Immune surveillance of cellular damage: lessons from Caenorhabditis elegans

Innate immune systems must detect infection rapidly and reliably, yet pathogens can often evade direct recognition by host pattern-recognition receptors. An alternative and increasingly appreciated strategy is damage-driven immune surveillance, whereby hosts detect pathogen-induced perturbations to essential cellular and tissue functions rather than microbial molecules themselves. This mode of detection is particularly prominent in Caenorhabditis elegans, which lacks professional immune cells and most canonical innate immune receptors, and therefore relies extensively on monitoring disruptions to core homeostatic pathways. Perturbations to protein translation, proteostasis, mitochondrial function, genome and nucleolar integrity, lysosomal homeostasis, and Golgi function can all trigger immune responses. Recent studies have further uncovered roles for inter-organelle communication, effector-triggered surveillance of lysosome-related organelles, and physiological signals such as intestinal distension in regulating immune activation. Here, we integrate these advances into an organelle- and tissue-centric framework and explore parallels with other organisms to identify emerging and potentially conserved principles of damage sensing in innate immunity. These findings highlight the surveillance of cellular homeostasis as a central strategy for immunity that operates beyond canonical pattern-recognition mechanisms.