To understand innate immunity, silence the genome


To fight off disease and infection, organisms must detect pathogens, activate immune cell signaling pathways, and produce molecules able to thwart a pathogenic attack. This system of innate immunity is conserved in organisms as diverse as plants, flies, and humans. Like most signaling pathways, the innate immune system is complex and the genetic and molecular interactions are generally not understood.

To elucidate one arm of the innate immune system in the Drosophila fruitfly, Edan Foley and Patrick O'Farrell sequentially silenced its conserved genes (over 7,000) to study the effect on the flies ability to mount an immune response. Their findings, published on-line in the open-access journal PLoS Biology, not only add to our understanding of the highly conserved innate immune system, but they have also demonstrated that a global genome silencing approach is feasible for elucidating complex molecular signaling systems.

Specifically they examined the Immune deficiency (Imd) pathway. Bacterial pathogens stimulate a transmembrane receptor, which activates the Imd protein, which then transmits the signal through intermediary proteins into the nucleus, to activate genes required for an immune response. Although this outline of the immune response is understood, the signaling pathway involves countless other uncharacterized interactions. To identify pertinent genes and their roles, Foley and O'Farrell took advantage of a technique, called RNA interference (RNAi), that can selectively target and "silence," or inhibit, nearly any gene. The authors silenced all Drosophila genes that had counterparts in mammals or the worm C. elegans (which share the fundamental properties of this innate immune response).

Foley and O'Farrell's RNAi screen identified many molecules involved in signaling, including two new genes: one, which they named sickie, is required to cause the protein Relish to move into the nucleus to activate gene expression; the second, called defense repressor 1 (dnr1), appears to inhibit this pathway by inhibiting activity of the protein Dredd, which interacts with Relish. Further characterization of the results of this screen will shed light on this complex - and important - immune response.

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