Toll-related receptors and the control of antimicrobial peptide expressionin Drosophila

Insects defend themselves against infectious microorganisms by synthesizing potent antimicrobial peptides, Drosophila has appeared in recent years as a favorable model to study this innate host defense. A genetic analysis of the regulation of the antifungal peptide drosomycin has demonstrated a key role for the transmembrane receptor Toll, which prompted the search for mam malian homologs. Two of these, Toll-like receptor (TLR)2 and TFR4 recently were shown to play a critical role in innate immunity against bacteria. Her e we describe six additional Toll-related genes (Toll-3 to Toll-8) in Droso phila in addition to 18-wheeler. Two of these genes, Toll-3 and Toll-4, are expressed at a low level. Toll-6, -7, and -8, on the other hand, are expre ssed at high levels during embryogenesis and molting, suggesting that, like Toll and 18w, they perform developmental functions. Finally, Toll-5 is exp ressed only in larvae and adults. By using chimeric constructs, we have tes ted the capacity of the signaling Toll/IL-1R homology domains of these rece ptors to activate antimicrobial peptide promoters and found that only Toll and Toll-5 can activate the drosomycin promoter in transfected cells, thus demonstrating specificity at the level of the Toll/IL-1R homology domain. I n contrast, none of these constructs activated antibacterial peptide promot ers, suggesting that Toll-related receptors are not involved in the regulat ion of antibacterial peptide expression. This result was independently conf irmed by the demonstration that a dominant-negative version of the kinase P elle can block induction of drosomycin by the cytokine Spaetzle, but does n ot affect induction of the antibacterial peptide attacin by lipopolysacchar ide.