An esp2 mutant worm, after exposure to GFP-labelled P. aeruginosa. Nomarski (top) and fluorescence (bottom) images courtesy of Dennis Hyong-Kun Kim, Frederick Ausubel and Rhonda Feinbaum.

Much of what we know about innate immunity comes from studies in Drosophila. Two papers now show that Caenorhabditis elegans, another genetically tractable organism, might be a useful additional model for studying innate immunity. The results show that C. elegans has an inducible response to pathogen infection and that this response shares many features with innate immunity in other organisms.

Kim et al. assayed the progeny of mutagenized worms, which had been exposed to the bacterium Pseudomonas aeruginosa, for enhanced susceptibility to pathogen (esp) infection. Two mutants, esp2 and esp8, that had severe phenotypes were isolated — both die much faster after exposure to P. aeruginosa than wildtype worms. The mutant genes were identified by phenotypic rescue — the esp2 mutant was rescued by the gene sek-1 , and esp8 by nsy-1 .

sek-1 encodes a mitogen-activated protein kinase kinase (MAPKK) homologue of mammalian MKK3/MKK6 and MKK4, and nsy-1 encodes an orthologue of the mammalian MAPKKK ASK1. Because these kinases activate the p38 kinase family and the JNK MAPKs in mammals, the authors tested the role of p38 and JNK in the C. elegans defence response. The esp2 and esp8 mutants had markedly reduced levels of p38 MAPK activity. Moreover, the knockdown of pmk-1 , one of two C. elegans p38 orthologues, by RNA interference produced a strong esp phenotype. Knockdown of pmk-2 and a jnk mutation, however, produced no enhanced susceptiblity to P. aeruginosa infection. Together, these results show that the p38 MAPK pathway is required for innate responses to pathogen infection, which is an important discovery as this signalling pathway is also crucially required in mammals for inflammatory and innate-immune response signalling pathways.

Mallo et al. used an expression screen to look for C. elegans genes that are upregulated in response to infection by the bacterium Serratia marcescens. Of 7,500 cDNAs that were surveyed, several were induced more than twofold; most of these encode lectins, which function in innate immunity in other organisms. Lysozyme 1 was also upregulated. As lysozymes have been implicated in innate-immune responses, Mallo et al. overexpressed lys-1 in C. elegans to see if this would enhance resistance to S. marcescens. It did, although only against a less pathogenic strain of the bacterium, possibly because this strain does not produce proteases that degrade the enzyme, whereas the more pathogenic strain does. The authors also assayed Dbl-1 mutants for their susceptibility to S. marcescens infection because Dbl-1 — a TGF-β-related gene — regulates some of the genes that were induced in the screen. Dbl-1 mutants were extremely susceptible to S. marcescens infection and, surprisingly, also to infection by the Escherichia coli strain OP50, which C. elegans is often cultured on.

So, 30 years after its discovery in Drosophila, these studies show that C. elegans also has an inducible innate-immune response — the components of which are conserved in other organisms — and illustrate the ease with which it can be investigated genetically in worms.