The cells in barrier tissues can distinguish pathogenic from commensal bacteria and target inflammatory responses only in the context of infection. As such, these cells must be able to identify pathogen infection specifically and not just the presence of an infectious organism, because many innocuous bacteria express the ligands that activate innate immunity in other contexts. Unravelling the mechanisms that underly this specificity, however, is challenging. Free-living nematodes, such as Caenorhabditis elegans, are faced with a similar dilemma, as they live in microorganism-rich habitats and eat bacteria as their source of nutrition. Nematodes lost canonical mechanisms of pattern recognition during their evolution and have instead evolved mechanisms to identify specific ligands or symptoms in the host that indicate active infection with an infectious microorganism. Here we review how C. elegans surveys for these patterns of pathogenesis to activate innate immune defences. Collectively, this work demonstrates that using C. elegans as an experimental platform to study host-pathogen interactions at barrier surfaces reveals primordial and fundamentally important principles of innate immune sensing in the animal branch of the tree of life.
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