© 2002 Nature Publishing Group

H I G H L I G H T S

NATURE REVIEWS | GENETICS VOLUME 3 | SEPTEMBER 2002 | 651

Much of what we know about innate immunity— an organism’s immediate response topathogen infection — comes from studies inDrosophila, which have shown that thecomponents of innate immunity are highlyconserved. Two papers now illustrate howCaenorhabditis elegans, another geneticallytractable organism, might also be a useful modelfor studying innate immunity. Their results showthat C. elegans has an inducible response topathogen infection and that this response sharesmany features with innate immunity in otherorganisms.

Kim et al. assayed the progeny ofmutagenized worms, which had been exposed to the bacterium Pseudomonas aeruginosafor enhanced susceptibility to pathogen (esp)infection. From a screen of 14,000 haploidgenomes, they isolated two mutants, esp2and esp8, that die much faster on exposure to P. aeruginosa than wild-type worms do.High-resolution SNP mapping revealed thechromosomal locations of the mutant genes,which were identified by phenotypic rescue —the esp2 mutant was rescued by the gene sek-1,and esp8 by nsy-1.

sek-1 encodes a MAP kinase kinase (MAPKK)homologue of mammalian MKK3/MKK6 andMKK4, and nsy-1 encodes an orthologue of themammalian MAPKKK ASK1. Because thesekinases activate the p38 kinase family and theJNK MAP kinases in mammals, the authors testedthe role of p38 and JNK in the C. elegans defenceresponse. The esp2 and esp8 mutants hadmarkedly reduced levels of p38 MAPK activity.Moreover, the knockdown of pmk-1, one of twoC. elegans p38 orthologues, by RNA interferenceproduced a strong esp phenotype. Knockdown of pmk-2 and a jnk mutation, however, producedno enhanced susceptiblity to P. aeruginosainfection. Together these results show that thep38 MAPK pathway is required for innateresponses to pathogen infection, which is animportant discovery as this signalling pathway is also crucially required in mammals forinflammatory and innate-immune responsesignalling pathways.

Mallo et al. used an expression screen to lookfor C. elegans genes upregulated in response toinfection by the bacterium Serratia marcescens.Of 7,500 cDNAs surveyed, several were induced

over twofold, most of which encoded lectins,which function in innate immunity in otherorganisms. Also upregulated was lysozyme 1.As lysozymes have been implicated in innate-immune responses, Mallo et al. overexpressedlys-1 in worms to see if this would enhance their resistance to S. marcescens. It did,although only against a less pathogenic strain of the bacterium, possibly because this straindoes not produce proteases that degrade theenzyme, whereas the more pathogenic straindoes. The authors also assayed Dbl-1 mutantsfor their susceptibility to S. marcescensinfection, because Dbl-1 — a TGF-β-relatedgene — regulates some of the genes induced in the screen. Dbl-1 mutants were extremelysusceptible to S. marcescens infection and,surprisingly, also to infection by the E. colistrain OP50, which C. elegans is often cultured on.

So, 30 years after its discovery in Drosophila,these studies show that C. elegans also has aninnate-immune response — the components of which are conserved in other organisms — and the ease with which this response can beinvestigated genetically in worms.

Jane Alfred

References and linksORIGINAL RESEARCH PAPER Kim, D. H. et al. A conserved p38MAP kinase pathway in Caenorhabditis elegans innate immunity.Science 297, 623–626 (2002) | Mallo, G. V. et al. Inducible antibacterialdefense system in C. elegans. Curr. Biol. 12, 1209–1214 (2002)FURTHER READING Kimbrell, D. & Beutler, B. The evolution andgenetics of innate immunity. Nature Rev. Genet. 2, 256–267 (2001)

C. elegans — aninnate choice?

I M M U N O G E N E T I C Sthe short-allele carriers is probablydue to increased neuronal activitythat, in turn, might be caused byincreased synaptic levels of sero-tonin. These results imply that thereis a direct genetic link between sero-tonin receptor function and theresponse of a particular part of thebrain to emotional information.Serotonin has been previouslylinked to depressive and suicidalbehaviour, and the authors suggestthat the amygdala might also medi-ate these behaviours. Such anapproach could prove to be power-ful in future investigations of thepotential links between behaviouraldifferences and genetic polymor-phisms.

Magdalena Skipper

References and linksORIGINAL RESEARCH PAPER Hariri, A. R. et al.Serotonin transporter genetic variation and theresponse of the human amydgala. Science 297,400–403 (2002)

loss of one of the two visiblemarkers in P(wHy) that are oneither side of hobo. A broad set ofgenomic deletions — which canbe up to 400 kb but with thehighest density ~60 kb — can begenerated in this way, all ofwhich, importantly, start at oneend of the hybrid element.

This deletion technique is notthe first gene disruption methodknown in flies: RNA interferenceand targeted gene knockoutshave been used by many labsover the past few years. Whatmakes the P(wHy) deletionsystem so appealing, however, isthat it can be applied globally tothe genome. Moreover, as thecomponents of P(wHy) havetheir equivalents outsideDrosophila, it might not be longbefore this phenotypic analysistool takes a leap into othereukaryotes.

Tanita Casci

References and linksORIGINAL RESEARCH PAPER Huet, F. et al.A deletion-generator compound elementallows deletion saturation analysis forgenomewide phenotypic annotation. Proc. Natl Acad. Sci. USA 99, 9948–9953(2002)FURTHER READING Kornberg, T. Anotherarrow in the Drosophila quiver. Proc. Natl Acad. Sci. USA 99, 9607–9608(2002)

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