Anti-Fungal Innate Immunity in C. elegans Is Enhanced by Evolutionary Diversification of Antimicrobial Peptides

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Abstract
Encounters with pathogens provoke changes in gene transcription that are an integral part of host innate immune responses. In recent years, studies with invertebrate model organisms have given insights into the origin, function, and evolution of innate immunity. Here, we use genome-wide transcriptome analysis to characterize the consequence of natural fungal infection in Caenorhabditis elegans. We identify several families of genes encoding putative antimicrobial peptides (AMPs) and proteins that are transcriptionally up-regulated upon infection. Many are located in small genomic clusters. We focus on the nlp-29 cluster of six AMP genes and show that it enhances pathogen resistance in vivo. The same cluster has a different structure in two other Caenorhabditis species. A phylogenetic analysis indicates that the evolutionary diversification of this cluster, especially in cases of intra-genomic gene duplications, is driven by natural selection. We further show that upon osmotic stress, two genes of the nlp-29 cluster are strongly induced. In contrast to fungus-induced nlp expression, this response is independent of the p38 MAP kinase cascade. At the same time, both involve the epidermal GATA factor ELT-3. Our results suggest that selective pressure from pathogens influences intra-genomic diversification of AMPs and reveal an unexpected complexity in AMP regulation as part of the invertebrate innate immune response. We are interested in how exactly the nematode Caenorhabditi elegans, widely used in biological research, defends itself against fungal infection. Like most animals, this worm responds to infection by switching on defense genes. We used DNA chips to measure the levels of all the worm's 20,000 genes and discovered new inducible defense genes. Many of them encode small proteins or peptides that can probably kill microbes. By looking in other nematode species, we saw that these antimicrobial peptide genes are evolving rapidly. This means that they could be important for the worms' survival in their natural environment. We also looked at how some of these genes are regulated and uncovered a sophisticated control mechanism involving a series of proteins called kinases that relay signals within cells. The genes we looked at are active in the worm's skin. Some of the antimicrobial peptide genes that we looked at are also switched on in the skin by high salt, but in this case, the regulation doesn't involve the same cascade of kinases. The responses to both infection and high salt do, however, require the same transcription factor (the protein that actually switches genes on), in this case called a GATA factor.