Worming out defence strategies: mechanisms of immunity through the lens of genetic screens in C. elegans

Since Sydney Brenner's foundational work in 1974, Caenorhabditis elegans has served as an impactful model for biological discovery primarily driven by genetic approaches, including mutagenesis-based screens and RNAi-based functional genomics. We discuss here how genetic screens in C. elegans have advanced our understanding of innate immunity mechanisms by comparing signalling pathways and responses to a wide range of bacteria, viruses, and eukaryotic pathogens including oomycetes, and microsporidia. Screens have uncovered both evolutionarily conserved pathways and species-specific mechanisms of nematode immunity across multiple functional categories. These include mediators of pathogen recognition that specifically detect microbial patterns or infection-associated damage, surveillance immunity systems that sense pathogen-induced cellular dysfunction, and regulatory mechanisms that control the activation of immune signalling or balance it with physiological costs. A major theme emerging from these studies is the importance of cross-tissue immune communication, as C. elegans coordinates responses between multiple tissues including neurons, intestine, and epidermis through complex signalling networks. Powerful genetic approaches, coupled with the continued development of new tools in the community, position C. elegans as an attractive whole-animal model for understanding fundamental principles of host-pathogen interactions and the evolutionary origins of innate immunity.