spatially graded PRR expression that results in cell-type-specific probabilities of threat-sensing across the tissue, a design broadly adopted by barrier organs. Selectively increasing PRR expression in lung epithelia in vivo exacerbated tissue damage upon inflammatory challenge. These results reveal a spatially tiered strategy to tolerate threats restricted within the epithelia, and yet enable progressively potent immune responses as threats invade deeper into the tissue.