Evolution of host innate defence: insights from Caenorhabditis elegans and primitive invertebrates

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Abstract
The nematode Caenorhabditis elegans was developed as a model for studying bacterial virulence and innate immunity in 1999. C. elegans does not have circulating cells and seems to rely almost exclusively on epithelial immunity to combat pathogen attack. Several parallel immune response pathways have been identified that activate distinct but partially overlapping sets of immune effectors. Despite its simplicity, the C. elegans immune response is highly pathogen specific and different pathogens activate distinct immune response pathways. Although C. elegans has a single Toll-like receptor (TLR), myeloid differentiation primary-response protein 88 (MYD88) and nuclear factor-κB (NF-κB) are not encoded in the C. elegans genome or in the genomes of other nematode species. Moreover, the single C. elegans TLR does not seem to have an important role in the immune response. Because some cnidaria (such as the sea anemone Nematostella vectensis) have TLRs, MYD88 and NF-κB, it seems that TLR signalling has been lost in the nematode lineage. A highly conserved p38 mitogen-activated protein kinase (MAPK) signalling cascade has a central role in the C. elegans immune response as it does in mammals. The p38 MAPK pathway is required for the activation of a set of immune effectors that are required to maintain a basal level of immune function. The p38 MAPK signalling pathway is active during both infection and wounding and functions in at least the intestine, neurons and epidermis in response to pathogen infection. Several highly conserved metazoan signalling pathways have dual roles, functioning as important components of the C. elegans immune response. It is of interest to determine whether the same pathways function in immune signalling throughout metazoan evolution, including acting in concert with TLR pathways in mammals. In addition to its role in stress resistance, lifespan extension and metabolic regulation in C. elegans, the DAF-2–DAF-16 insulin signalling pathway confers resistance to a wide variety of pathogens when DAF-16 is constitutively activated. The C. elegans β-catenin homologue β-catenin/armadillo-related family member 1 (BAR-1) and the downstream homoebox protein egg laying defective protein 5 (EGL-5) have central roles in activating the C. elegans immune response to infection by Staphylococcus aureus but not Pseudomonas aeruginosa. Roles for β-catenin and homeobox proteins in immune signalling in flies and mammals have also been recently shown. The G protein-coupled receptor FSHR-1 is the first candidate immune receptor to be identified in C. elegans.